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Hepatocellular Carcinoma

Hepatocellular Carcinoma. Thomas Hargrave M.D. January 16, 2009. HCC Is Common and Increasing. 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.

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Hepatocellular Carcinoma

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  1. Hepatocellular Carcinoma Thomas Hargrave M.D. January 16, 2009

  2. HCC Is Common and Increasing 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. • 662,000 deaths from liver cancer yearly worldwide • Age-adjusted US incidence has increased 2-fold: 1985-1998 • American Cancer Society statistics for liver cancer in 2008 • Estimation of new cases: 21,370 • Estimation of deaths: 18,410 • 5th leading cause of cancer deaths in males

  3. HCC Epidemiology Worldwide Incidence of Hepatocellular Carcinoma High (> 30:100,000) El-Serag HB, Gastroenterology 2004 Intermediate (3-30:100,000) Low or data unavailable (< 3:100,000)

  4. Recent Changes in the Incidence of HCC HCC Epidemiology Changes in the Incidence of HCC 1978-1992 -30 Singapore, Chinese -24 Spain, Zaragoza -20 India, Bombay -18 China, Shanghai 10 Switzerland, Geneva 12 Hong Kong 14 NewZealand, Maori 21 NewZealand, Non-Maori 46 Japan, Osaka 50 UK, So. Thames 71 Canada, Alberta 83 Italy, Varese France, Bas-Rhin 90 Australia, NSW 108 20 40 60 80 100 120 -40 -20 0 McGlynn K, et al, Int J Cancer 2001

  5. HCC Epidemiology Age-Adjusted Incidence Rates For HCC (1976-2002) 3.5 3.3 3.1 3 2.7 2.5 2.3 Rate per 100,000 2.0 2 1.8 1.6 1.4 1.4 1.5 1 0.5 0 76-78 79-81 82-84 85-87 88-90 91-93 94-96 97-99 2000-02 Year El-Serag HB, Mason A, N Engl J Med 1999 El-Serag HB et al, Ann Intern Med 2003

  6. HCC Epidemiology Racial Distribution of HCC in the United States 3000 Asian 2500 Black 2000 White Number of Cases 1500 1000 500 0 75-77 78-80 81-83 84-86 87-89 90-92 93-95 96-98 Year El-Serag HB, Mason A, N Engl J Med 1999

  7. 9 8 7 6 5 4 3 2 1 0 HCC Epidemiology Racial Incidence Rates For HCCIn The United States 8.4 White Black Other (Asian) 8 7.9 7.2 7.2 6.6 6.3 6 5.2 5 Age-Adjusted Incidence Rate per 100,000 4.6 3.9 3.7 3.4 2.9 2.6 2.5 2.5 2.5 2.3 1.9 1.7 1.4 1.3 1.1 1.1 1 76-78 79-81 82-84 85-87 88-90 91-93 94-96 97-99 2000-02 Year El-Serag HB et al, Ann Intern Med 2003

  8. 20 18 16 14 12 10 8 6 4 2 0 HCC Epidemiology Temporal Trends in The Age Distribution of Hepatocellular Carcinoma 1982 – 84 1991 – 93 2000 – 02 Incidence Rate per 100,000 PY 20-24 30-34 40-44 50-54 60-64 70-74 80-84 25-29 35-39 45-49 55-59 65-69 75-79 85+ Age (years) El-Serag HB, Mason A, N Engl J Med 1999

  9. Risk Factors for HCC in US Patients Worldwide, 75% to 80% of HCC attributable to chronic HBV (50% to 55%) or HCV (25% to 30%) Known Risk Factor in the US: Viral Hepatitis (N = 691) 100 80 60 47 Presence of Risk Factor Among HCC Patients (%) 33 40 15 20 5 0 HBV HBV + HCV Neither HCV Di Bisceglie AM, et al. Am J Gastroenterol. 2003;98:2060-2063. El-Serag HB. Gastroenterology. 2004;127:S27-S34. Bosch FX, et al. Gastroenterology. 2004;127:S5-S16.

  10. HCC Epidemiology Risk Factors for HCC Risk Factors for HCC • Cirrhosis from any cause (3-8%/yr) • HCV • HBV • Heavy alcohol consumption • Non-alcoholic fatty liver disease • HBV without cirrhosis (0.02-0.06%/yr) • Inherited metabolic diseases • Hemochromatosis • Alpha-1 antitrypsin deficiency • Glycogen storage disease • Porphyriacutaneatarda • Tyrosinemia • Autoimmune hepatitis

  11. HCV Cirrhosis and HCC HCC Epidemiology HCV Cirrhosis and HCC Multiple smallfoci of HCC

  12. HCC Epidemiology Why HCC is Rising? Why is HCC Incidence Rising? Increasing prevalence of patients with cirrhosis • Rising incidence of cirrhosis • HCV (main reason) • HBV • Other (?NAFLD/insulin resistance) • Improved survival of patients with cirrhosis El-Serag HB, Gastroenterology 2004

  13. Prevalence of HCV in United States Males:1999-2002 Annals Internal Medicine 2006; 144:705

  14. Projected Rates of HCV-Related Cirrhosis and HCC Davis GL, et al. Liver Transpl. 2003;9:331.

  15. HCC Epidemiology Alcohol Intake and the Risk of HCC Alcohol Intake and the Risk of HCC 20 No HCV with HCV 15 10 Odds Ratios 5 0 20 40 60 80 100 120 140 Grams of Alcohol / Day Donato F, et al, Am J Epidemiol 2002

  16. HBV DNA Associated with Increased Risk of HCC in Non-Cirrhotics HBV DNA Associated with Increased Risk of HCC • Likelihood of HCC in individuals with detectable HBV DNA is3.9 times more than those with undetectable HBV DNA • Risk associated with increasing HBV DNA levels • These data support possibility of preventing long-term risk of HCC by inducing sustained suppression of HBV replication Yang HI, et al, N Engl J Med 2002

  17. HBe Antigen and Risk of HCC 11,893 Noncirrhotic Taiwanese Males Followed 8 Yrs 12 HBsAg+, HBeAg+ (RR = 60.2) 10 8 Percent cumulative incidence 6 4 HBsAg+, HBeAg- (RR = 9.6) 2 HBsAg-, HBeAg- 0 10 0 1 2 3 4 5 6 7 8 9 Year Yang HI, et al, N Engl J Med 2002

  18. HBV DNA and Risk of HCC: Untreated Non-Cirrhotic HBeAg+ HBV DNA (copies/mL) • 3465 HBeAg (+) Non-cirrhotic Taiwanese Patients followed for a mean of 11.5years • 65% had HBV DNA > 100,000,000 Incidence of HCC Per Year (%) Chen et al. JAMA. 2006;295:65-73 (B).

  19. Risk Factors for HCC in US Patients Worldwide, 75% to 80% of HCC attributable to chronic HBV (50% to 55%) or HCV (25% to 30%) Known Risk Factor in the US: Viral Hepatitis (N = 691) 100 80 • (?NAFLD/insulin resistance?) 60 47 Presence of Risk Factor Among HCC Patients (%) 33 40 15 20 5 0 HBV HBV + HCV Neither HCV Di Bisceglie AM, et al. Am J Gastroenterol. 2003;98:2060-2063. El-Serag HB. Gastroenterology. 2004;127:S27-S34. Bosch FX, et al. Gastroenterology. 2004;127:S5-S16.

  20. HCC Epidemiology Non-alcoholic Fatty Liver Disease (NAFLD) and HCC Non-alcoholic Fatty Liver Disease (NAFLD) and HCC Single center study, Univ. Michigan • 105 consecutive patients with HCC • 51% due to HCV-associated cirrhosis • Cryptogenic cirrhosis in 29% • Half had histologic features consistent with NASH • Estimated that 13% of HCC and cryptogenic cirrhosis may have NAFLD/NASH Marrero J, et al, Hepatology 2002

  21. Prospective Study Cancer Mortality in Obese US Adults (n=900,053):1982-1998 Men Prostate (>35) 1.34 Non-Hodgkin’s Lymphoma(>35) 1.49 1.52 All Cancers (>40) All Other Cancers (>30) 1.68* Kidney (>35) 1.70 Type of Cancer (Highest BMI Category) Multiple Myeloma (>35) 1.71 Gall Bladder (>30) 1.76 Colon and Rectum (>35) 1.84 1.91* Esophagus (>30) Stomach (>35) 1.94 Pancreas (>35) 2.61* 4.52 Liver (>35) 0 1 2 3 4 5 6 7 Relative Risk of Death (95% Confidence Interval) Calle EE, & et al, N Engl J Med 2003

  22. Women Men 0 10 20 30 40 50 60 HCC Epidemiology Obesity and Liver Cancer 8 35 to 39.9 48 6 30 to 34.5 19 BMI 5 20 to 29.9 10 5 18.5 to 25 9 Death Rate per 100,000 Calle, et al, NEJM 2003

  23. Impact of Diabetes and Overweighton Liver Cancer Occurrence in Cirrhosis 771 Compensated ETOH or HCV Cirrhotics Prospectively Screened for HCC 1.0 .8 BMI <23.9, diabetes - BMI <23.9, diabetes + BMI 23.9-27.3 diabetes - BMI 23.9-27.3 diabetes + BMI >27.3, diabetes - BMI >27.3, diabetes + .6 Probability of HCC Free Survival P<0.0001 .4 .2 N = 771 0 0 2 4 6 8 10 Time (Years) N’Kontchou G, Clin Gastro Hepatol 2005

  24. Cancer and Insulin Resistance Excess weight / adiposity FFA , TNFa Resistin , Adiponectin Tumor development Insulin resistance Insulin IR Target cellsApoptosis Cell proliferation Blood and tissue: IGFBP 1 IGFBP2 IGF1R IGF1 bioavailability

  25. Screening / Surveillance for Hepatocellular Carcinoma

  26. HCC Screening Cost-Effectiveness of HCC Surveillance Cost-Effectiveness of HCC Surveillance • Surveillance with bi-annual alpha-fetoprotein (AFP) and ultrasonography in Child class A cirrhotics had cost-effectiveness ratios between $26,000 and $55,000 per QALY • 2 other studies show cost-benefits of HCC surveillance Sarasin FP, et al, Am J Med 1996 Arguedas MR, et al, Am J Gastroenterol 2003 Lin OS, et al, Aliment Pharmacol Ther 2004

  27. HCC Screening Alpha-fetoprotein Cross-Sectional Studies Specificity % Author Cutoff No. of HCC Sensitivity % 65 88 Peng 20 205 Trevisani 16 170 60 90 25 Cedrone 100 74 95 89 Soresi 30 197 65 53 Lee 200 54 79 79 Nguyen 20 163 63 Marrero JA, Clin Liver Dis 2005

  28. Specificity of AFP Surveillance for HCC: PPV 9- 46% *5% prevalence of HCC. 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.

  29. Current Serologic Surveillance Tests Not Sufficiently Sensitive/Specific 100 85.9 84.8 84.8 80 73.7 72.7 67.7 61.6 60 Sensitivity (%) 40 20 0 AFP-L3% DCP AFP AFP-L3% + DCP AFP-L3% + AFP DCP + AFP AFP-L3% + DCP + AFP Tumor Marker Prospective analysis of 99 patients with histologically proven, unresectable HCC Carr BI, et al. Dig Dis Sci. 2007;52:776-782.

  30. HCC Screening Ultrasound in HCC in Cohort Studies Colli A, et al, Am J Gastro 2006

  31. HCC Surveillance by Ultrasound: NPV 98-100% Collier J and Sherman M. AASLD 1995. Morris Sherman, MB BCh, PhD, FRCP(C). Data on file. Performance characteristics of ultrasound as a screening test

  32. HCC Screening HCC Doubling TimeRationale for Surveillance Every 6 Months Taouli B, et al, J Comput Assist Tomogr 2005

  33. Surveillance Interval: 6 vs 12 Months 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. • 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

  34. 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 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 NCCN, National Comprehensive Cancer

  35. HCC Screening Surveillance for HCC Improves MortalityA Randomized Controlled Trial Screened group Control group Person-years in study 38,444 41,077 HCC occurrence Cases 86 67 Total incidence (per 100,000) 223.7 163.1 Rate ratio (95% CI) 1.37 (0.99, 1.89) Deaths from HCC Deaths 32 54 Total mortality (per 100,000) 83.2 131.5 Rate ratio (95% CI) 0.63 (0.41, 0.98)

  36. Diagnosis of Hepatocellular Carcinoma

  37. HCC Diagnosis Clinical Features at Presentation Symptoms Percent of Patients None 23% Abdominal Pain 32% Ascites 8% Jaundice 8% Anorexia/weight loss 10% Malaise 6% Bleeding 4% Encephalopathy 2% Gastroenterology 2002

  38. HCC Diagnosis Guidelines for Diagnosis of HCC Ultrasound findings Typical features of HCC = vascular nodule on arterial phase with washout in delayed phases Bruix J, et al, Hepatology 2005

  39. HCC Diagnosis Dual Blood Supply of Liver • The vascular supply of HCC arises from the hepatic artery through neovascularization. • Normal hepatocytes receive 80% of blood flow from portal vein • Imaging of the liver has to be performed in a triple phase manner to account for the early arterial phase followed by the portal venous phase and the delayed phases Yu JS, et al, Am J Roentgenol 1999

  40. HCC Diagnosis: MRI Triple Phase Imaging of Hepatocellular Carcinoma Arterial Phase Pre-contrast Portal Venous Phase 5-min Delayed

  41. HCC Diagnosis Dynamic MRI Spiral CT for Diagnosis of HCC Variables Dynamic MRI Spiral CT Sensitivity 76% (58/76) 61% (43/70) Specificity 75 % (18/24) 66% (12/18) PPV 90% (58/64) 87% (43/49) NPV 50% (18/36) 30% (12/39) LR positive test 3.04 1.79 n= 55 cirrhotics (29 with HCC) Burrel M, et al, Hepatology 2003

  42. Treatment of Hepatocellular Carcinoma

  43. Population-based Survival Estimates in the United States 0 1 2 3 HCC Treatment HCC Survival Estimates in the United States 100 Median Survival 6-8 months 80 White Hispanic 60 Black Survival (%) Asian 40 20 0 Years Following Diagnosis Davila J, & El-Serag HB, Clin Gastroenterol Hepatol. 2006

  44. HCC Treatment Key Concepts in the Management of Hepatocellular Cancer Key Concepts in the Management of Hepatocellular Cancer • Potentially Curative • Liver transplantation (75% 5-year survival) • Surgical resection • Palliative • Radiofrequency ablation (RFA) • Transarterial chemoembolization (TACE) • Percutaneous ethanol or acetic acid ablation • Cryoablation • Systemic Chemotherapy

  45. HCC Treatment Key Concepts in the Management of Hepatocellular Cancer Key Concepts in the Management of Hepatocellular Cancer • Liver transplantation achieves the best outcome in HCC patients with decompensated cirrhosis who meet criteria • Surgical resection is most effective for non-cirrhotic patients or those with cirrhosis and preserved liver function and can be followed by salvage OLT • Patients with small tumors are best stratified for resection or OLT by the presence of clinically-significant portal hypertension and/or increased serum bilirubin • Local ablative methods are an option for small solitary nodules and those who are not surgical candidates • Transarterial chemoembolization improves survival in intermediate-advanced HCC

  46. HCC Treatment Management of Hepatocellular Carcinoma Requires a Multidisciplinary Approach Hepatobiliary Surgery Hepatology Oncology Pathology Radiology Liver Transplant Program

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

  48. Management of HCC in Patients with Cirrhosis HCC Treatment

  49. HCC Pts Evaluated 1989 – 2001 611 pts Unresectable 385 pts (70%) Resected 180 pts (30%) Transplant Eligible Transplant Ineligible 74 pts (80%) 36 pts (20%) 78% with cirrhosis HCC Treatment Surgical Resection of HCC:Outcome in a US Cancer Center Ann Surg. 2003; 238:315-21.

  50. Treatment of HCC in US atNon-Federal Hospitals in 2000 2 databases evaluated for trends in HCC 48,349 HCC deaths 1980-1998 15 11.0 10 Treatment (%) 5.5 4.9 5 3.5 1.8 0 Surgical Resection Liver Transplant Local Ablation Embolization Chemotherapy Kim WR, et al. Gastroenterology. 2005;129:486-493.

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