1. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Annual Report of Hepatoma Keelung CGMH Risk Factors, Surveillance Strategies, and Treatment Options for Hepatocellular Carcinoma

2. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC  662,000 deaths from liver cancer yearly worldwide  Leading cause of death among male malignancies in Taiwan (2007 ) World Health Organization. Available at: http://www.who.int/whosis/en/. Accessed October 6, 2008. American Cancer Society. Cancer facts & figures 2008. Atlanta: American Cancer Society; 2008.

3. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Sangiovanni A, et al. Gastroenterology. 2004;126:1005-1014. Cause of Death, n (%)All PatientsHCC-Free Patients Patients Who Developed HCC Tumor progression54 (36)0 (0)54 (66) Nonliver-related conditions28 (19)23 (34)5 (6) Liver failure25 (17)18 (27)7 (9) Gastrointestinal hemorrhage21 (14)13 (19)8 (10) OLT-related complications2 (1)0 (0)2 (2) Unknown19 (13)13 (19)6 (7) Total149 (100)67 (100) 82 (100) 1987-2001: Causes of Death in Patients With Compensated Cirrhosis  HCC-free outpatients with compensated cirrhosis followed for 148 months with periodic ultrasound in Italy (N = 417)

4. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Treatment for HCC Often Suboptimal  Proportion of patients receiving potentially curative therapy N = 2963 from 1992-1999 in USA –34.0% of patients with single lesions – 34.0% of patients with lesions < 3 cm –19.2% of patients with lesions > 10 cm –4.9% of patients with metastatic disease  11.5% of patients ideal for transplantation received it  12.9% of patients ideal for surgical resection received it El-Serag HB, et al. J Hepatol. 2006;44:158-166.

5. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC HCC Surveillance

6. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Is Surveillance “Worthwhile”?  How do we define “worthwhile”? –Improvement in survival of 3 months [1]  Surveillance considered cost-effective if it achieves this 3-month improvement in survival at a cost of < $50,000 per life-year saved [2] 1. Naimark D, et al. J Gen Intern Med. 1994;9:702-707. 2. Laupacis A, et al. CMAJ. 1992;146:473-481.

7. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Surveillance for HCC  Objective –To reduce mortality from HCC  A single randomized controlled trial of 18,816 people with HBV infection or history of chronic hepatitis in urban Shanghai, China enrolled –Surveillance group offered US and AFP every 6 months (n = 9373) –Control group received no surveillance (n = 9443) –surveillance hepatitis B carriers with semiannual AFP and US reduces HCC-related mortality by 37% Zhang BH, et al. J Cancer Res Clin Oncol. 2004;130:417-422.

8. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Identification of At-Risk Population for HCC Surveillance  What level of risk makes surveillance worthwhile? –Incidence  According to randomized controlled trials –Hepatitis B: 0.28% per year [1]  According to cost-efficacy analyses –Hepatitis B: 0.2% per year [3] –Non-hepatitis B cirrhosis: > 1.4% per year [4] 1. Zhang BH, et al. J Cancer Res Clin Oncol. 2004;130:417-422. 2. Sarasin FP, et al. Am J Med. 1996;101:422-434. 3. Morris Sherman, MB BCh, PhD, FRCP(C). Data on file. 4. Arguedas MR, et al. Am J Gastroenterol. 2003;98:679-690.

9. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC The Benefit of Surveillance  For HCC incidence of 1.5%/ year, → survival increases for 3 months after surveillance  For HCC incidence of 6%/year → increase of 9 months.  Cost-effective -when the incidence of HCC > 1.4%..  Recommendation :Surveillance for risk of HCC >=1.5%/year  Sarasin, FP, Am J Med 1996;101:422-434. Arguedas Am J Gastroenterol 2003;98679-690.  Lin OS, Aliment Pharmacol Ther 2004;19:1159-1172

10. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Hepatitis B Carriers Suitable for HCC Surveillance  Hepatitis B carriers [1-4] –Asian males > ~ 40 years (incidence ~ 0.4% to 0.6% per year) –Asian females > ~ 50 years (incidence ~ 0.2% per year) –Africans older than 20 years of age (incidence unknown but likely > 0.2% per year) –Cirrhosis (HCC incidence: 3% to 5%/year) –Family history of HCC: mainly Asian and African Beasley RP, et al. Lancet. 1981;2:1129-1133. Koike K, et al. Oncology. 2002;62(suppl 1):29-37. Beasley RP. Hepatology. 1982;2(suppl):21S-26S. Fattovich G, et al. Gut. 1991;32:294-298. Manno M, et al. Gastroenterology. 2004;127:756-763. Hsu YS, et al. Hepatology. 2002;35:1522-1527. Fattovich G. J Hepatol. 2003;39(suppl 1):S50-S58.

11. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Factors Affecting HCC Risk  Active disease –Elevated ALT  Persistently elevated AFP  Low platelet count  HBV DNA level  Histologic changes –Dysplasia –Geographic morphologic changes –PCNA ( Proliferating cell nuclear antigen) positive  Use of TIPS (?) Beasley RP, et al. Lancet. 1981;2:1129-1133. Degos F, et al. Gut. 2000;47:131-136. Oka H, et al. Hepatology. 1994;19:61-66. Zhang JY, et al. Am J Trop Med Hyg. 1998;59:947-951. Colombo M, et al. N Engl J Med. 1991; 325:675-680.Ganne-Carrie N, et al. Hepatology. 1996;23:1112-1118. Lee RG, et al. Hepatology. 1997;26:1415-1422. Chen CJ, et al. JAMA. 2006;295:65-73.

12. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Screening and Surveillance Methodology: Serologic Tests and Radiology Current Serologic Screening Tests Are Insufficiently Sensitive

13. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Sensitivity of AFP Surveillance for HCC StudySensitivity, % Case-control studies  Trevisani 2001 60 Surveillance studies  Tanaka 1990 64  Pateron 1994 50  Borzio 1995 47  Sherman 1995 64  Solmi 1996 54  Zoli 1996 62  McMahon 2000 97  Bolondi 2001 41  Tong 2001 59 Trevisani F, et al. J Hepatol. 2001;34:570-575. Tanaka S, et al. Cancer. 199015;66:2210-2214. Pateron D, et al. J Hepatol. 1994;20:65-71. Borzio M, et al. Gastroenterology. 1995;108:812-817. Sherman M, et al. Hepatology. 1995;22:432-438. Solmi L, et al. Am J Gastroenterol. 1996;91:1189-1194. Zoli M, et al. Cancer. 1996;78:977-985. McMahon BJ, et al. Hepatology. 2000;32:842-846. Bolondi L, et al. Gut. 2001;48:251-259. Tong MJ, et al. J Gastroenterol Hepatol. 2001;16:553-559.

14. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Specificity of AFP Surveillance for HCC *5% prevalence of HCC. StudySpecificity, %PPV, % Case-control studies  Trevisani 2001 9125* Surveillance studies  Pateron 1994 8633  Sherman 1995 919  McMahon 2000 9531  Bolondi 2001 8246  Tong 2001 9111 Trevisani F, et al. J Hepatol. 2001;34:570-575. Pateron D, et al. J Hepatol. 1994;20:65-71. Sherman M, et al. Hepatology. 1995;22:432-438. McMahon BJ, et al. Hepatology. 2000;32:842-846. Bolondi L, et al. Gut. 2001;48:251-259. Tong MJ, et al. J Gastroenterol Hepatol. 2001;16:553-559.

15. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Other Tumor Markers  Des-gamma-carboxy prothrombin (DGCP), also known as Prothrombin Induced by Vitamin K Absence II (PIVKA) ≧ 40 mAU/ml  The ratio of glycosylated AFP L3 (Lectin fraction) to total AFP>15%, alpha fucosidase and glypican

16. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC HCC Surveillance by Ultrasound  Performance characteristics of ultrasound as a screening test Performance Characteristic, % Cohort 1 Years 1-5 Cohort 1 Years 6-8 Cohort 2 Years 1-3 Sensitivity 798780 Specificity 948791 PPV 151314 NPV 98100 Collier J and Sherman M. AASLD 1995. Morris Sherman, MB BCh, PhD, FRCP(C). Data on file.

17. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC HCC Surveillance by CT Scan  No evidence to support the use of CT scanning for routine HCC surveillance –PPV and NPV unknown –Accurate use of CT requires 4-phase contrast CT –Radiation exposure is significant –In the absence of contrast CT, false-positive rate very high –Cannot distinguish small HCC from dysplastic nodules or arterialized cirrhotic nodules –Flow abnormalities create diagnostic difficulty

18. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Standard angiography and CTAP angiography  Contrast enhanced ultrasound (CEUS) could also be used for this non-invasive diagnosis.  Other radiological tests. In particular lipiodol angiography is not sensitive for small HCC.  Standard angiography and CTAP( arterioportal angiography) should not be routinely performed.

19. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Surveillance Interval: 6 vs 12 Months  Trevisani et al [1] –Survival similar with 6-month vs 12-month surveillance  Santagostino et al [2] –Rate of detection of single nodules (vs multinodular HCC) similar with 6-month vs 12-month surveillance  Kim et al [3] –Survival improved with 6-month vs 12-month surveillance 1. Trevisani F, et al. Am J Gastroenterol. 2002;97:734-744. 2. Santagostino E, et al. Blood. 2003;102:78-82. 3. Kim DY, et al. AASLD 2007. Abstract 368.

20. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC AASLD and NCCN Surveillance Guidelines AASLD Guidelines  Surveillance recommended in at-risk groups –Specific hepatitis B carriers –Nonhepatitis B cirrhosis  US preferred surveillance tool –AFP alone should not be used unless US unavailable  Patients should be screened at 6- to 12-month intervals NCCN Guidelines National Comprehensive Cancer Network (21 家世界頂級癌症中心組成的非營利性學術聯盟 )  US and AFP, AP, and albumin for surveillance in high-risk patients –Every 3-6 months  Continue screening every 3 months in those with high AFP but no evidence on imaging Bruix J, et al. Hepatology. 2005;42:1208-1236. National Comprehensive Cancer Network. Available at: http://www.nccn.org/professionals/physician_gls/PDF/hepatobiliary.pdf. Accessed October 14, 2008.http://www.nccn.org/professionals/physician_gls/PDF/hepatobiliary.pdf

21. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Japan Society of Hepatology (JSH) - 2007 Consensus-Based Clinical Practice Manual

22. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Population at Risk for HCC

23. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Summary  At-risk patients should be screened for HCC  Ultrasound surveillance is preferable –AFP increased the detection rate  Surveillance should take place at 3-6-month intervals for high risk patients –Evidence for better survival than 12-month intervals

24. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC

25. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Diagnosis of Hepatoma

26. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC EASL conference on HCC diagnosis Tumors>2 cm  The diagnosis of HCC can be made without biopsy :  In Cirrhotic patients who have a mass> 2 cm that shows characteristic arterial vascularization on two imaging modalities, - Triphasic CT scan and MRI.  The positive predictive value of the clinical and radiological findings exceeds 95%

27. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Tumors 1-2 cm in diameter  Lesions between 1-2 cm in a cirrhotic liver have a high likelihood of being HCC.  These lesions should be biopsied irrespective of their vascular profile  Biopsy of small lesions (2 cm) may not be reliable  Needle placement may be difficult  D.D. Dysplasia and well-differentiated HCC

28. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Lesions Less Than 1 cm in Diameter  Low likelihood of being HCC  Malignancy is even less likely if they do not show contrast uptake on dynamic imaging  Even if CT or MRI show tiny nodules with arterial vascularization. They may not correspond to HCC foci.  Need to be followed-up every 3-6 months. (level III).  Lack of growth over a period of more than 2 years suggests that the lesion is not HCC

29. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Recommendations  if the vascular profile on imaging is not characteristic or if the nodule is detected in a non-cirrhotic liver,  -- Biopsy should be performed (level II).  Biopsies of small lesions should be evaluated by expert pathologists. If the biopsy is negative for HCC patients should be followed by ultrasound or CT scanning at 3-6 monthly intervals  If the lesion enlarges but remains atypical for HCC a repeat biopsy is recommended (level III).

30. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Diagnosis in High Risk Patients

31. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Atypical Image on Dynamic CT/MRI(JSH)  When a lesion is intensely enhanced in the early arterial phase and becomes low-attenuation in the equilibrium phase,, R/O FNH and A-P shunt, Uptake by Kupffer cells is investigated by  1.SPIO (superparamagnetic iron oxide -enhanced MRI )  2.Sonazoid-enhanced ultrasonography.  When high SPIO-enhanced MRI signals or a defect in the  Kupffer phase of Sonazoid-enhanced ultrasonography  are confirmed, the lesion is diagnosed as HCC

32. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC

33. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Tumor Staging

34. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Currently there are 3 staging systems for HCC:  (1) TNM staging as tumor spreading staging,  (2) liver function staging  (3) systems integrating (1) and (2). For TNM staging, 

35. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Staging System  UICC ( international union against cancer) or AJCC (American joint committee on cancer) classification is used internationally (2005)  These are thought inappropriate because the cut-off tumor size is set to 5 cm (JSH)  Portal microinvasion and intrahepatic metastasis occurs in 27% and 10% of tumors with a tumor size of 2 cm or more

36. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC

37. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC

38. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC TNM Stage by LCSG

39. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Functional staging & TNM

40. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC

41. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Barcelona-Clinic- Liver-Cancer (BCLC) staging system

42. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC

43. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Barcelona-Clinic- Liver-Cancer (BCLC) staging system

44. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Cancer of the Liver Italian Program (CLIP)  The CLIP score retrospective evaluation of 435 Italian patients with HCC diagnosed from 1990 to 1992.

45. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Japan Integrated Staging Score

46. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC The Treatment of HCC

47. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Liver Transplantation for HCC: Milan Criteria (Stage 1 and 2) + Absence of macroscopic vascular invasion, absence of extrahepatic spread Single tumor, not > 5 cm Up to 3 tumors, none > 3 cm Mazzaferro V, et al. N Engl J Med. 1996;334:693-699.

48. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Treatment: Chemoembolization  Normal liver gets 75% of blood supply from portal vein and 25% of blood supply from hepatic artery  Tumor receives most of its blood supply from the hepatic artery  Injection into the hepatic artery spares most of the normal liver  Embolization of the hepatic artery prevents systemic absorption of chemotherapy agents and induces ischemic necrosis of tumor Tumor Liver Portal vein Hepatic artery Catheter placement for chemoembolization

49. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Chemoembolization: Randomized Trials (Nearly Identical Techniques) Technique Survival, % Year 1Year 2Year 3 TACE 573126 Supportive care 32113 Technique Survival, % Year 1Year 2 TACE8263 Supportive care6327 Llovet et al [2] : N = 112 with unresectable HCC, 80% to 90% HCV positive, 5-cm tumors (~ 70% multifocal) Lo et al [1] : 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.

50. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Intra-arterial Locoregional Therapy  Established –TACE –Radioembolization: yttrium-90 radioactive microspheres  Undergoing clinical trials –Drug-eluting beads

51. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC  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 µm –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.

52. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Clinical Response to Yttrium-90 Microspheres OutcomeDancey et al [1] (N = 20) Carr et al [2] (N = 65) Geschwind et al [3] (N = 80) Salem et al [4] (N = 43) Response rate, % 3947 Median survival 378 days (> 104 Gy)  Okuda stage I 649 days628 days24.4 mos  Okuda stage II 302 days384 days12.5 mos 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.

53. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for 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) DEB-TACE Conventional TACE 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

54. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Targeted Molecular Therapies Mechanisms of Action (cont’d)  Multiple pathways –Sorafenib –RAF/MEK/ERK signaling –VEGFR-2 –PDGF-β –Brivanib –VEGFR-2 –FGFR-1 kinase –Pazopanib –VEGFR-1, -2, -3 –PDGF-α, -β –c-KIT

55. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC 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.

56. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC 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 01234567891011121314151617 P <.001 A OS Months Since Randomization Probability of No Symptomatic Progression 01234567891011121314151617 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 0123 4 56789 10 11 Placebo Sorafenib P < 0.001 C Time to Radiologic Progression 0.00 0.25 0.50 0.75 1.00 12

57. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Staging Strategy and Treatment for Patients With HCC Liver transplant PEI/RF Curative treatments TACE HCC Single Increased Associated diseases Normal No YesNoYes 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

58. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Treatment Algorithm for Hepatoma

59. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Annual Report of Hepatoma 2008

60. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Annual Report of Hepatoma Patients 2008  A total of 126 patients were recruited from cancer registration, pathology report  Female : Male = 38:88  The age aged from 23 to 91 years old  Mean ± SD = 65.46 ± 13.28

61. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC

62. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC HACE 33.3% OP13.5% Conservative13.5 % Transfer 5.6% RFA 24.6% C/T 7.9%

63. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Pathology  Pathology was obtained in 91 among 126 patients  9 were not diagnostic : Negative 1, Fatty liver 1, cirrhosis 6, chronic active hepatitis 1  Grade I 2  Grade II 31  Grade III 30  Grade IV 2  HCC without grading 13  Carcinoma 4

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65. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC

66. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC

67. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Diagnosis of Hepatoma  The most sensitive modality capable of objectively depicting the early carcinogenesis process among currently available imaging systems is  (1) CTAP  (2) CTHA (hepatic arteriography)  (3) contrast-enhanced ultrasonography(US)  (4) SPIO-MRI [24, 25]

68. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC The Risk of HCC in Patients with Chronic Hepatitis C  In cirrhotic patients, the incidence 2%-8% / year.  Anti-HCV-positive conferred a 20-fold increased risk of HCC (12,008 men)  Surveillance for cirrhosis or bridging fibrosis or transition to cirrhosis.

69. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Staging system CLIP scores or BCLC stages are used in Europe and North America as staging systems.  the BCLC stage is basically a treatment selection system for deciding on a therapeutic strategy,  CLIP and JIS scores are prognostic prediction stagings.  The CLIP score and BCLC stage tend to detect relatively large HCCs,  JIS score is most useful for countries where many  small liver cancers are detected.  28 Bruix J, Sherman M, Llovet JM, et al: Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL Conference. J Hepatol 2001; 35: 421–430.  29 Llovet JM, Bru C, Bruix J: Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999; 19: 329–338

70. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Interferon & Lamivudine  No convincing evidence that interferon treatment of chronic hepatitis B reduces the incidence of HCC.  A single RCT suggests that lamivudine treatment reduce the incidence of HCC in HBV-related cirrhosis ??

71. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC

72. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Hepatitis C treated with interferon  A single RCT in Japan suggested that the incidence of HCC was reduced in both responders and non-responders  In a meta-analysis, benefit is mainly seen in sustained virological responders, and  the effect was small.

73. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC

74. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Recommendations 17. Local ablation is safe and effective therapy for patients who cannot undergo resection, or as a bridge to transplantation (level II). 18. Alcohol injection and radiofrequency are  equally effective for tumors <2 cm. However, the  necrotic effect of radiofrequency is more predictable in all tumor sizes and in addition, its efficacy is clearly superior to that of alcohol injection in larger tumors (level I).

75. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Surgical Recommendations  Recommendations Patients who have a single lesion can be offered surgical resection if they are non-cirrhotic or have cirrhosis but still have well preserved liver function, normal bilirubin and hepatic vein pressure gradient <10 mmHg (level II). Pre or post-resection adjuvant therapy is not recommended (level II)

76. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC 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.

77. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Embolization: Summary  Well-performed comparative studies between chemoembolization, radioembolization, and bland embolization needed  Chemoembolization has longest “track record” and data suggest survival advantage  Radioembolization data rapidly accumulating –Advantages include lack of induction of ischemia, outpatient procedure without postembolization syndrome  Bland embolization –Response demonstrable but not clear if benefits in cost; questionable benefits in toxicity outweigh likely decreased response –Potential role (especially niche role, such as in patients with poor hepatic function or in combination with ablative therapy) remains to be proven

78. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Transarterial Embolization and Chemoembolization  Recommendations  19. TACE is recommended as first line non-curative therapy for non-surgical patients with large/multifocal HCC who do not have vascular invasion or extrahepatic spread (level I).  20. Tamoxifen, antiandrogens, octreotide or hepatic artery ligation/embolization are not recommended (level I).

79. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Chemoembolization: Predictors of Survival  Lo et al [1] –Absence of presenting symptoms (ECOG PS < 2) –Absence of portal vein obstruction –Tumor size (≤ vs > 5 cm) –Okuda stage (I vs II)  Llovet et al [2] –Absence of constitutional syndrome (ECOG PS < 2) –Low serum bilirubin –Treatment response (modified WHO criteria, > 6 months) 1. Lo CM, et al. Hepatology. 2002;35:1164-1171. 2. Llovet JM, et al. Lancet. 2002;359:1734-1739.

80. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Targeted Molecular Therapies: Mechanisms of Action  VEGF antagonists –Cediranib –ABT-869  NF-κB antagonists –Perifosine  Proteasome inhibitors –Bortezomib

81. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC  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.

82. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Diagnosis of HCC  AFP > 200 & radiological appearance suggestive of HCC (large and/or mutifocal disease with arterial hypervascularity), Biopsy is not essential.  If the imaging appearances are atypical. Tumor biospy should be considered.

83. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Selecting an HCC Surveillance Interval  Dependent on –Tumor growth rate –Prognosis of HCC at different sizes –< 1-2 cm –2-3 cm –> 3 cm –Ideal surveillance interval unknown –Tumor growth rates suggest every 4-12 months  Does not depend on degree of risk

84. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Targeted Molecular Therapies: Mechanisms of Action (cont’d)  EGFR tyrosine kinase inhibitors –Lapatinib –Sunitinib –Erlotinib  TRAIL receptor antibodies –Mapatumumab  BCR-ABL inhibitors –Dasatinib

85. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC CLIP score - prognostic system for patients with HCC

86. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Zhang BH, et al. J Cancer Res Clin Oncol. 2004;130:417-422. Outcome of HCC Surveillance  18,816 people with HBV infection or history of chronic hepatitis in urban Shanghai, China enrolled –Surveillance group offered US and AFP every 6 months (n = 9373) –Control group received no surveillance (n = 9443) 223.7 163.1 0 50 100 150 200 250 300 Control Total Incidence (per 100,000) Screened 83.2 131.5 Total Mortality (per 100,000) 0 50 100 150 200 250 300 Rate ratio: 1.37 (95% CI; 0.99-1.89) Rate ratio: 0.63 (95% CI; 0.41-0.98) ControlScreened

87. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC  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.

88. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC  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

89. clinicaloptions.com/hep Risk Factors, Surveillance Strategies, and Treatment Options for HCC Incidence of HCC in Risk Groups SubgroupIncidence per Year (%) All hepatitis B carriers > 40 yrs of age0.2 Cirrhotic hepatitis B carriers3-8 Hepatitis C cirrhosis3-5 Stage 4 primary biliary cirrhosis3-5 Alcoholic cirrhosis? Genetic hemochromatosis? Nonalcoholic steatohepatitis? Beasley RP, et al. Lancet. 1981;2:1129-1133. Koike K, et al. Oncology. 2002;62(suppl 1):29-37. Beasley RP. Hepatology. 1982;2(suppl):21S-26S. Fattovich G, et al. Gut. 1991;32:294-298. Manno M, et al. Gastroenterology. 2004;127:756-763. Hsu YS, et al. Hepatology. 2002;35:1522-1527. Fattovich G. J Hepatol 2003;39(suppl 1):S50-S58. Fattovich G, et al. Gastroenterology. 1997;112:463-472. Niederau C, et al. Hepatology. 1998;28:1687-1695. Niederau C, et al. N Engl J Med. 1996;334:1422-1427. Degos F, et al. Gut. 2000;47:131-136. Caballeria L, et al. Am J Gastroenterol. 2001;96:1160-1163.