HEPATOCELLULAR CARCINOMA Screening and Diagnosis. Objectives

Transcription

1 HEPATOCELLULAR CARCINOMA Screening and Diagnosis Richard K. Sterling, MD, MSc, FACG Professor of Medicine Chief, Section of Hepatology Virginia Commonwealth University Richmond, VA Objectives Definitions Who is the population at risk How often to screen and with what tools Why screen (Impact on survival) Diagnosis Where do we go from here October

2 Epidemiology of HCC HCC is the most common primary liver cancer 87-98% occur in patients with cirrhosis of any cause Estimated incidence of 2-8 %/yr Increased risk DM, obesity, male Rate is increasing 300% since % Definitions Screening Application of a diagnostic test in patients at risk for HCC, but in whom there is no a priori reason the suspect HCC is present. Surveillance The continuous monitoring of disease occurrence (using the screening test) Enhanced follow-up Additional testing (CT or MRI) to confirm or refute a diagnosis of HCC Shorten interval October

3 Who is the population at risk? Cirrhosis HCV HBV Alcohol NASH HHC A-1-AT AT PBC AIH PSC Hepatitis B Cirrhosis is not needed Asian males > 40 yrs Asian females > 50 yrs Africans > 20 yrs Family history of HCC ThosewithhighHBV high DNA AASLD Guidelines 2011 Surveillance: How often and with what? Interval 6-12 months is based on tumor doubling time US + biomarkers US alone Every 6 months US + biomarkers US every 6-12 months Biomarker every 3-6 months CT every 6-12 months (not recommended) October

4 Imaging for HCC Ultrasound Sensitivity 58-89% 89% Specificity >90% CT Sensitivity 28-88% Specificity >90% MRI Sensitivity % Specificity >95% Ideal Bio-Marker Specific for HCC Negative in those with cirrhosis i Sensitive at an early stage Easily measurable Reproducible Minimally invasive Acceptable Cost October

5 AFP AFP-L3% DCP (PIVKA II) Glypican-3 (GPC-3) Golgi protein 73 (GP-73) Biomarkers AFP Identified in 1963 Polypeptide glycoprotein 600 aminoacids MW ~ 70,000 Da Synthesized on long arm of chromosome 4 Major serum protein in fetal life Synthesized in visceral endoderm and fetal liver Levels fall to < 10 ng/ml shortly before birth Elevated levels in adults can be seen in germ cell tumors and in chronic liver disease (often correlates with increased ALT) No correlation with stage October

6 AFP Sensitivity: 39-64% depends d on cut off value Often elevated in chronic hepatitis Specificity: 76-91% ng/ml Sensitivity Specificity AFP-L3% Fucosylated variant of AFP High affinity to the sugar chain to Lens Culinaris- agglutinin (LCA) More specific for HCC than total AFP levels > 10% Libasys system - FDA approved - Total AFP and AFP-L3% Associated with stage of HCC October

7 HCC incidence by time course 50.0% 45.0% 40.0% HCC incidence: % 35.0% 30.0% 25.0% 20.0% 15.0% p= % 50% 5.0% 0.0% Months AFP-L3% Positive AFP Positive Analysis group; HCC: G2, No HCC: G3 (N = 332) Positive: AFPL3% > 10% AFP > 20 ng/ml Sterling et al. AJG Not all HCC make all biomarkers Patient number of AFP-L3%, DCP and AFP in those with HCC (n=685) AFP > 20 DCP > AFP-L3% > 10 Toyoda et al. Clin Gastro and Hep 2006;4: (23%) all negative October

8 Baseline Biomarkers Baseline Variable No HCC (N=809) HCC (N=46) p Total AFP ng/ml 14.7(31.5) 24.2(32.6).07 % AFP 20 ng/ml % AFP 50 ng/ml DCP mau/ml 26.9(152.3) 25.1(32.5).94 % DCP 40 mau/ml % DCP 90 mau/ml % DCP 150 mau/ml % AFP L3 > 10% Sterling et al. AJG 2012 Frequency of AFP, DCP, and AFP-L3 elevations in controls and HCC cases AFP 20 AFP 50 AFP 200 AFP 20 & 2x mean prev yr AFP L3% 10% AFP 20 & AFP L3% 10% 27% 12% 2% 15% 15% 9% 20% 4% 17% 37% 41% 54% No HCC HCC DCP 40 DCP 90 DCP 150 DCP 90 & 2x mean prev yr 15% 26% 24% 41% 50% 57% 70% 85% AFP 20 & DCP 90 AFP 20 & DCP 90 & AFP L3% 10% 1% 8% 13% 28% 0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% Percent of Patients Many patients without HCC also had increased biomarkers October

9 Predictors of Elevated Biomarkers at Mo 36 DCP 90 mau/ml HCC (by M48) 14.9% (108/724) OR 95%CI p Treatment Female Black PLT Albumin <.001 AST ALP INR Predictors of Elevated Biomarkers at Mo 36 DCP 90 mau/ml AFP 20 ng/ml HCC (by M48) 14.9% (108/724) 20.4%(148/724) OR 95%CI p OR 95% CI p Treatment Female <.0001 Black PLT <.0001 Albumin <.001 AST <.0001 ALP INR October

10 Performance of elevated AFP-L3 or combination of biomarkers during months 37 to 48 in predicting HCC during months 37 to 60 No HCC Sen Spec PPV NPV AUC P HCC % % % % AFPL3 10 % AFP 20 &DCP 40 AFP 20 & L3>10% AFP 20& L3 10% & DCP < < <.0001 Utility when biomarkers are used in combination: False Positives False Positive AFP: 25% AFP-L3%: 7% DCP: 9% AFP-L3% 15 (3.7%) True Negative 258 (64%) 26 (6.5%) 3 (0.7%) 2 (0.5%) 7 (1.7%) 9 (2.2%) 81(20.2%) DCP N = 401 Wako Data from North American Study AFP October

11 Future Use of Serum Markers AFP DCP AFP-L3% Others Diagnostic Criteria for HCC EASL 2012 Histologic (gold standard) Non-invasive i Focal lesion > 2 cm with arterial hypervascularization on two imaging techniques Focal lesion 1-2 cm with arterial hypervascularization on 2 imaging i modalities Note: AFP is no longer required October

12 What if you find something? AASLD and EASL Guidelines Mass on US in a cirrhotic liver < 1 cm 1-2 cm > 2 cm Size counts Bruix and Sherman 2011 EASL J Hep 2012 Mass < 1 cm Repeat US in 3-4 months (enhanced surveillance) No change over months Enlarging mass Resume routine Surveillance q 6-12 mo Additional imaging CT or MRI October

13 Mass 1-2 cm 4 phase dynamic CT or MRI Arterial enhancement and Venous washout on 2 techniques Atypical appearance or typical vascular pattern on only 1 study Presumed HCC Consider biopsy Risk of seeding < 2% Mass > 2 cm CT or MRI Atypical pattern Consider biopsy Typical pattern Arterial enhancement Venous washout No HCC HCC Follow with repeat imaging October

14 Why: Impact of Surveillance Detect HCC at an earlier stage Improve outcomes Randomized controlled trial of screening for HCC* Zhang et al. J Cancer Res Clin Oncol 2004;130: Stage Survival 50 % 40 % I II III < 5cm Screen Control Year Screen Control * 18,816 Chinese patients with chronic HBV age Surveillance = AFP and US q 6 months October

15 Impact of Surveillance on Stage Toyoda et al. Clin Gastro and Hep 2006;4: % 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Center (565) PCP (485) None (591) Surveillance 1641 patients with HCC from referred to a single center 20% HBV, 56% HCV, mean age 64, 75% male Stage 4 Stage 3 Stage 2 Stage 1 Impact of Surveillance on Survival Toyoda et al. Clin Gastro and Hep 2006;4:1170 Survival % Center vs. PCP and None: p<.0001 PCP vs. None: p< Years after diagnosis Center PCP None October

16 Surveillance of HCC in Patients with HCV Improves Survival Tanaka et al. Liver International 2006;26: * * * * Surveillance Yes (182) No (202) 10 0 Size Single 3 yr 5 yr Child (mm) % A % Survival * p <.001 Child B/C Quality of Surveillance vs. HCC Tumor Stage at Diagnosis Percent of Patients HCC Tumor Stage Stage 1 Stage 2 Std of Care Substandard Unrecognized Cx Quality of Surveillance Stravitz et al. Amer J Med 2008 October

17 1.0 Quality of Surveillance vs. Survival after HCC Diagnosis.8.6 Mean 3-Year Survival val Survi Years Std of Care: 40% -Substandard: 27% -Unrecognized Cx: 13%* * = p <.005, survival of C vs. A or B, by Cox regression Stravitz et al. Amer J Med 2008 Quality of Surveillance vs. Access to Liver Transplantation and Loco-regional Therapy 100% Percent of Patients 80% 60% 40% 20% No treatment* LRT without OLT OLT* *p <.001 by Chi square, standard of care vs. unrecognized Cx 0% Std of Care Substandard Unrecognized Cx Quality of Surveillance Stravitz et al. Amer J Med 2008 October

18 Where do we go from here? Screen/Surveillance New Mass on US Elevated AFP/L3%/DCP Biomarker panel HCC CT/MRI No HCC Refer to Transplant Center AFP-L3%, DCP, and others in combination Enhanced f/u Routine Conclusions The annual risk of HCC is 2-8% All patients at risk should be in surveillance All patients at risk should be in surveillance All patients with cirrhosis Patients with HBV with high risk Surveillance includes imaging (+ biomarkers) Every 6 months Surveillance picks up HCC at earlier stage Surveillance picks up HCC at earlier stage Increased treatment options (OLT, RFA, TACE) Improved survival Sorafenib for advance disease in compensated cirrhosis October

19 Take Home Message You need to look for HCC before it looks for you! Discovery Comes to the Prepared Mind October

20 Thank you for your attention October