Screening for HCCwho, how and how often? Catherine Stedman Associate Professor of Medicine, University of Otago, Christchurch Gastroenterology Department, Christchurch Hospital
HCC Global Epidemiology 5 th most common cancer in world 3 rd cause of cancer-related mortality (WHO) Marrero et al. Hepatology 68;2:723-50
Natural history of HCC Cirrhosis- present in >80% of people with HCC Fateen J Hepatocellular carcinoma 2017:4;71-9
HCC screening: who?
Surveillance considerations. Level of risk for HCC (HCC incidence) Age Overall health & functional status Willingness and ability to comply with surveillance
AASLD: Patients at the highest risk for HCC and benefit from surveillance are those with cirrhosis Population Group Threshold Incidence for Efficacy of Surveillance (>0.25 LYG; % per year) Incidence of HCC Hepatitis C cirrhosis 1.5 3% 5% per year Hepatitis B Cirrhosis 0.2 1.5 3% 8% per year Stage 4 PBC 1.5 3% 5% per year Genetic hemochromatosis and cirrhosis Alpha 1 antitrypsin deficiency and cirrhosis 1.5 Unknown, but probably >1.5% per year 1.5 Unknown, but probably >1.5% per year Other cirrhosis 1.5 Unknown AASLD guideline Marrero et al Hepatol 2018;68(2):723
Does HCC Surveillance in cirrhosis work? Only one randomized trial- included people with or without cirrhosis
Does HCC Surveillance in cirrhosis work? Meta-analysis 47 studies that examined association of HCC surveillance with outcomes in 15,158 patients with cirrhosis who developed HCC HCC detected by surveillance in 41% Limitations: All non randomized cohort and casecontrol studies Subject to lead-time bias (but adjusted for this) Length-time bias Selection bias Most did not adjust for MELD Pooled odds results: With surveillance Without surveillance Early detection rates 70.9% 29.9% Curative treatment receipt 51.3% 23.8% Survival for 3 yrs 50.8% 28.2% Singal et al PLOS Medicine 2014;11(4):e1001624
Different views No association between screening for HCC and reduced cancer-related mortality in patients with cirrhosis VA case-matched control study 238 cases with cirrhosis who died from HCC with diagnosis of cirrhosis at least 4 yr prior Controls matched by yr of cirrhosis, race, ethnicity, age, sex, aetiology of cirrhosis, MELD, VA medical centre. Identified all USS/AFP within 4 yrs and indication for tests Results: No significant difference between cases and controls in proportion who underwent screening USS/AFP within 4 yrs Suggest screening might be more likely to identify slower growing tumours which have a lower stage Moon et al Gastroenterol 2018;155:1128-9
Different views No association between screening for HCC and reduced cancer-related mortality in patients with cirrhosis VA case-matched control study 238 cases with cirrhosis who died from HCC with diagnosis of cirrhosis at least 4 yr prior Controls matched by yr of cirrhosis, race, ethnicity, age,sex, aetiology of cirrhosis, MELD, VA medical centre. Identified all USS/AFP within 4 yrs and indication for tests Results: No significant difference between cases and controls in proportion who underwent screening USS/AFP within 4 yrs Suggest BUT it is screening now impossible might be to more do likely an HCC to surveillance identify slower RCT growing tumours which have a lower stage Moon et al Gastroenterol 2018;155:1128-9
Cost effectiveness of HCC surveillance Cost effectiveness depends on HCC incidence Effective interventions increase longevity by 100 days Cost effective interventions cost <$50,000/year of life gained Cirrhotics: Surveillance increased longevity by 3 months if incidence 1.5%, did not prolong survival if lower incidence (Sarasin et al Am J Med 1996;101:422) Surveillance with AFP & USS cost effective regardless of HCC incidence (Lin et al Aliment Pharmacol Ther 2004;19:1159) Non-cirrhotic HBV:? Cost effective for incidence>0.2%/yr AASLD guideline Marrero et al Hepatol 2018;68(2):723
Hepatitis C cirrhosis Most common cause of HCC in Western countries; incidence 2-8%/yr 20x increase in HCC risk Possible increase in non-cirrhotic HCV but <1%/year Successful DAA therapy reduces risk by 71% but ongoing risk persists (HCC reported up to 10 yr after SVR) Decision making must be based on pre-treatment fibrosis assessment Current recommendations are that all people with HCV-related cirrhosis should undergo ongoing surveillance indefinitely after SVR
Hepatitis C- what about F3 fibrosis? EASL- recommend surveillance in F3 AASLD say not cost effective (>1.5%/yr) NICE: surveillance for Fibroscan >10.5KPa Issues Non-invasive assessments are not perfect Some people with fibroscan 9.5-12.5 will be cirrhotic Increasing trend to look at two non-invasive markers to be sure
Cumulative incidence of HCC 65% cured 63% cured Christchurch Data: Hepatitis C subgroup analysis 332 patients with F3/F4 on USS surveillance 63% achieved SVR virological remission) (sustained Time to HCC Diagnosis 73% of all were cured with DAA (Directacting antiviral agents) Incidence rates similar in F3 and F4 cohorts Annual incidence 2.2% 75% of F3 HCC early stage compared to 72% of F4 HCC But cure rates 74% in F3 vs 40% in cirrhosis Years P = 0.6 (logrank) Lamba et al NZSGE 2016
Ioannou et al AASLD 2017 #142 Eradication of HCV Induced by DAAs is Associated With a Reduction in HCC Risk HCC incidence after any antiviral treatment by cirrhosis and SVR status 1.00 0.95 No cirrhosis SVR and HCC risk reduction (multivariable analysis): IFN only AHR 0.32 [95% CI 0.27 0.37] DAA + IFN AHR 0.21 [95% CI 0.13 0.32] DAA only AHR 0.21 [95% CI 0.09 0.53] 0.90 0.85 0.80 0.75 Cirrhosis + no SVR Cirrhosis + SVR No cirrhosis + no SVR No cirrhosis + SVR Cirrhosis Irrespective of cirrhosis status, SVR was associated with a 71% reduction in HCC risk (AHR 0.30, 95% CI 0.26 0.35) (Online HCC Risk Calculator being developed) 0 1 2 3 4 5 6 7 8 9 10
Hepatitis C-F3 fibrosis Overall guidelines vary in this group Important to look carefully at quality of liver fibroscan assessment, & other factors such as platelets or diabetes NZ HCV guidelines : Recommend surveillance if baseline fibroscan >10.5KPa Future directions: May include use of modelling to predict individual HCC risks more accurately in both cirrhotics with/without SVR and non-cirrhotics Ioannou et al J Hepatol 2018;69:1088-98
Hepatitis B Clear association with HCC HBV DNA integrates into host genome- associated with HCC risk even if not cirrhotic Risk factors that increase HCC risk in HBV: Persistent HBeAg and High HBV DNA Heavy smoking/alcohol (9x increase) Family history of HCC
HCC risk stratification scores in HBV REACH-B Age, gender HBV DNA, HBeAg Cutoff of 8 had 98% negative predictive value @ 10 yrs Developed in Asia primarily for treatment naïve noncirrhotic?suboptimal in Caucasians and in those on antivirals mreach-b CUHCC CAG-HCC LSM-HCC Liver stiffness replaces HBV DNA Cutoff of 10 + presence/absence cirrhosis LSM <8; 8-13; >13KPa Commenced antiviral during followup if required Performed better but needs further validation in untreated cohorts Jung Hepatology 2015; 62 (6): 1757
Validation of hepatitis B virus related hepatocellular carcinoma prediction models in the era of antiviral therapy It is telling that in the subgroup of 460 not on antiviral therapy, mreach B (model that does not use HBV DNA) performed as well as, if not better than, the models that did use HBV DNA in their models. - Editorial comment Receiver operating characteristic curves of the risk prediction models to predict HCC development at 3 (A) and 5 years (B), and Liver Related Event development at 3 (C) and at 5 years (D). Validation of hepatitis B virus related hepatocellular carcinoma prediction models in the era of antiviral therapy, Volume: 62, Issue: 6, Pages: 1757-1766, First published: 06 August 2015, DOI: (10.1002/hep.28115)
Chronic Hepatitis B on antiviral therapy HCC yearly incidence reduces between first 5 and second 5 years of treatment from 3.22 to 1.57%
J Hepatol 2016:64:800-6
J Hepatol 2016:64:800-6 EASL guidelines recommend HCC surveillance for Caucasians with intermediate (PAGE-B 10-17) and high risk (PAGE-B >18) J Hepatol 2018;69:182-236
Kim et al J Hepatol 2018;69:1066-73 Modified PAGE-B score predicts risk of HCC in Asians with chronic HBV on antiviral therapy 3000 Asian patients with CHB receiving antiviral therapy Assessed 5 scores plus developed modified PAGE-B
Kim et al J Hepatol 2018;69:1066-73
Or the AASLD approach HCC: Surveillance benefit in chronic hepatitis B Population Group Threshold Incidence for Efficacy of Surveillance (>0.25 LYG; % per year) Incidence of HCC HBV carriers with cirrhosis 0.2 1.5 3% 8% per year Asian male HBV carriers over age 40 Asian female HBV carriers over age 50 HBV carrier with family history of HCC African and/or North American blacks with HBV 0.2 0.4% 0.6% per year 0.2 0.3% 0.6% per year 0.2 Incidence higher than without family history 0.2 HCC occurs at a younger age
Non-cirrhotic Hepatitis B..my thoughts Untreated HBV (eg Hepatitis Foundation/Primary Care) REACH-B or mreach-b score probably best Threshold for surveillance REACH-B =8; mreach-b=10 Treated HBV (secondary care) Caucasians: PAGE-B Asians: Modified PAGE-B Surveillance for intermediate or high threshold (with intermediate group risk drops to 0.2% at 5 yrs) Plus Those with family history HCC Africans? At lower age Or pragmatic AASLD approach of just offering to Asians based on gender (Male>50 and female >40) But this ignores risks in other groups (eg Caucasians on treatment) and there is also a huge literature gap for Maori/Pacific Islander groups
HCC screening: how?
Ultrasound: both AASLD and EASL recommend 6 monthly USS USS is currently the only screening test recommended by regional liver societies for HCC surveillance Pooled sensitivity of USS only 63% for early HCC Performer variations and inter-rater reliability Patient factors including obesity and gaseous distension Tumor factors including location and echogenicity Factors related to background liver with heterogenous pattern in macronodular cirrhosis or severe steatosis Fateen J Hepatocellular carcinoma 2017:4;71-9 27% false positives Need to improve surveillance quality
Alpha-fetoprotein AFP is a strong predictor of future development of HCC Even low levels of AFP within normal range are strongly predictive AFP (ng/ml) HCV (n=44,007) Adjust Hazard Ratio) P-value 3.0 1 <0.001 >3.0-5.0 1.9 <0.001 >5.0-10.2 2.48 <0.001 >10.2-28.9 3.51 <0.001 >28.9 4.88 <0.001 Ioannou et al. PLOSone 2018;Sept27
AFP in HCC surveillance AFP is suboptimal as a serological test for surveillance Fluctuating levels in viral hepatitis Only elevated in 10-20% of early HCC When combined with USS may provide additional HCC detection in 6-8% of cases Viraemia control with antivirals/svr: AFP diagnostic accuracy improves but insufficient evidence to calculate cost effectiveness (EASL) EASL: - Addition of AFP in patients with active liver inflammation is not recommended AASLD: Recommend USS +/- AFP Recent meta-analysis suggests USS + AFP increases sensitivity for detection of early HCC by 18% But still controversial Tzartzeva et al Gastroenterol 2018;154:1706-18
HCC screening: how often? 6 monthly in both EASL and AASLD Guidelines
Impact of adherence to HCC surveillance guideline screening intervals French prospective ANRS CO12 CirVir cohort 1671 patients with viral cirrhosis undergoing HCC surveillance Analysis of 216 with HCC Association between compliance with HCC surveillance guidelines with: Early diagnosis Allocation of curative treatment Longer adjusted overall survival Adjusted overall survival 53.2 month vs 25.4 month. (HR for OS, 2.19; 95% CI 1.16-4.14 P=0.015) Costentin et al Gastroenterol 2018;155(2):431-2
When to stop surveillance Child Pugh C cirrhosis if not listed for transplantation When other comorbidities preclude treatment of HCC
Future directions. Diagnose those with cirrhosis or high risk non-cirrhotic HBV Ensure all appropriate people are offered HCC surveillance (<20% most studies)
Future directions for HCC screening Tailored risk-based strategies Incorporating known HCC risk factors coupled with emerging biomarkers that include germline single nuclear polymorphisms Different imaging-mri MRI for highest risk groups? MRI for patients with poor characteristics for USS? Potential new tests. Biomarkers e.g. AFP-L3% and des gamma carboxy prothrombin Next generation sequencing of common HCC mutations in plasma? Circulating tumor cells