Hepatocellular CarcinomaThomas Hargrave M.D.January 16, 2009

HCC Is Common and Increasing662,000 deaths from liver cancer yearly worldwideAge-adjusted US incidence has increased 2-fold: 1985-1998American Cancer Society statistics for liver cancer in 2008Estimation of new cases: 21,370Estimation of deaths: 18,4105th leading cause of cancer deaths in malesWorld 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.

Worldwide Incidence of Hepatocellular CarcinomaHigh (> 30:100,000)Low or data unavailable (< 3:100,000)Intermediate (3-30:100,000)HCC EpidemiologyEl-Serag HB, Gastroenterology 2004

Changes in the Incidence of HCC 1978-1992McGlynn K, et al, Int J Cancer 2001-40-20020406080100120-30-24-20-18101214214650718390108Singapore, ChineseSpain, ZaragozaIndia, BombayChina, ShanghaiSwitzerland, GenevaHong KongNewZealand, MaoriNewZealand, Non-MaoriJapan, OsakaUK, So. ThamesCanada, AlbertaItaly, VareseFrance, Bas-RhinAustralia, NSWRecent Changes in the Incidence of HCCHCC Epidemiology

Age-Adjusted Incidence Rates For HCC (1976-2002)El-Serag HB, Mason A, N Engl J Med 1999El-Serag HB et al, Ann Intern Med 2003Year76-7879-8182-8485-8788-9091-9394-9697-992000-021.41.41.61.82.02.32.73.13.5 32.521.510.50Rateper 100,0003.3HCC Epidemiology

Racial Distribution of HCC in the United StatesYear75-7781-8384-8687-8990-9293-9596-98WhiteBlackAsian78-80Number of Cases300025002000150010005000HCC EpidemiologyEl-Serag HB, Mason A, N Engl J Med 1999

Racial Incidence Rates For HCCIn The United StatesYear76-7882-8485-8788-9091-9394-9697-992000-02Age-Adjusted Incidence Rateper 100,00012.561.1WhiteBlackOther (Asian)79-812.5582.55.21.12.66.31.32.96.61.43.47.21.73.77.21.93.98.42.34.67.9HCC EpidemiologyEl-Serag HB et al, Ann Intern Med 2003

Temporal Trends in The Age Distribution of Hepatocellular CarcinomaIncidence Rateper 100,000 PYAge (years)20-2430-3435-3940-4445-4950-5455-5925-291982 841991 932000 0260-6465-6970-7475-7980-8485+HCC EpidemiologyEl-Serag HB, Mason A, N Engl J Med 1999

Risk Factors for HCC in US PatientsWorldwide, 75% to 80% of HCC attributable to chronic HBV (50% to 55%) or HCV (25% to 30%) 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.Known Risk Factor in the US: Viral Hepatitis (N = 691)5153347020406080100HBV + HCVHBVHCVNeitherPresence of Risk Factor Among HCC Patients (%)

Risk Factors for HCC Cirrhosis from any cause (3-8%/yr)HCV HBVHeavy alcohol consumptionNon-alcoholic fatty liver diseaseHBV without cirrhosis (0.02-0.06%/yr)Inherited metabolic diseasesHemochromatosis Alpha-1 antitrypsin deficiency Glycogen storage diseasePorphyria cutanea tardaTyrosinemia Autoimmune hepatitisRisk Factors for HCC HCC Epidemiology

HCV Cirrhosis and HCCMultiple small foci of HCCHCV Cirrhosis and HCCHCC Epidemiology

Why is HCC Incidence Rising?

Rising incidence of cirrhosisHCV (main reason)HBVOther (?NAFLD/insulin resistance)Improved survival of patients with cirrhosisIncreasing prevalence of patients with cirrhosisWhy HCC is Rising?HCC EpidemiologyEl-Serag HB, Gastroenterology 2004

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

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

Alcohol Intake and the Risk of HCCDonato F, et al, Am J Epidemiol 20020510152020406080100120140Grams of Alcohol / DayOdds RatiosNo HCVwith HCVAlcohol Intake and the Risk of HCCHCC Epidemiology

HBV DNA Associated with Increased Risk of HCC in Non-CirrhoticsLikelihood of HCC in individuals with detectable HBV DNA is 3.9 times more than those with undetectable HBV DNARisk associated with increasing HBV DNA levelsThese data support possibility of preventing long-term risk of HCC by inducing sustained suppression of HBV replicationYang HI, et al, N Engl J Med 2002HBV DNA Associated with Increased Risk of HCC

HBe Antigen and Risk of HCC Yang HI, et al, N Engl J Med 2002Percent cumulative incidence0YearHBsAg+, HBeAg+(RR = 60.2)HBsAg+, HBeAg-(RR = 9.6)HBsAg-, HBeAg-2468101201234567891011,893 Noncirrhotic Taiwanese Males Followed 8 Yrs

HBV DNA and Risk of HCC: Untreated Non-Cirrhotic HBeAg+3465 HBeAg (+) Non-cirrhotic Taiwanese Patients followed for a mean of 11.5years65% had HBV DNA > 100,000,000

HBV DNA (copies/mL)Incidence of HCCPer Year (%)Chen et al. JAMA. 2006;295:65-73 (B).

Risk Factors for HCC in US PatientsWorldwide, 75% to 80% of HCC attributable to chronic HBV (50% to 55%) or HCV (25% to 30%) 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.Known Risk Factor in the US: Viral Hepatitis (N = 691)5153347020406080100HBV + HCVHBVHCVNeitherPresence of Risk Factor Among HCC Patients (%)(?NAFLD/insulin resistance?)

Non-alcoholic Fatty Liver Disease (NAFLD) and HCCSingle center study, Univ. Michigan105 consecutive patients with HCC51% due to HCV-associated cirrhosisCryptogenic cirrhosis in 29% Half had histologic features consistent with NASHEstimated that 13% of HCC and cryptogenic cirrhosis may have NAFLD/NASH

Marrero J, et al, Hepatology 2002Non-alcoholic Fatty Liver Disease (NAFLD) and HCCHCC Epidemiology

Prospective Study Cancer Mortality in Obese US Adults (n=900,053):1982-1998Calle EE, & et al, N Engl J Med 200301Prostate (>35)Relative Risk of Death (95% Confidence Interval)1.341.491.521.68*1.701.711.761.841.91*1.942.61*4.52MenType of Cancer(Highest BMI Category)234567Non-Hodgkins Lymphoma(>35)All Cancers (>40)All Other Cancers (>30)Kidney (>35)Multiple Myeloma (>35)Gall Bladder (>30)Colon and Rectum (>35)Esophagus (>30)Stomach (>35)Pancreas (>35)Liver (>35)

Obesity and Liver CancerCalle, et al, NEJM 200358Death Rate per 100,00035 to 39.930 to 34.520 to 29.918.5 to 25486191059BMIHCC Epidemiology

Impact of Diabetes and Overweighton Liver Cancer Occurrence in CirrhosisNKontchou G, Clin Gastro Hepatol 2005BMI 27.3, diabetes +P

Cancer and Insulin ResistanceExcess weight / adiposityFFA , TNFa Resistin , AdiponectinInsulin resistanceBlood and tissue: IGFBP 1 IGFBP2IGF1 bioavailabilityInsulinIRIGF1RTumor developmentTarget cells Apoptosis Cell proliferation

Screening / Surveillance for Hepatocellular Carcinoma

Cost-Effectiveness of HCC SurveillanceSurveillance with bi-annual alpha-fetoprotein (AFP) and ultrasonography in Child class A cirrhotics had cost-effectiveness ratios between $26,000 and $55,000 per QALY2 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 2004Cost-Effectiveness of HCC SurveillanceHCC Screening

Alpha-fetoprotein Cross-Sectional StudiesMarrero JA, Clin Liver Dis 20056316320Nguyen5354200Lee6519730Soresi2574100Cedrone6017016Trevisani6520520PengSensitivity%No. of HCCCutoffAuthor797989959088Specificity%HCC Screening

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.

StudySpecificity, %PPV, %Case-control studiesTrevisani 20019125*Surveillance studiesPateron 19948633Sherman 1995919McMahon 20009531Bolondi 20018246Tong 20019111

Current Serologic Surveillance Tests Not Sufficiently Sensitive/SpecificProspective analysis of 99 patients with histologically proven, unresectable HCCCarr BI, et al. Dig Dis Sci. 2007;52:776-782.61.672.767.784.873.784.885.9020406080100AFP-L3%DCPAFPAFP-L3%+ DCPAFP-L3%+ AFPDCP + AFPAFP-L3%+ DCP+ AFPSensitivity (%)Tumor Marker

Ultrasound in HCC in Cohort StudiesHCC ScreeningColli A, et al, Am J Gastro 2006

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

Performance Characteristic, %Cohort 1Years 1-5Cohort 1Years 6-8Cohort 2Years 1-3Sensitivity798780Specificity948791PPV151314NPV98100100

HCC Doubling TimeRationale for Surveillance Every 6 MonthsTaouli B, et al, J Comput Assist Tomogr 2005HCC Screening

Surveillance Interval: 6 vs 12 MonthsTrevisani et al[1]Survival similar with 6-month vs 12-month surveillanceSantagostino et al[2]Rate of detection of single nodules (vs multinodular HCC) similar with 6-month vs 12-month surveillanceKim et al[3]Survival improved with 6-month vs 12-month surveillance1. 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.

AASLD and NCCN Surveillance GuidelinesAASLD Guidelines Surveillance recommended in at-risk groupsSpecific hepatitis B carriersNonhepatitis B cirrhosisUS preferred surveillance toolAFP alone should not be used unless US unavailablePatients should be screened at - 6 to 12-month intervalsNCCN GuidelinesUS and AFP, AP, and albumin for surveillance in high-risk patientsEvery 3-6 monthsContinue screening every 3 months in those with high AFP but no evidence on imagingNCCN, National Comprehensive Cancer

Surveillance for HCC Improves MortalityA Randomized Controlled Trial Screened group Control group

Person-years in study38,44441,077HCC occurrenceCases8667Total incidence (per 100,000)223.7163.1Rate ratio (95% CI)1.37 (0.99, 1.89)

Deaths from HCCDeaths3254Total mortality (per 100,000)83.2131.5Rate ratio (95% CI)0.63 (0.41, 0.98)HCC Screening

Diagnosis of Hepatocellular Carcinoma

Clinical Features at PresentationSymptomsPercent of Patients

None23%Abdominal Pain32%Ascites 8%Jaundice 8%Anorexia/weight loss10%Malaise 6%Bleeding 4%Encephalopathy 2%Gastroenterology 2002HCC Diagnosis

Guidelines for Diagnosis of HCCTypical features of HCC = vascular nodule on arterial phase with washout in delayed phasesUltrasound findingsBruix J, et al, Hepatology 2005HCC Diagnosis

< 1 cm1-2 cm> 2 cm

Repeat US every 3-6 moDynamic CT, contrast US or MRI2 testsTypical = HCCAtypical = biopsyDynamic CT, contrast US or MRI1 testTypical = HCCAtypical = biopsy

Dual Blood Supply of LiverThe vascular supply of HCC arises from the hepatic artery through neovascularization. Normal hepatocytes receive 80% of blood flow from portal veinImaging 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 phasesYu JS, et al, Am J Roentgenol 1999HCC Diagnosis

Triple Phase Imaging of Hepatocellular CarcinomaPre-contrastPortal Venous PhaseArterial Phase5-min DelayedHCC Diagnosis: MRI

Dynamic MRI Spiral CT for Diagnosis of HCCVariablesDynamic 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 1.79Burrel M, et al, Hepatology 2003n= 55 cirrhotics (29 with HCC)HCC Diagnosis

Treatment of Hepatocellular Carcinoma

HCC Survival Estimates in the United StatesWhiteBlackAsianHispanic0Years Following DiagnosisSurvival (%)20406080100Davila J, & El-Serag HB, Clin Gastroenterol Hepatol. 2006 Population-based Survival Estimates in the United StatesHCC Treatment Median Survival 6-8 months

Key Concepts in the Management of Hepatocellular CancerPotentially CurativeLiver transplantation (75% 5-year survival)Surgical resectionPalliativeRadiofrequency ablation (RFA)Transarterial chemoembolization (TACE)Percutaneous ethanol or acetic acid ablationCryoablationSystemic Chemotherapy

Key Concepts in the Management of Hepatocellular CancerHCC Treatment

Key Concepts in the Management of Hepatocellular CancerLiver transplantation achieves the best outcome in HCC patients with decompensated cirrhosis who meet criteriaSurgical resection is most effective for non-cirrhotic patients or those with cirrhosis and preserved liver function and can be followed by salvage OLTPatients with small tumors are best stratified for resection or OLT by the presence of clinically-significant portal hypertension and/or increased serum bilirubinLocal ablative methods are an option for small solitary nodules and those who are not surgical candidatesTransarterial chemoembolization improves survival in intermediate-advanced HCCKey Concepts in the Management of Hepatocellular CancerHCC Treatment

Management of Hepatocellular Carcinoma Requires a Multidisciplinary ApproachLiver Transplant ProgramPathologyOncologyRadiologyHepatobiliary SurgeryHepatologyHCC Treatment

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

Management of HCC in Patients with CirrhosisHCC Treatment

Surgical Resection of HCC:Outcome in a US Cancer CenterHCC TreatmentAnn Surg. 2003; 238:315-21.

Treatment of HCC in US atNon-Federal Hospitals in 20002 databases evaluated for trends in HCC48,349 HCC deaths 1980-1998Kim WR, et al. Gastroenterology. 2005;129:486-493.0510154.91.83.55.511.0SurgicalResectionLiverTransplantLocalAblationEmbolizationChemotherapyTreatment (%)

Treatment for HCC Often SuboptimalProportion of patients receiving potentially curative therapy (N = 2963)34.0% of patients with single lesions34.0% of patients with lesions < 3 cm 19.2% of patients with lesions > 10 cm 4.9% of patients with metastatic disease11.5% of patients ideal for transplantation received it12.9% of patients ideal for surgical resection received itEl-Serag HB, et al. J Hepatol. 2006;44:158-166.

Survival(Kaplan Meier Estimate)Follow up Duration (Years) TransplantResectionAblationTACE10.80.60.40.20Outcomes of HCC Treatment: Observational Population-based studyEl-Serag HB, et al, J Hepatology 2006 44:1582,963 patients with HCC diagnosed between 1992 and 1999 in SEER-Medicare datasetsMedian Age:74

Not transplant candidate/has cancer-related symptomsSummary of NCCN Treatment GuidelinesSurgical eval/ biopsyResectable Ablation Transplant TransplantSorafenibChemo-embolizationClinical trialAblationChemo + RTRTRadio-embolizationSupportive careSystemic/intra-arterial chemoTransplant if appropriate candidate Sorafenib Clinical trialNo cancer-related symptoms Sorafenib Ablation Clinical trialSorafenibAblationClinical trialChemo-embolizationRTRadio-embolizationSupportive careSorafenibClinical trialSupportive careCancer-related symptomsNCCN. Available at: http://www.nccn.org/professionals/physician_gls/PDF/hepatobiliary.pdf. Accessed October 23, 2008.Potentially resectable, inoperable massUnresectable/ Denies SurgeryInoperable by PS, comorbidity (local disease)MetastaticExtensive/ no cancer-related symptoms

HCC: SummaryHCC is one the most rapidly increasing cancers in the USThe 5-year survival is 8-12%Less than 20% are candidates for surgery/transplant at diagnosisTreatment is mainly palliativeReferral to a tertiary center indicatedScreening to detect early HCC is the main priority of primary care physicians

Hepatitis B Carriers Suitable for HCC SurveillanceHepatitis B carriersAsian 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: Screen from the time of diagnosis (mainly Asian and African)

AASLD and NCCN Surveillance GuidelinesAASLD Guidelines Surveillance recommended in at-risk groupsSpecific hepatitis B carriersNonhepatitis B cirrhosisUS preferred surveillance toolAFP alone should not be used unless US unavailablePatients should be screened at - 6 to 12-month intervalsNCCN GuidelinesUS and AFP, AP, and albumin for surveillance in high-risk patientsEvery 3-6 monthsContinue screening every 3 months in those with high AFP but no evidence on imagingNCCN, National Comprehensive Cancer

Focus Screening Efforts on Patients Under Age 65 Incidence Rateper 100,000 PYAge (years)20-2430-3435-3940-4445-4950-5455-5925-291982 841991 932000 0260-6465-6970-7475-7980-8485+El-Serag HB, Mason A, N Engl J Med 1999

HCC: Preventative Measures?Although unproven, data suggest that maximal suppression of HBV DNA may reduce the annual incidence of HCCObscenely expensiveEradication of HCV significantly reduces the risk of HCCMinimize ETOHMinimize risk factors for hyperinsulinemiaStatins?Coffee

HCC After IFN Therapy for HCVFollow-up (yr)Cumulative Incidenceof HCC (%)Imai Y, et al, Ann Intern Med 199801234567No ResponseRelapse510152025300SustainedResponseHCC Epidemiology

Statins vs HCCRetrospective, case-controlled study VA database >1,400.000 veterans14,021 HVC positive34% on statinsHCC diagnosed in 409After controlling for age, genotype, statin use was associated with a significant reduction in risk for HCC

V. Khurana et al. Statins Are Protective Against HCC in HCV InfectionDDW 2005. May 14-14 Abstract S1535

Dont Forget Your CoffeeMeta-analysis of published studies on HCC that included quantitative information on coffee consumptionTen studies were retrieved: 2,260 HCC casesThe overall summary RR for low or moderate coffee drinkers was 0.70 (95% CI 0.57-0.85), and that for high drinkers was 0.45 (95% CI 0.38-0.53)Hepatology 2007 Aug;46(2):430-5

*Slide 4Epidemiology of Hepatocellular CarcinomaHCC, hepatocellular carcinoma; US, ultrasound.*Slide 5Worldwide Incidence of Hepatocellular CarcinomaThe incidence of HCC varies considerably around the world with the highest rates in Southeast Asia and sub-Saharan Africa (areas where HBV infection is endemic and high). The United States have recently moved into the intermediate incidence areas (age-adjusted incidence rates close to 4 per 100,000 person-years).

El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology. 2004 Nov;127(5 Suppl 1):S27-34.Slide 6Recent Changes in the Incidence of HCCThe incidence of HCC has been declining in some high-incidence areas, such as China and Hong Kong. This is partly related to HBV vaccination of children, and to reduction of aflatoxin exposure in grains.On the other, HCC incidence in several low and intermediate incidence areas, have been increasing. For example, hepatitis C related HCC has been responsible for most the observed recent rise in the United States.

McGlynn KA, Tsao L, Hsing AW, Devesa SS, Fraumeni JF Jr. International trends and patterns of primary liver cancer. Int J Cancer. 2001 Oct 15;94(2):290-6. Lok AS. Prevention of hepatitis B virus-related hepatocellular carcinoma. Gastroenterology. 2004 Nov;127(5 Suppl 1):S303-9. Review. PMID: 15508098.Chang MH, Shau WY, Chen CJ, Wu TC, Kong MS, Liang DC, Hsu HM, Chen HL, Hsu HY, Chen DS; Taiwan Childhood Hepatoma Study Group. Hepatitis B vaccination and hepatocellular carcinoma rates in boys and girls. JAMA. 2000 Dec 20;284(23):3040-2.Slide 8Age-Adjusted Incidence Rates For HCC (1976-2002)The age-adjusted incidence rates (per 100,000 person years in the underlying general population) of HCC diagnosed between 1975 and 2002. The rates shown above the bars represent the average annual rates (not the sum) during each three-year period. Cases were confirmed with histology or cytology, which is likely to underestimate the true count of HCC cases. The data source is Surveillance, Epidemiology, and End Results (SEER) Population-based registries, which included information from 12 registries (14% of the US population).

El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med. 2003 Nov 18;139(10):817-23. Erratum in: Ann Intern Med. 2004 Jan 20;140(2):151.El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999 Mar 11;340(10):745-50.Slide 11Racial Distribution of HCC in the United StatesThe case counts (instead of age adjusted incidence rates) highlights the point that most cases of HCC are detected in Whites (non Hispanic as well as Hispanic). Asians constituted 23% of cases, Blacks 12%, and 65% White both Hispanic and non Hispanic.

El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999 Mar 11;340(10):745-50. Slide 9Racial Incidence Rates For HCC In The United StatesThe average annual age-adjusted incidence rates for HCC shown for three-periods between 1976 and 2002 and broken down by racial groups (source: SEER: Surveillance Epidemiology and End Results). Although the highest incidence rates are observed in Asians, the highest proportional increase was observed among Whites (non Hispanic as well Hispanic). Black African Americans have intermediate rates.

El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med. 2003 Nov 18;139(10):817-23. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999 Mar 11;340(10):745-50. Slide 12Temporal Trends in The Age Distribution of Hepatocellular CarcinomaThe age specific rates are shown per 5 year age groups. HCC is rare below age 40, increases progressively thereafter. As the incidence of HCC has increased in the United States (during 2000-02), the age distribution curve has shifted to the left indicting that younger persons are becoming progressively more affected. Persons between 45 and 65 have been disproportionately affected with HCC.

El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999 Mar 11;340(10):745-50. El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med. 2003 Nov 18;139(10):817-23.

HCC, hepatocellular carcinoma; US, United States.Slide 25Risk Factors for HCCSlide 33HCV Cirrhosis and HCCExplanted liver showing features of cirrhosis and multiple small foci of HCC throughout the liver in a miliary pattern (arrows).

Slide 21Why is HCC Incidence Rising?

El-Serag HB. Hepatocellular carcinoma: recent trends in the United States.Gastroenterology. 2004 Nov;127(5 Suppl 1):S27-34. *Davis et al used a natural history model to project the prevalence of HCV infection and HCV-related cirrhosis, liver failure, and mortality over the next 40 years. Thes results are shown here and on the next slide.According to this model, the prevalence of infection should gradually decline, due to aging and natural deaths among those currently infected. However, the rate of complications in the surviving pool of infected individuals is expected to increase dramatically over the next few decades. Without identification and treatment of infected individuals, the peak of HCV morbidity and mortality will be reached in the year 2030, when there will be an estimated 880,000 individuals with cirrhosis and 146,000 with decompensated cirrhosis requiring transplantation.

Slide 38Alcohol Intake and the Risk of HCCThe investigators enrolled 464 subjects (380 men) with a first diagnosis of HCC as cases and 824 subjects (686 men) unaffected by hepatic diseases as controls; all were hospitalized in Brescia, northern Italy, in 1995-2000. Spline regression models showed a steady linear increase in the odds ratio of HCC for increasing alcohol intake, for values of >60 g of ethanol per day. The effect of alcohol drinking was evident even in the absence of hepatitis B or hepatitis C virus infection. In addition, a synergism between alcohol drinking and either infection was found, with approximately a twofold increase in the odds ratio for each hepatitis virus infection for drinkers of >60 g per day.

Donato F, Tagger A, Gelatti U, Parrinello G, Boffetta P, Albertini A,Decarli A, Trevisi P, Ribero ML, Martelli C, Porru S, Nardi G. Alcohol and hepatocellular carcinoma: the effect of lifetime intake andhepatitis virus infections in men and women.Am J Epidemiol. 2002 Feb 15;155(4):323-31. Slide 53HBV DNA Associated with Increased Risk of HCCSimilarly, infected individuals with detectable HBV DNA are more likely to develop HCC than those without, with the risk increasing with increasing HBV DNA.

Yang HI, Lu SN, Liaw YF, You SL, Sun CA, Wang LY, Hsiao CK, Chen PJ, ChenDS, Chen CJ; Taiwan Community-Based Cancer Screening Project Group. Hepatitis B e antigen and the risk of hepatocellular carcinoma.N Engl J Med. 2002 Jul 18;347(3):168-74.

Slide 52HBe Antigen and Risk of HCCIn 1991 and 1992, the investigators enrolled 11,893 men without evidence of hepatocellular carcinoma from seven townships in Taiwan. Serum samples obtained at the time of enrollment were tested for HBsAg and HBeAg by radioimmunoassay. The diagnosis of hepatocellular carcinoma was ascertained through data linkage with the computerized National Cancer Registry in Taiwan and with death certificates. There were 111 cases of newly diagnosed hepatocellular carcinoma during 92,359 person-years of follow-up. The incidence rate of hepatocellular carcinoma was 1169 cases per 100,000 person-years among men who were positive for both HBsAg and HBeAg, 324 per 100,000 person-years for those who were positive for HBsAg only, and 39 per 100,000 person-years for those who were negative for both. After adjustment for age, sex, the presence or absence of antibodies against hepatitis C virus, cigarette-smoking status, and use or nonuse of alcohol, the relative risk of hepatocellular carcinoma was 9.6 (95 percent confidence interval, 6.0 to 15.2) among men who were positive for HBsAg alone and 60.2 (95 percent confidence interval, 35.5 to 102.1) among those who were positive for both HBsAg and HBeAg, as compared with men who were negative for both.

Yang HI, Lu SN, Liaw YF, You SL, Sun CA, Wang LY, Hsiao CK, Chen PJ, ChenDS, Chen CJ; Taiwan Community-Based Cancer Screening Project Group. Hepatitis B e antigen and the risk of hepatocellular carcinoma.N Engl J Med. 2002 Jul 18;347(3):168-74. Template _1**This slide summarizes PAUSElost the line HCC, hepatocellular carcinoma; US, United States.Slide 63Non-alcoholic Fatty Liver Disease (NAFLD) and HCCIn this study from the University of Michigan, 105 consecutive patients with HCC were studied. The most common etiology of liver disease was hepatitis C (51%) and cryptogenic cirrhosis (29%). Half of the patients with cryptogenic cirrhosis had histologic or clinical features associated with nonalcoholic fatty liver disease (NAFLD). NAFLD accounted for at least 13% of the cases. Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM, Lok AS. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology. 2002 Dec;36(6):1349-54. Slide 65Mortality from Cancer in Obese US Men (n=900,053)In a prospectively studied population of more than 900,000 U.S. adults (404,576 men and 495,477 women) who were free of cancer at enrollment in 1982, there were 57,145 deaths from cancer during 16 years of follow-up. In both men and women, body-mass index was also significantly associated with higher rates of death due to cancer of the liver (in addition to the esophagus, colon and rectum, gallbladder, pancreas, and kidney).

Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studiedcohort of U.S. adults.N Engl J Med. 2003 Apr 24;348(17):1625-38. Slide 64Obesity and Liver CancerIn a prospectively studied population of more than 900,000 U.S. adults (404,576 men and 495,477 women) who were free of cancer at enrollment in 1982, there were 57,145 deaths from cancer during 16 years of follow-up. In both men and women, body-mass index was also significantly associated with higher rates of death due to cancer of the liver (in addition to the esophagus, colon and rectum, gallbladder, pancreas, and kidney).

Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studiedcohort of U.S. adults.N Engl J Med. 2003 Apr 24;348(17):1625-38. Slide 68Impact of Diabetes and Overweight on Liver Cancer Occurrence in CirrhosisIn this French study, a cohort of 771 patients with well-compensated alcohol- or HCV-related cirrhosis who were screened prospectively for HCC. At enrollment, the mean age was 61.4 +/- 10 years and 431 patients were men. Cirrhosis was caused by alcohol (n = 478), HCV (n = 220), or both factors (n = 73). The mean body mass index (BMI) was 25.4 kg/m(2) and 231 patients were diabetic. During a mean follow-up period of 4.2 +/- 3 years, 220 patients developed HCC. There was a positive linear relationship between BMI level and HCC incidence during follow-up evaluation (Kaplan Meier shown above). In multivariate analysis, predictive factors were a BMI between 25-30 kg/m(2) (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.4-2.7), BMI of 30 kg/m(2) or more (HR, 2.8; 95% CI, 2.0-4.0), diabetes (HR, 1.6; 95% CI, 1.2-2.1), age 60-70 years (HR, 2.4; 95% CI, 1.3-4.3), age older than 70 years (HR, 3.0; 95% CI, 1.7-5.5), male sex (HR, 2.0; 95% CI, 1.4-2.7), HCV (HR, 1.6; 95% CI, 1.1-2.2), and mixed (HR, 2.6; 95% CI, 1.7-4.0) etiology.

N'Kontchou G, Paries J, Htar MT, Ganne-Carrie N, Costentin L,Grando-Lemaire V, Trinchet JC, Beaugrand M. Risk factors for hepatocellular carcinoma in patients with alcoholic or viral Cirrhosis.Clin Gastroenterol Hepatol. 2006 Aug;4(8):1062-8. Slide 61Cancer and Insulin Resistance. In obesity, increased release from adipose tissue of free fatty acids (FFA), tumour-necrosis factor- (TNF) and resistin, and reduced release of adiponectin lead to the development of insulin resistance and compensatory, chronic hyperinsulinaemia (BOX 4). Increased insulin levels, in turn, lead to reduced liver synthesis and blood levels of insulin-like growth factor binding protein 1 (IGFBP1), and probably also reduce IGFBP1 synthesis locally in other tissues. Increased fasting levels of insulin in the plasma are generally also associated with reduced levels of IGFBP2 in the blood. This results in increased levels of bioavailable IGF1. Insulin and IGF1 signal through the insulin receptors (IRs) and IGF1 receptor (IGF1R), respectively, to promote cellular proliferation and inhibit apoptosis in many tissue types. These effects might contribute to tumorigenesis.These tumorigenic effects of insulin could be directly mediated by insulin receptors in the (pre)neoplastic target cells, or might be due to related changes in endogenous hormone metabolism, secondary to hyperinsulinaemia.Slide 79Screening / Surveillance for Hepatocellular CarcinomaSlide 86Cost-Effectiveness of HCC SurveillanceThere have been 3 studies that have evaluated whether screening for HCC is cost-effective. Two important points need to be highlighted about these studies. One, is that all of this studies have concentrated on patients with cirrhosis secondary to chronic hepatitis C. The other point is that all the studies evaluated the cost-effectiveness of the screening strategy of using alpha-fetoprotein (AFP) and hepatic ultrasonography (US).In the study by Sarasin and colleagues (Am J Med 1996;:), they evaluated the strategy of screening patients with compensated cirrhosis secondary to hepatitis C. They showed that surveillance with biannual AFP and US in child class A cirrhosis had cost-effectiveness ratios between $26,000 and $55,000 quality adjusted life years or QALY, depending on the availability of liver transplantation. It has been established that for a strategy to be cost-effective it has to be under $55,000, which is the acceptable cost-effectiveness of dialysis.There have been 2 other studies that have corroborated the findings. Therefore, the strategy of surveillance for HCC seems to be a cost-effective one.

Sarasin FP, et al. Am J Med 1996;101:422-434.Arguedas MR,et al. Am J Gastroenterol 2003;98679-690. Lin OS, et al. Aliment Pharmacol Ther 2004;19:1159-1172. Slide 91Alpha-fetoprotein Cross-Sectional StudiesThis slide reviews the largest case-controlled studies performed to evaluate the performance of AFP. All of the studies were performed in patients with cirrhosis.As can be seen, the cutoff of AFP that would maximize the sensitivity and specificity has been highly variable in the studies. The sensitivity has ranged from 25% to 65%, and the specificity ranges from 79% to 96%. This is considered suboptimal to be utilized as a screening test.The problems with these studies are the variable sample size, which limits the power of the studies, and that in all studies more than 80% of the cases (i.e., patients with HCC) had advanced stage. Because the goal of surveillance is the detection of small tumors, studying patients with advanced tumors would not be helpful towards reaching the goal.

Marrero JA. Clin Liver Dis. 2005;9:235-51.AFP, alpha-fetoprotein; HCC, hepatocellular carcinoma; PPV, positive predictive value.*AFP, alpha-fetoprotein; AFP-L3, lens culinaris agglutinin-reactive fraction of alpha-fetoprotein; DCP, des-gamma-carboxy prothrombin; HCC, hepatocellular carcinoma.*Slide 94Ultrasound in HCC in Cohort StudiesThis slide reviews the studies that have evaluated hepatic ultrasound (US) for the diagnosis of HCC.The overall pooled estimates are a sensitivity of 60.5%, a pooled specificity of 96%, and a positive likelihood ratio, the likelihood that a positive test leads to a diagnosis of HCC, of 17.7 (greater than 10 is considered excellent).However, only the studies by Chalasani and Tanaka were performed to evaluate the performance of US as a surveillance test. The others were to determine US as a diagnostic test.

Colli A, et al. Am J Gastro 2006;101(3):513.

HCC, hepatocellular carcinoma; NPV, negative predictive value; PPV, positive predictive value.*Slide 96HCC Doubling Time Rationale for Surveillance Every 6 MonthsThe interval for the performance of HCC surveillance has not been fully established. However, it has been estimated that the best interval for surveillance of HCC is every 6 months based on tumor doubling time. This slides shows a graph indicating the tumor doubling time of 9 patients in which the natural history was established. The observed tumor doubling time was indicated by the yellow circle, red triangle, purple x, green cross and light blue diamond. The expected doubling time is shown by the orange line and estimated to be around 180 days (ie 6 months). The observed doubling time for small tumors is shorter than larger tumors at baseline, so for diagnosing smaller tumors during surveillance an interval of 6 months seems to be the best time.

Taouli B, et al. J Comp Assist Tomogr 2005;29(4):425-9 HCC, hepatocellular carcinoma.*AASLD, American Association for the Study of Liver Diseases; AFP, alpha-fetoprotein; AP, alkaline phosphatase; NCCN, National Comprehensive Cancer Network.Slide 98Surveillance for HCC Improves Mortality A Randomized Controlled TrialThis slide shows the results of the randomized controlled study.The screening group had a larger number of cases compared to the control group, as well as a higher incidence rate. The rate ratio of HCC development was not statistically significant though there was a trend for a higher development of HCC in the screening group.There was a significant decrease in the number of HCC developed in the screening group versus the control group, with a reduced rate ratio of 0.63.

Zhang BH, et al. J Cancer Res Clin Oncol 2004;130:417-422.Slide 104Diagnosis of Hepatocellular CarcinomaSlide 105Clinical Features at PresentationThere are no specific symptoms associated with HCC. However, the symptoms that occur are as a result of liver disease and a space occupying mass in the right upper quadrant of the abdomen.Slide 112Guidelines for Diagnosis of HCCThis slide shows the recommended algorithm endorsed by the American Association for the Study of Liver Disease (AASLD) for the diagnosis of HCC.If the screening test in a cirrhotic patient is abnormal, then an evaluation for the diagnosis of HCC should be performed. Ultrasound and AFP are the recommended tests but the AFP should not be used alone. If the ultrasound shows a hepatic nodule < 1 cm, then US is recommended in 3-6 months.If the ultrasound shows a hepatic nodule between 1-2 cm, then a triple phase imaging that includes CT scan, MRI or contrast enhanced US should be performed. If 2 tests show typical features of HCC (arterially enhancing mass with washout of contrast in delayed phases), the diagnosis is confirmed. If atypical features appear on imaging, then biopsy is recommended.If the ultrasound shows a hepatic nodule > 2 cm, then a triple phase imaging is also recommended. Only 1 test is recommended for the diagnostic evaluation. If typical features appear on the imaging, then the diagnosis of HCC is confirmed. If atypical features are seen, then biopsy is recommended.

Bruix J, et al. Hepatology 2005; 42: 1208-1236.Slide 106Dual Blood Supply of LiverImaging is the best recall test for the diagnosis of HCC.However, t is important to remember that the liver has a dual blood supply, about 80% through the portal vein and about 20% through the hepatic artery. As the liver fibrosis progresses to cirrhosis and then towards cancer, the blood supply in the cirrhotic nodule changes from portal venous to arterial blood supply, a process called angiogenesis. (Yu JS, et al. Am J Roentgen 1999)Therefore, when performing computerized tomography (CT) or magnetic resonance imaging (MRI) it is important for the testing to be done with an arterial phase, portal venous phase and delayed phases. The next will show an example of a triple phase imaging.

Yu JS et al. Am J Roentgenol 1999;173:597-604.

Slide 107Triple Phase Imaging of Hepatocellular CarcinomaThis is a MRI of the liver.The left upper panel shows a precontrast examination indicating a cirrhotic-appearing liver with the presence of ascites.The right upper panel shows the arterial phase. The arrow shows an arterially enhancing lesion in the posterior right lobe.The left lower panel shows the portal venous phase, and at th is phase we can see the intrahepatic branches of the portal vein enhance and the enhancement of the aorta dimish. In this phase, the arterially enhancing lesion is not well visualized due lack of arterial enhacement (i.e., lack of arterial blood supply in the lesion) in this phase. If the MRI is performed without an arterial phase, this lesion would be missed.The right lower panel shows the 5 minute delayed phase. The location that corresponds to the arterially enhancing lesion now appears darker than the surrounding liver, a process called washout. This is delayed phase hypointensity of the mass compared to the surrounding liver, and this is an important feature of HCC.Slide 108Dynamic MRI Spiral CT for Diagnosis of HCCThere seems to be a controversy with regards to which is better: MRI or CT scans.This slide shows compared the performance characteristics of MRI and CT in patients with cirrhosis. The authors studied 45 patients who were listed for transplantation, and a CT and MRI examinations were performed within 6 weeks of each other and within 6 months of a transplant. A total of 18 patients had HCC at the time of explant examination, which was the gold standard for which CT and MRI were compared to. MRI had a better sensitivity, specificity, positive and negative predictive values compared to CT scan.Two other studies compared MRI versus CT, and MRI seems to be better at determining the diagnosis of HCC.

Burrel M, et al. Hepatology 2003;38:1034-1042.Krinski G, et al. Radiology 2001;219:445-454. Rode A, et al. J Comput Assist Tomogr 2001;25:327-336. Slide 104Diagnosis of Hepatocellular CarcinomaSlide 167Population-based Survival Estimates in the United States

Davila JA, El-Serag HB. Racial differences in survival of hepatocellular carcinoma in the United States: a population-based study. Clin Gastroenterol Hepatol. 2006 Jan;4(1):104-10.

Slide 166Key Concepts in the Management of Hepatocellular Cancer

Slide 166Key Concepts in the Management of Hepatocellular Cancer

Slide 234Management of Hepatocellular Carcinoma Requires a Multidisciplinary ApproachHCC, hepatocellular carcinoma.Slide 226Management of HCC in Patients with Cirrhosis

Slide 189Surgical Resection of HCC: Outcome in a US Cancer Center 611 pts were seen at Memorial Sloan Kettering with the diagnosis of HCC from 1990 to 2001.180 (30%) underwent hepatectomy and from a prospective database, 36 patients eligible for transplantation were identified.Demographic data, tumor characteristics, and patient outcome were analyzed.The 5-year overall survival in the 36 transplant-eligible patients who underwent resection was 69%.

Cha CH, Ruo L, Fong Y, Jarnagin WR, Shia J, Blumgart LH, DeMatteo RP. Resection of hepatocellular carcinoma in patients otherwise eligible for transplantation. Ann Surg. 2003; 238:315-21.

HCC, hepatocellular carcinoma; US, United States.HCC, hepatocellular carcinoma.Slide 227Outcomes of HCC Treatment: Observational Population-based studyThe cumulative 5-year survival in. 2,963 patients with HCC diagnosed between 1992 and 1999 and identified in SEER-Medicare datasets Patients were grouped into 4 groups depending on the type of therapy received. Median overall survival was 104 days following HCC diagnosis with the longest survival in the transplant group (852 days) and the shortest survival in the group with no treatment (58 days). In the survival analysis, transplantation led to the longest survival, followed by resection. Neither ablation nor TACE yielded prolonged survival (3 year survival was less than 10%).

El-Serag HB, Siegel AB, Davila JA, Shaib YH, Cayton-Woody M, McBride R, McGlynn KA. Treatment and outcomes of treating of hepatocellular carcinoma among Medicare recipients in the United States: a population-based study. J Hepatol. 2006 Jan;44(1):158-66. NCCN, National Comprehensive Cancer Network; PS, performance status; RT, radiotherapy.HCC, hepatocellular carcinoma.*AASLD, American Association for the Study of Liver Diseases; AFP, alpha-fetoprotein; AP, alkaline phosphatase; NCCN, National Comprehensive Cancer Network.Slide 12Temporal Trends in The Age Distribution of Hepatocellular CarcinomaThe age specific rates are shown per 5 year age groups. HCC is rare below age 40, increases progressively thereafter. As the incidence of HCC has increased in the United States (during 2000-02), the age distribution curve has shifted to the left indicting that younger persons are becoming progressively more affected. Persons between 45 and 65 have been disproportionately affected with HCC.

El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999 Mar 11;340(10):745-50. El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med. 2003 Nov 18;139(10):817-23.

*Slide 41HCC After IFN Therapy for HCVIn this Japanese retrospective cohort study, 419 consecutive patients with chronic hepatitis C who started interferon therapy between January 1992 and December 1993 (interferon group) and 144 patients with chronic hepatitis C who had liver biopsy between January 1986 and December 1989 and did not receive interferon (controls). Median follow-up in the interferon and control groups was 47.6 and 46.8 months, respectively. During follow-up, hepatocellular carcinoma was found in 28 interferon-treated patients and 19 controls. Cox proportional hazards regression analysis that included all patients revealed that interferon therapy (P=0.041), older age (P=0.003), greater histologic activity (P=0.029), and higher histologic stage (P=0.049) were independent factors associated with the development of hepatocellular carcinoma. The risk ratios for development of hepatocellular carcinoma in patients with sustained response, relapse, and nonresponse were 0.06 (95% CI, 0.01 to 0.46), 0.51 (CI, 0.20 to 1.27), and 0.95 (CI, 0.48 to 1.84), respectively, compared with controls. SR: Sustained response was defined as persistent normalization of alanine aminotransferase (ALT) levels during interferon therapy and follow-up. Relapse was defined as a normal serum ALT level at the end of treatment with an increase to an abnormal level after cessation of treatment.NR: Nonresponse included all other ALT patterns.

Imai Y, Kawata S, Tamura S, Yabuuchi I, Noda S, Inada M, Maeda Y, Shirai Y,Fukuzaki T, Kaji I, Ishikawa H, Matsuda Y, Nishikawa M, Seki K, Matsuzawa Y. Relation of interferon therapy and hepatocellular carcinoma in patients withchronic hepatitis C. Osaka Hepatocellular Carcinoma Prevention Study Group.Ann Intern Med. 1998 Jul 15;129(2):94-9.