Hashem B El-Serag, MD, MPH Dan L Duncan Professor of Medicine -CPRIT HCC.pdf · Hepatocellular...
Transcript of Hashem B El-Serag, MD, MPH Dan L Duncan Professor of Medicine -CPRIT HCC.pdf · Hepatocellular...
Hepatocellular Carcinoma: Epidemiology
and PreventionHashem B El-Serag, MD, MPH
Dan L Duncan Professor of MedicineChief, Gastroenterology and Hepatology
Baylor College of MedicineHouston, Texas
USA
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Year of HCC Diagnosis
AIR Survival
The Incidence and 5-Year Survival of HCC in United States
El-Serag HB. N Engl J Med 2011
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Temporal Trends in Age-Adjusted Incidence Rates of HCC by Race
1975-771993-952005-07
Ramirez AG, et al PLoS One. 2012
HCC Incidence Rates are Higher in Latinos > non LatinosAmong Latinos, HCC is highest in Texas esp southern counties
Ramirez AG, et al PLoS One. 2012
Age Distribution of HCC in Latinos: A Shift to the Left
Overall age adjusted incidence rate8.9 cases per 100,000 (95% 8.5-9.3)
Cirrhosis and HCCCirrhosis and HCC
Multiple smallfoci of HCCMultiple smallfoci of HCC
HCV Cirrhosis and HCC
HCV is the Dominant Risk Factors for HCC in the United States
• HBV most frequent in Asians
• HCV most frequent in whites and blacks
(N=691)
HCV InfectionHCV Infection
Chronic Hepatitis Chronic Hepatitis
CirrhosisCirrhosis
HCCHCC1%1%
(1%-3%/year)(1%-3%/year)
100100
25years
25years
90%90%(60%- 95%)(60%- 95%)
15%15%(10%- 30%)(10%- 30%)
HCV to HCC PyramidHCV to HCC Pyramid
Goodgame B, et al., Am J Gastroenterol 2003Goodgame B, et al., Am J Gastroenterol 2003
HCV-related Cirrhosis by Cohort
0
200,000
400,000
600,000
800,000
1,000,000
1,200,000
1950 1960 1970 1980 1990 2000 2010 2020 2030
Year
Cirrhosis Male >50Cirrhosis Male 31-50Cirrhosis Male <30Cirrhosis Female >50Cirrhosis Female 31-50Cirrhosis Female <30
Num
ber o
f Per
sons
Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings L (submitted for publication).
Risk Factors for HCC in Chronic HCV
Risk Factors for HCC in Chronic HCV
Older age Duration of HCV infection Male sex Race Alcoholism Obesity Diabetes HBV co-infection HIV co-infection ABSENCE OF TREATMENT
Older age Duration of HCV infection Male sex Race Alcoholism Obesity Diabetes HBV co-infection HIV co-infection ABSENCE OF TREATMENT
100%
20%
10%
Diagnosisand treatment
Cure
All HCVpatients
PEG-IFN/RBV
100%
20%
95% SVR
19%
100%
90%
85%
95% SVR and higher rates of diagnosis/treatment
Highly Efficacious Treatments Are Not Enough
Veldt, Heathcote, Wedemeyer et al., Ann Inn Med 2007
Sustained Response to Interferon Therapy:HCCs still occur
Non‐SVR
SVR
In Whom?• Age• Cirrhosis
? Role:• Etoh• MetSynd
CDC and USPSTF Recommendations for HCV Screening
• Regardless of risk factors, one-time testing for HCV of adults born between 1945–19651,2
– Testing of persons of all ages at risk for HCV infection
• CDC also recommends for those identified withHCV infection1
– Brief alcohol screening and intervention as clinically indicated
– Referral to appropriate care and treatment services for HCV infection and related conditions
Centers for Disease Control and Prevention (CDC). MMWR. 2012;61(4):1-18Moyer VA; on behalf of the U.S. Preventive Services Task Force. Ann Intern Med. 2013;159(1):51-60.
Globesity
2006
Diet
Obesity
InsulinResistance
NAFLD
NASH
CirrhosisDiabetes
High BPHigh TGLow HDL
Relative Risk of Malignancies in individuals with BMI > 35 (compared to BMI < 25)
0 1 2 3 4 5
All Cancers
Kidney
MM
Colon
Esophagus
Stomach
Pancrease
Liver
RR = 4.52
Calle EE, et al. NEJM 2003 (data basd on 900,000+ Men and Women)
Obesity and Risk of HCC: A Critical Look
• Most—but not all—studies suggest a modestincrease in the relative risk of HCC in obese persons
• Systematic review of 10 cohort studies – positive association between BMI and risk of HCC in 7
studies (relative risks ranging from 1.4 to 4.1)– no association in 2 studies– inverse association in 1 study
• Limitations: small number of HCC cases, misclassification, inconsistent adjustment for confounders
Saunders D, et al. APT 2010
Distal vs. Proximal Associations
• Proximal associations• Understand cancer pathogenesis in
general• May help in diagnosis, prevention
and treatment
ObesityDiabetes HCC
Abdominal FatHumoral MechanismsNAFLD?NASH
A high waist-to-hip ratio (WHR) conferred a 3-fold higher HCC risk to subjects in the upper tertile of WHR > those in the lowest tertile. (Aleksandrova K et al Hepatology 2014)
Does it make “epidemiological” sense?
• Abdominal obesity more likely–Caucasians more than
African Americans –Men more than
women
Inflammatory and Metabolic Biomarkers and Risk of Liver and Biliary Tract Cancer
Aleksandrova et al. Hepatology 2014
DiabetesN=173,643DiabetesN=173,643
No Diabetes N=650,620No Diabetes N=650,620
P<0.0001
Diabetes Is Associated with a Two-fold Increase in Risk of HCC: A Cohort Study in US Veterans
Diabetes Is Associated with a Two-fold Increase in Risk of HCC: A Cohort Study in US Veterans
El-Serag HB, et al, Gastroenterology 2004El-Serag HB, et al, Gastroenterology 2004
Years of Follow upYears of Follow up00 22 44 66 88 1010 1212 1414
HC
C R
ate
(%)
HC
C R
ate
(%)
0.250.25
0.200.20
0.150.15
0.100.10
0.050.05
0.000.00
Diabetes Is Associated with a Two-fold Increase in Risk of HCC
Diabetes Is Associated with a Two-fold Increase in Risk of HCC
Risk of HCC in Patients with Diabetes Mellitus: a Meta-analysis of Cohort Studies
• A total of 25 cohort studies– 18 studies showed that DM was associated
with an increased incidence of HCC• SRRs = 2.01, 95% CI: 1.61-2.51
– Independent of geographic location, alcohol consumption, history of cirrhosis, HBV or HCV
– Risk factors of HCC among diabetics are unclear
Wang C et al., Int J Cancer 2012
Diet
Obesity
InsulinResistance
NAFLD
NASH
CirrhosisDiabetes
High BPHigh TGLow HDL
Steatosis
Fatty liver +
inflammation +
liver injury
Fibrosis and nodular
regeneration
NAFLD PrevalenceDallas Heart Study
NAFLD PrevalenceDallas Heart Study
Study cohort(~1100 African Americans, 700 Caucasians, 400
Hispanics)
Study cohort(~1100 African Americans, 700 Caucasians, 400
Hispanics)
H1-NMR spectroscopyH1-NMR spectroscopy
Assess risk factors for fatty liver
Assess risk factors for fatty liver
No risk factors(n = 375)
No risk factors(n = 375)
Define normalliver fat contentDefine normal
liver fat content
Assess prevalence of increased liver fat (steatosis)in entire population & ethnic subgroups
Assess prevalence of increased liver fat (steatosis)in entire population & ethnic subgroups
Browning, et al., Hepatology 2004; 40:1387Browning, et al., Hepatology 2004; 40:1387
HispanicsHispanics WhitesWhites BlacksBlacks
45%45%
33%33%24%24%
Fatty liverFatty liver
Prevalence of Hepatic SteatosisVaries with Ethnicity
Prevalence of Hepatic SteatosisVaries with Ethnicity
Prevalence of Hepatic Steatosis: Varies with EthnicityPrevalence of Hepatic Steatosis: Varies with Ethnicity
Browning, et al., Hepatology 2004; 40:1387Browning, et al., Hepatology 2004; 40:1387
NAFLD and Risk of HCC
• No evidence from population based data• Possible increase in HCC risk in clinic based cohorts of
NASH– ? Magnitude– ? Risk factors
• Consistent evidence from clinic based cohorts with NAFLD/NASH cirrhosis– Magnitude < HCV cirrhosis
White D, Kanwal F, El-Serag. Clin Gastro Hep 2012
HCC in the Absence of Cirrhosis inUnited States Veterans
• ~13% of 1500 HCC cases developed in absence of cirrhosis
• These cases were more likely than HCC in cirrhosis to have
– NAFLD or idiopathic compared to HCV or alcohol
– Co-morbidities associated with metabolic syndrome
• While a small proportion, this poses logistical problems for HCC surveillance
El-Serag HB et al. DDW 2014 Mittal S et al DDW 2014
Prevalence in general population
Risk estimate of HCC
Population attributable fraction
HBV 0.5-1% 20-25 5-10%HCV 1-2% 20-25 20-25%Alcoholic liver disease
10-15% 2-3 20-30%
Metabolic syndrome
30-40% 1.5-2.5 30-40%
Prevalence, Relative Risk Estimates, and Population Attributable Fraction
Obesity/DiabetesPopulation Attributable Fraction (PAF)
PAF calculation includes excess fraction• differences between cancer risk in obese and
non-obese irrespective of the presence of other cofactors
PAF does not consider etiological fraction• differences between the groups limited to cases
caused solely by obesity (which may be much smaller)
PAF calculations do not account for time lag between acquiring obesity/diabetes and developing HCC
Temporal Trends of HCC by Major Risk Factors in National VA System in the US
Mittal S et al., Clin Gastroenterol Hepatol 2015
Prevention of HCC
• HBV vaccination• Treatment of viral hepatitis• Screening and surveillance for
HCC• ?? Statins, metformin, coffee,
weight loss
Zhang H et al. Scand J Gastroenetrol 2013
Metformin and Reduced Risk of HCC in Diabetic Patients: a Meta-analysis
• Seven studies: – Three cohort studies
– Four case-control studies
• Significantly reduced risk of HCC in metformin users versus nonusers in diabetic patients – RR: 0.24, 95% CI 0.13–0.46, p < 0.001
Statins and Risk of HCC
Adjusted OR for Any Statin Use was 0.63 (95% CI: 0.54,0.73)
Singh S, et al Gastroenterology 2009
Statins and HCCSystematic Review
• Ten studies– 7 observational, 3 clinical trials
• Pooled OR: 0.63 (0.52-0.76) – Not in the 3 clinical trials
• Not other lipid lowering medications• Unclear
– Dose, duration, type
• Epidemiologic studies: coffee consumption is inversely related to – Serum liver enzyme activity– Liver cirrhosis– HCC
• For each additional 1 cup of coffee:– Case-control studies
• (0.77, 0.72-0.83) – Cohort studies
• (0.75, 0.65-0.85)
Coffee and Hepatocellular Carcinoma
Metabolic Syndrome and HCCWhich Came First? the Chicken or the Egg
Cross Sectional Studies XCase-Control Studies X
HCC Screening Level II- Evidence
• Several non-randomized trials and observational cohort and case–control studies reported
• Patients who undergo HCC surveillance via US and serum AFP tests are significantly more likely than patients found to have symptomatic HCC – diagnosed with early-stage HCC – receive curative therapy– lower cancer-specific mortality
Surveillance for HCC
• Recommendations– Ultrasound and serum biomarker (AFP) in patients
with cirrhosis every 6 months• Limitations
– Effectiveness not examined in US– Poor performance of AFP esp if used alone– Limited implementation in practice
Many at-risk patients are not identified prior to HCC presentation
Singal et al, Cancer Prevent Research 2012Singal et al, Cancer Prevent Research 2012
Surv
ey R
epon
ses
Refused treatmentDid not f/u with clinician
Received treatmentClinician did not recommend
treatmentUnaware of diagnosis
Reasons for Lack of Treatment Among Respondents to the NHANES Hepatitis C
Follow-Up QuestionnaireN = 133
Abbreviation: NHANES, National Health and Nutrition Evaluation Survey.Volk ML, et al. Hepatology. 2009;50:1750-1755.
REACH‐B Model• 60 year‐old HBeAg+ male ALT
47, HBV DNA 50,000• REACH‐B score=13
Variable Data ScoreSex M/F 0‐2
Age Q 5 yearsover 30 0‐6
ALT<1515‐44>45
0‐2
HBeAg +/‐ 0‐2
HBV DNA
Und.~104~105~106>106
0‐4
yearsYang HI. Lancet Oncol 2011; 12: 568–74
%
Source: Gastroenterology 2012; 142:1264-1273.e1
Alcohol and Viral Hepatitis
Obesity and HCC EpidemiologySummary
• Relative risk of HCC is modestly elevated in obese and diabetic persons but the absolute risk is low.– Weak/modest causal association
• Factors influencing HCC risk among obese person are unclear.– Abdominal obesity– Early onset/ long duration
• Factors that influence HCC risk among diabetics are unclear– Type 2 diabetes– Long duration– Not treated with metformin– ???? Alcohol
• Proximal associations include inflammatory mechanisms, NAFLD/NASH, others– The possibility of obesity related HCC developing in non‐cirrhotic liver
• Obesity/diabetes related HCC has not translated (yet) into a large burden
Patients with NASH are Significantly Less Likely to Have Recognized Liver Disease
Variable Adjusted Odds Ratio
Viral etiology 3.60 (1.31 – 9.94)NAFLD etiology 0.12 (0.02 – 0.74)Hepatic decompensation 2.23 (0.88 – 5.61)Bilirubin level 1.05 (0.91 – 1.21)Platelet count 1.00 (0.99 – 1.00)
Singal et al, Cancer Prevent Research 2012Singal et al, Cancer Prevent Research 2012
18% of patients with NASH had recognized liver disease87% of patients with viral liver disease had recognized liver disease65% of remaining patients had recognized liver disease
Principal InvestigatorsThe Texas Hepatocellular Carcinoma Consortium (THCCC)
ADMINISTRATIVE CORE
Hashem B. El‐Serag, MD, MPHBaylor College of Medicine
COHORTS & SAMPLES CORE (CSC)
Jorge Marrero, M.D.UT Southwestern
STATISTICAL COORDINATING CORE (SCC)
Ziding Feng, PhDMD Anderson Cancer Center
PROJECT 1
Fasiha Kanwal, MD, MSHSBaylor College of Medicine
PROJECT 2
Hashem B. El‐Serag, MD, MPHBaylor College of Medicine
PROJECT 3
David Moore, PhDBaylor College of Medicine
PROJECT 4
Laura Beretta, PhDMD Anderson Cancer Center
PROJECT 5
Amit Singal, MDUT Southerwestern
Our overarching goal is to reduce the burden and mortality of HCC in Texas. • multidisciplinary group of investigators with vast experience and
expertise in HCC research. • researchers from UT Southwestern Medical Center and Parkland Health
and Hospital System in Dallas, Baylor College of Medicine and MD Anderson in Houston, and UT San Antonio
• inclusion of sites all across Texas will enrich the diversity and representativeness of our patients, ensuring a racially and ethnically diverse cohort with a wide range of socioeconomic status.
• critical gaps and needs in the HCC prevention process and appropriate ways to address them
Overview of THCCC
Aim 1: To examine the risk of HCC in NAFLD patients in all Texas VA centers
Aim 2: To identify predictors of HCC in NAFLD. We will assess the role of demographic (e.g., age, race) and metabolic traits (e.g., diabetes, obesity, dyslipidemia, hypertension diagnoses and biomarkers like hemoglobin A1c) in the development of HCC in NAFLD patients.
Aim 3: To determine the chemopreventive effect of common treatments in NAFLD including metformin and statins and the risk of HCC among patients with NAFLD.
Project 1: Risk Factors of Hepatocellular Carcinoma in Non‐Alcoholic Fatty Liver Disease
(PI: Fasiha Kanwal)
Aim 1: Examine the Association between Metabolic Syndrome and HCC Risk in Cirrhosis.
Gross and molecular phenotype, genotype
Aim 2: Develop and optimize an index for predicting the risk of progression from cirrhosis to HCC using a set of candidate factors derived from the literature, Aim 1 or uncovered by other THCCC projects.
Project 2: Metabolic Syndrome and HCC Risk Stratification in Patients with Cirrhosis
(PI: Hashem El‐Serag)
Aim 1: Test the ability of the CAR inverse agonist androstanol to prevent tumorigenesis in wild type mice in response to chronically elevated bile acids and jet lag.
Aim 2: Test the ability of human specific CAR activators to promote hepatocarcinogenesis in humanized mice.
Aim 3: Determine whether elevated serum bile acids or circadian disruption increase risk of human HCC.
Project 3: Circadian Disruption and Bile Acids as HCC Risk Factors
(PI: David Moore)
Aim 1: To evaluate the ability of novel HCC biomarkers to distinguish between patients with cirrhosis but no HCC and patients with cirrhosis and HCC in a surveillance setting
Aim 2: To evaluate the performance of AFP, AFP‐L3, DCP, OPN and selected panel from Aim 1 in detecting HCC during surveillance: A Phase‐3 Validation Study
Aim 3: Genomic classification of the incident HCC tumors and association between novel biomarkers, somatic mutations and HCC subtypes
Project 4: Novel Biomarkers For Hepatocellular Carcinoma (PI: Laura Beretta)
Aim 1: Compare the clinical effectiveness of the intervention strategies to increase completion of the HCC surveillance process
Aim 2: Compare patient‐reported satisfaction and acceptability of the HCC surveillance strategies
Aim 3: Evaluate whether intervention effects are moderated by patient sex, race/ethnicity, socioeconomic status, health care utilization, and documented vs. unrecognized cirrhosis
Project 5: A Comparative Effectiveness Randomized Controlled Trial of Strategies to Increase
HCC Surveillance Timeline (PI: Amit Singal)
• Hashem El‐Serag, MD, MPH (Baylor)• Laura Beretta, PhD (MDACC)• Ziding Feng, PhD (MDACC)• David Moore, MD (Baylor)• Jorge Marrero, MD (UTSW)• Amit Singal, MD (UTSW)• Fasiha Kanwal, MD (Baylor)
Risk Assessment
PrimaryPrevention
Detection Diagnosis CancerTreatment
Identify at‐risk patients
Primary prevention
HCC surveillance
HCC detection
Follow‐up abnormal result
• Lou Ann Fang (Baylor)• D Bessig (Baylor)• Fred Porddad (UTSA)
Summary
• HCC is the fastest rising cause of cancer related deaths in the US
• Hispanics are the group most affected with the increase in HCC
• Hepatitis C (and possibly NAFLD) are the main reasons for HCC in Hispanics
• Texas has one of the highest HCC incidence rates in US, and high prevalence of people with HCC risk factors