Hepatocellular Carcinoma: Epidemiology and Screening W. Ray Kim, MD Professor and Chief Gastroenterology and Hepatology Stanford University School of Medicine
Case A 67 year old Filipino-American woman presents with abnormal liver tests. HBV infection for 20 years. Undetectable HBV DNA: No HBV therapy BMI 32. Diabetes for 5 years under control with metformin. ALT 57 U/L, Bilirubin 0.9 mg/dl, Albumin 3.4 g/dl Ultrasound: slight nodularity and increased echogenicity (fat?) Which of the following is true regarding her risk of HCC? 1. Patients with undetectable HBV DNA carry the same risk as subjects without HBV infection. 2. She meets the NCI criteria for HCC surveillance. 3. Controlled diabetes does not increase the risk of HCC. 4. Non-alcoholic fatty liver disease is an important reason for rising incidence of HCC in the US.
Case A 67 year old Filipino-American woman presents with abnormal liver tests. HBV infection for 20 years. Undetectable HBV DNA: No HBV therapy BMI 32. Diabetes for 5 years under control with metformin. ALT 57 U/L, Bilirubin 0.9 mg/dl, Albumin 3.4 g/dl Ultrasound: slight nodularity and increased echogenicity (fat?) Which of the following is true regarding her risk of HCC? 1. Patients with undetectable HBV DNA carry the same risk as subjects without HBV infection. 2. She meets the NCI criteria for HCC surveillance. 3. Controlled diabetes does not increase the risk of HCC. 4. Non-alcoholic fatty liver disease is an important reason for rising incidence of HCC in the US.
Global Incidence of HCC 35 Age-Standardized Incidence per 100,000 30 25 20 15 10 5 Males Females 0 IARC. GLOBOCAN 2012. http://globocan.iarc.fr. 4
Incidence of HCC in the US SEER data: Cancer registry (reported to National Cancer Institute) Includes 10 geographic areas representative of entire US 5 states (Connecticut, Hawaii, Iowa, New Mexico, Utah) 5 metro (Seattle, SF Bay, LA, Detroit, Atlanta) represents 14% of the US population 98% case ascertainment 78-86% of cases had histologic or cytologic diagnosis No information about underlying liver disease El-Serag, NEJM 1999;745, El-Serag, Annals 2003;817
HCC data in SEER Cancer Incidence and Mortality in the US
Regional Variations in HCC Mortality Mortality Rate / 100,000 Age-Adjusted 5.24 to 6.12 (6) 4.49 to 5.24 (5) 4.28 to 4.49 (5) 4.09 to 4.28 (5) 3.94 to 4.09 (5) 3.75 to 3.94 (6) 3.50 to 3.75 (5) 3.19 to 3.50 (5) 2.74 to 3.19 (5) 2.21 to 2.74 (4) Sparse Data (0) El-Serag, Gastroenterology 2004
Median age=63 Age Distribution of Incident HCC in the US
Characteristics of Incident HCC Cases
SEER Data HCC Incidence in the US
12 10 Incidence of HCC in Olmsted County Women Men Total 10.9 8 6 5.6 5.4 6.8 4 2 3.5 3.5 2.2 1.9 3.8 0 1976-1990 1991-2000 2001-2008 * * IRR=1.87, p=0.01 in comparison to 1991-2000
Patient Characteristics HCC in Olmsted County, MN 1976-1990 (n=30) 1991-2000 (n=26) 2001-2008 (n=47) Age 63.5 60.7 69.4 White% 93% 85% 75% HCV 0% 23% 45% HBV 10% 4% 4% EtOH 43% 35% 36% Unknown cause 33% 42% 17%
UNOS Waitlist Registration 10 9 8 7 6 5 4 3 2 1 0 HCV HCV all HCV HCC HCV ESLD 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 4 3 2 1 0 NASH NASH all NASH HCC NASH ESLD 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Prevention of HCC Primary Tertiary Secondary
Which of the following is true? Quiz 1. Randomized controlled trials have shown that screening of HCC saves lives. 2. Serum alpha feto protein has no prognostic role. 3. Because of poor sensitivity, ultrasound is not used for HCC screening. 4. More frequent surveillance is needed for patients at high risk. 5. All of above
Which of the following is true? Quiz 1. Randomized controlled trials have shown that screening of HCC saves lives. 2. Serum alpha feto protein has no prognostic role. 3. Because of poor sensitivity, ultrasound is not used for HCC screening. 4. More frequent surveillance is needed for patients at high risk. 5. All of above
Surveillance for HCC Goals of Cancer Screening The goal is to reduce mortality. Early case detection may not be good enough. Survival (from the time of diagnosis) is not an adequate endpoint (lead-time bias). Natural history of screen-detected cancers not identical to that of clinically detected cancers (length bias) J Natl Cancer Inst 2001
HCC Surveillance Improves Mortality Randomized trial: US+AFP q6m vs. no intervention up to 5 years 19,200 patients with HBsAg+ or history of chr. hepatitis Suboptimal adherence: 58% (median 5 testing per pt) Surveillance No Surveillance N 9373 9443 Person-years 38,444 41,077 Mean age at entry 42 41 # HCC diagnosed 86* 67 # of Deaths 32 54 Rate (per 100K) 83.2 131.5 Rate ratio 0.63 (0.41-0.98) Zhang. J Cancer Res Clin Oncol 2004;417 * includes 17 prevalent cases
National Cancer Institute PDQ (Physician Data Query) Summary Benefits Screening would not result in a decrease in mortality from hepatocellular cancer. Study Design: Randomized controlled trials. Internal Validity: Fair. Consistency: Multiple studies, large number of participants. External Validity: Fair. Harms Screening would result in rare but serious side effects. Study Design: Randomized controlled trials and observational studies. Internal Validity: Fair. Consistency: Multiple studies, large number of participants. External Validity: Good. www.cancer.gov
HBV+ Asian M>40y Asian F>50y African > 20y Family history of HCC AASLD Recommendations Cirrhosis - HBV, HCV - PBC - Genetic hemochromatosis - A1ATD - Other Surveillance for HCC should be performed with US. (II) Surveillance interval: 6 months (II) No shortening of interval in patients at higher risk (III) Bruix & Sherman. Hepatology 2010
Liver Stiffness and HCC Risk Meta-analysis of 9 studies All viral hepatitis LSM (transient elastography) Overall: 11% increase in HCC risk per 1 kpa increase in LSM Cirrhotic patients: Each 1 kpa increase in LSM increased HCC risk by 4% Singh. CGH 2013;11:1574
Incidence of HCC on Transplant Waitlist Incidence of HCC on Transplant Waitlist (UNOS data, 02-11) Incidence of de novo HCC on UNOS waitlist (new exception score) 1,960 new HCCs (6%) in 34,932 registrants Flemming. Cancer 2014;120:3485
Surveillance Testing Ultrasound Sensitivity: 65-80% Specificity: >90% Operator-dependent Suboptimal in obese patients Alpha fetoprotein Not elevated in up to 40% of HCC AFP alone should not be used unless ultrasound is not available May not add much to US unless low quality Bruix. Hepatology 2005;42:1208
HCC Surveillance: The Big Picture Disease HCC Incidence Hepatic decompensation Patient Demographics Comorbidity Healthcare Availability of Transplantation Competing Programs Medical and Value Decision