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A Cautionary Tale…

A Cautionary Tale…. Hesham M. Elgouhari, M.D., FACP Assistant Professor of Medicine Hepatologist & Medical Director Avera Center For Liver Disease Avera McKennan Hospital& University Health Center Sioux Falls, South Dakota. The Case-History.

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A Cautionary Tale…

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  1. A Cautionary Tale… Hesham M. Elgouhari, M.D., FACP Assistant Professor of Medicine Hepatologist & Medical Director Avera Center For Liver Disease AveraMcKennan Hospital& University Health Center Sioux Falls, South Dakota

  2. The Case-History A 76 YOM presented with progressive fatigue and SOB for 3 weeks No Hematemesis/Melena/BRBPR Abdominal discomfort. No progressive distention No Jaundice or Pruritus New noticing of confusion per Family History of PUD S/P Partial Gastrectomy in 1976 Colonoscopy recently revealed small rectal polyp Biopsy-proven cirrhosis in 2008 locally

  3. The Case:History Drinks 1-2 beer per day for the last few years but more prior No DM, HTN, or HPL Has Psoriasis and gout Prostate Cancer S/P resection

  4. The Case:PE Elderly Male with mild respiratory distress VS: BP 108/67, P 85, RR 20, Temp 98, BMI 38 HEENT: Temporal wasting, No Jaundice Cardiopulmonary: No significant findings Abdomen: Slightly distended, No tenderness Ext: +1 edema bilaterally Neuro: Has asterixis. No focal signs Skin: Spider Angiomatosis and Palmarerythema

  5. The Case: Investigations CBC: Hb 5.8, Plat 270 K, WBC 9800 CMP: Creat 1.5, T Bili 2.7, Alb 2.6, AST 56, ALT 38, AP 92, INR 1.5 AFP 13 HBV and HCV serology: Unremarkable AIH markers: High IgG with negative ANA& SMA A1ATP: Normal U/S: Hepatic steatosis/No focal mass, Patent BVs EGD: EV-I, Patent Billroth II GJ

  6. Questions… Thoughts….

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  10. Now… What should we do??

  11. Diagnosis: 1-Decompensated Cirrhosis 2-HCC (NO BIOPSY) 3-Mild Ascites 4-Portal HTN 5-Mild HE

  12. The Case: Management CT Chest and Bone Scan: Negative for mets TACE in April and July 2011 Does not want Evaluation for LT Stable

  13. Hepatocellular Carcinoma (HCC)

  14. HCC Epidemiology HCC and The Globe • HCC is the most common primary liver cancer • The incidence is increasing worldwide • Among men, HCC is the 5th most common cancer • It is the 3rd lethal cancer worldwide • 711,000 Cases of HCC in 2007 • Every year, 694,000 deaths from liver cancer

  15. HCC Epidemiology Age-Adjusted Rates of Death for HCC Per 100,000 population H. El Serag and A. Mason, NEJM, 1999 Kiyosawa K, Jpn. J. Inf. Dis., 55, 69-77, 2002

  16. HCC Epidemiology Age-Adjusted Incidence Rates For HCC in The United States (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

  17. HCC is One of the Fastest Rising Cancers in Middle Age White Men 10 45 – 49 Years 50 – 54 Years 8 6 4 2 0 76-78 79-81 82-84 85-87 88-90 91-93 94-96 97-99 2000-02 Year of Diagnosis HCC Epidemiology Incidence rate per 100,000 El-Serag HB et al, Ann Intern Med 2003

  18. HCC Epidemiology More recently… • HCC is the fastest growing cause of cancer-related death in men • Expected to continue to increase until 2015-2020

  19. HCC Epidemiology Why HCC is Rising? Why HCC incidence is 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

  20. HCC Epidemiology Future Trends in HCC Incidence Future Trends in HCC Incidence Distribution of risk factors among HCC cases • HCV 24% to 60% • NASH/NAFLD 13% up to 50% Prevalence of risk factors in the general population • HCV 2% • Obesity 30%, overweight 60% • HBV 0.4%

  21. Prevalence of HCV HCC Epidemiology Worldwide 170 million (3%) United States Anti-HCV positive 3.9 million (1.8%) HCV RNA positive 2.7 million (1.4%) Alter MJ et al, New Engl J Med 1999 Lavanchy D & McMahon B, In: Liang TJ & Hoofnagle JH (eds.) Hepatitis C. New York: Academic Press, 2000

  22. 1% (1%-3%/year) 15% (10%- 30%) 25 years 90% (60%- 95%) 100 HCC Epidemiology HCV to HCC Pyramid HCC Cirrhosis Chronic Hepatitis HCV Infection Goodgame B, et al., Am J Gastroenterol 2003

  23. HCC Epidemiology HCC After IFN Therapy for HCV 30 25 20 No Response Cumulative Incidence of HCC (%) 15 10 Relapse 5 Sustained Response 0 0 1 2 3 4 5 6 7 Follow-up (yr) Imai Y, et al, Ann Intern Med 1998

  24. Clinical Outcome of Chronic Hepatitis B HCC Epidemiology Chronic HBV Infection Inactive Carrier State Chronic Hepatitis Cirrhosis HCC

  25. Impact of HBV Vaccine on Incidence of HCC in Children HCC Epidemiology 8 6 Annual Incidence of HCC (per 1,000,000) 4 2 0  1981-1986 1986-1990 1990-1994 Universal Vaccination of Newborns Chang MH, N Engl J Med 1997

  26. NAFLD Spectrum of Hepatic Pathology HCC Epidemiology Steatohepatitis Steatosis Cirrhosis Hepatocellular carcinoma

  27. HCC Epidemiology Coffee and Hepatocellular Carcinoma • A source of antioxidants • Animal experiments: inhibitory effects against chemical carcinogenesis in liver tissue • Epidemiologic studies: coffee consumption is inversely related to • serum liver enzyme activity • liver cirrhosis • HCC

  28. Definitions HCC Surveillance Definitions • Screening • Screening is a public health service in which members of a defined population are offered a test to identify those individuals who are more likely to be helped than harmed by further tests or treatment to reduce the risk of a disease or its complications. • Surveillance • The continuous monitoring of disease occurrence (using the screening test) within an at-risk population to achieve the same goals as screening • For HCC, surveillance is recommended Meissner Hi, et al,Cancer 2004 Sherman M, et al, Hepatology 1998

  29. Patients for Whom HCC Surveillance Is Recommended HCC Surveillance Asian males HBV carriers older than 40 yrs of age Asian female HBV carriers older than 50 yrs of age HBV carrier with HCC family history African/N American blacks with HBV Cirrhotic HBV carriers Hepatitis C with cirrhosis Stage 4 primary biliary cirrhosis Genetic hemochromatosis and cirrhosis Alpha-1 antitrypsin deficiency and cirrhosis Other cirrhosis 80% of patients with HCC have underlying cirrhosis Bruix J, et al. AASLD HCC guidelines. July 2010. Simonetti RS, et al. Dig Dis Sci. 1991;36:962-972.

  30. Screening for HCC: AASLD Recommendations HCC Surveillance Screening for HCC:AASLD Recommendations • Population in which screening should be done • Cirrhosis (any etiology) • HBV: older, family history, cirrhosis • Surveillance for HCC should be performed with ultrasonography • AFP alone should not be used for surveillance unless ultrasonography is not available • Screening should occur every 6 months

  31. Ultrasound Surveillance in Early HCC: Systematic Review HCC Surveillance Sensitivity % Study 95% CI Weight Arrigoni1988 0.69 (0.49, 0.89) 9.60 Oka 1990 0.68 (0.54, 0.81) 11.56 Cottone1994 0.87 (0.77, 0.96) 12.81 Zoli1996 0.91 (0.84, 0.98) 13.41 Tradati1998 0.33 (-0.11, 0.78) 4.30 Henrion2000 0.67 (0.38, 0.96) 7.16 Bolondi2001 0.82 (0.73, 0.91) 13.03 Tong 2001 0.58 (0.41, 0.75) 10.47 Santa 2003 0.25 (0.62, 0.82) 4.93 Subtotal 0.72 (0.62, 0.82) 87.27 (I2 = 76.7%, p<0.0001) Kobayashi 1985 0.50 (0.16, 0.84) 5.98 Pateron1994 0.23 (-0.08, 0.54) 6.75 Subtotal 0.35 (0.09, 0.62) 12.73 (I2 = 23.8%, p = 0.252) Ultrasound Surveillance in Early HCC: Systematic Review 0 1.0 Singal A, et al. APT 2009

  32. HCC Surveillance Performance Characteristicsof AFP Based on Cutoff Level Sensitivity Specificity 100 80 % 60 40 Cutoff 10-11 17-21 50 > 100 Studies 4 7 4 5 ng/ml Colli A, et al, Am J Gastro 2005

  33. HCC Surveillance Surveillance for HCC Improves Mortality:A Randomized Controlled Trial • A study of hepatitis B carriers in China • 18,816 randomized to surveillance with AFP + US biannual vs. no surveillance • Adherence to surveillance was 58% Zhang BH, et al, J Cancer Res Clin Oncol 2004

  34. HCC Surveillance 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)

  35. HCC Surveillance Surveillance for HCC Reduces Mortality:A Randomized Controlled Trial .8 Control Screening .6 Survival Probability (%) .4 .2 0 0 1 2 3 4 5 Time (Years) Zhang BH, et al, J Cancer Res Clin Oncol 2004

  36. HCC Surveillance Effect of Surveillance on Outcomes • Retrospective analysis of patients with cirrhosis and HCC (N = 269) • Standard-of-care surveillance (n = 172) • Ultrasound or other abdominal imaging ≥1 time/year • Substandard surveillance (n = 48) • Lack of abdominal imaging within 1 year of cancer diagnosis • Absence of surveillance (n = 59)

  37. HCC Surveillance Surveillance Recommendations Surveillance Recommendations • The target population for surveillance are those with liver cirrhosis (and HBV-infected patients) • AFP and US are the recommended screening tests for HCC in patients at the highest risk • Based on tumor doubling time and studies, the recommended interval for surveillance is every 6 months in patients with cirrhosis • Screening increases likelihood of HCC diagnosis • Small and potentially treatable • May reduce mortality

  38. HCC Surveillance • Review records of patients > 65 YO diagnosed with HCC between 1994-2002 • Number of cirrhotic patients with HCC was 1,873 • Only 17% received regular surveillance

  39. HCC Surveillance Those seen by Gastroentrologist/Hepatologist or by a Doctor with an academic affiliation were more likely to have regular surveillance by 4.5 fold and 2.8 fold respectively than those seen by PCPs only Getting ”Better”: Regular surveillance increased from 9% in 1994-1996 to 21% in 2000-2002

  40. HCC Diagnosis Dual Blood Supply of Liver • The vascular supply of HCC arises from the hepatic artery through neovascularization. • 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

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

  42. 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

  43. HCC Prognosis Patient Survival Comparing Detection of HCC by Surveillance vs Presentation With Symptoms 100 80 Symptoms Surveillance 60 Survival, % 40 20 P < .001 0 0 24 12 36 48 72 60 96 84 Months Follow up Tong MJ et al. J Clin Gastroenterol. Sept 9, 2009

  44. Barcelona Clinic Liver Cancer Staging Classification (BCLC) Stage 0 Stage A-C Stage D PST 0, Child-Pugh A Okuda 1-2, PST 0-2, Child-Pugh A-B Okuda 3, PST >2,Child-Pugh C Very early stage (0) Early stage (A) Intermediate stage (B) Advanced stage (C) Terminalstage (D) Single <2 cm Carcinoma in situ Single or 3 nodules <3 cm, PST 0 Multinodular, PST 0 Portal invasion, N1, M1, PST 1–2 Single 3 nodules <3 cm Portal pressure / bilirubin Portal invasion, N1, M1 Increased Associated diseases Normal No Yes Resection Liver transplantation(CLT/LDLT) PEI/RFA Chemoembolism Sorafenib Curative treatments50%-75% at 5 years Randomized controlled trials 40%-50% at 3 years vs 10% at 3 years Symptomatic treatment CLT/LDLT = cadaveric liver transplantation/living donor liver transplantation; PST = Performance Status Test. HCC Treatment Barcelona Clinic Liver CancerStaging Classification (BCLC) Llovet JM et al. Lancet. 2003; 362:1907

  45. Liver Transplantation for HCCMilan Criteria HCC Treatment OR Single tumor, not > 5 cm Up to 3 tumors, none > 3 cm Extra MELD Points + Absence of macroscopic vascular invasion, absence of extrahepatic spread 5-yr survival with transplantation: ~ 70% 5-yr recurrent rates: < 15% Mazzaferro V, et al. N Engl J Med. 1996;334:693-699. Llovet JM. J Gastroenterol Hepatol. 2002;17(suppl 3):S428-S433.

  46. Multidisciplinary HCC Management HCC Treatment • HCC is the intersection of 2 diseases • Liver disease and cancer • Skilled Radiologists “pathologists” needed for diagnosis • Specialists required to deliver treatment options • Surgeons for resection or transplantation • Radiologists for ablation and chemoembolization • Hepatologists and oncologists follow treatment strategy and labs

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

  48. Thank you…

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