Surveillance for Hepatocellular Carcinoma Hashem B. El-Serag, MD, MPH Dan L. Duncan Professor of Medicine Chief, Gastroenterology and Hepatology Houston VA & Baylor College of Medicine Houston, TX Outline Surveillance for HCC Who, how Diagnosis of HCC Surveillance for HCC in Practice October 2012 1
The Incidence and 5-Year Survival of HCC in United States idence rate per 100,0 000 Inci 6 5 4 3 2 1 AIR Survival 16.0% 14.0% 12.0% 10.0% 8.0% 6.0% 4.0% 2.0% 5-y year Survival 0 2007 2006 2005 2004 2003 2002 2001 2000 1999 1998 1997 1996 1995 1994 1993 1992 1991 1990 1989 1988 1987 1986 1985 1984 1983 1982 1981 1980 1979 1978 1977 1976 1975 1974 1973 Year of HCC Diagnosis 0.0% El-Serag HB. N Engl J Med 2011 Viral Hepatitis in HCC in the United States (N=691) 33% 15% 5% 47% HCV Both HBV Neither HBV most frequent in Asians HCV most frequent in whites and blacks October 2012 2
Malignant Transformation Multi-Step HCC Hepatitis C Hepatitis B Ethanol NASH Liver Cirrhosis Dysplastic Nodules Normal Liver Hepatocellular Carcinoma: Treatment HCC Very early stage 1 HCC <2 cm Carcinoma in situ Early stage 1 HCC or 3 nodules <3 cm, PS 0 Intermediate stage No portal vein thrombosis Multinodular, PS 0 Advanced stage Portal invasion Metastases, PS 0-2 Terminal stage 1 HCC 3 nodules <3 cm Portal pressure / bilirubin Associated diseases Normal Resection OLT PEI / RFA Potentially curative treatments El-Serag HB, et al. Gastroenterology 2008 Chemoembolization Palliative treatments Sorafenib Symptomatic Therapy October 2012 3
HCC Surveillance: Randomized Trials Cirrhosis (NONE) Hepatitis C infection (NONE) Hepatitis B infection (carriers) China Two trials One showed benefit One did not show benefit Surveillance for HCC Improves Mortality: A Randomized Controlled Trial Screened Group (AFP + US q 6 mo) Control Group Person-years F/U 38,444 41,077 HCC Occurrence HCC cases Incidence Rate Ratio Deaths from HCC Number Mortality Rate Rate Ratio 86 223.7 1.37 (0.99-1.89) 32 83.2 0.63 (0.41-0.90) 67 163.1 54 131.5 Zhang BH, et al. J Cancer Res Clin Oncol 2004;130:417 October 2012 4
Surveillance for HCC Reduces Mortality: A Randomized Controlled Trial of AFP+US q 6 months %) val Probability ( Survi.8.6.4.2 0 0 Control Screening 1 2 3 4 5 Time (Years) Zhang BH, et al. J Cancer Res Clin Oncol 2004 Population-based Study of AFP for Surveillance 1487 HBsAg positive 16 yr follow up 26,752 AFP determinations 32 developed HCC survival advantage compared to historical controls McMahon BJ, et al. Hepatology 2000 October 2012 5
Recommended Groups for HCC Surveillance Population Group Asian male hepatitis B carriers > age 40 Asian female hepatitis B carriers > age 50 Hepatitis B carrier with family history of HCC Threshold Incidence for Efficacy of Surveillance (>0.25 LYG)(%/year) Incidence of HCC (%/year) 0.2 0.4 0.6 0.2 0.3 0.6 0.2 Incidence higher than without family history African/North American Blacks 0.2 HCC occurs at a younger age Cirrhotic hepatitis B carriers 0.2-1.5 3 8 Hepatitis C cirrhosis 1.5 3 5 Sherman M. Semin Liver Dis. 2010;30(1):3-16. Groups in Whom the Risk of HCC is Increased, but in Whom Efficacy of Surveillance Has Not Been Demonstrated Population Group Threshold Incidence for Efficacy of Surveillance (>0.25 LYG)(%/year) Incidence of HCC (%/year) Hepatitis B carriers <40 (males) or 50 (females) 0.2 <0.2 Hepatitis C and stage 3 fibrosis 1.5 <1.5 Noncirrhotic NAFLD 1.5 <1.5 Sherman M. Semin Liver Dis. 2010;30(1):3-16. October 2012 6
Performance Characteristics of AFP Based on Cutoff Level 100 Sensitivity Specificity % 80 60 40 Cutoff 10-11 17-21 50 > 100 Studies 4 7 4 5 ng/ml Colli A, et al. Am J Gastro 2005 Combination (AFP, AFP-3, DCP) vs. AFP Alone HCV-related cirrhosis were followed up prospectively for two years (34 of 298 who were free of HCC at entry) Only AFP (>2 ng/ml): sensitivity, specificity, and positive and negative predictive values: 61, 71, 34 and 88% respectively Combination: 77, 59, 32 and 91% respectively Marginal improvement in surveillance for entry HCC Sterling RK et al. Clin Gastro Hep 2009 October 2012 7
Surveillance of HCC in HCV-cirrhsis: HALT C Trial (Lok AS, et al. Gastroenterology 2009) Timing in relation to HCC diagnosis DCP 40 mau/ml Sensitivity (%) Specificity (%) 0 74 86-6 63 88-12 43 94 AFP 20 ng/ml 0 61 81-6 57 76-12 47 75 DCP ± AFP 0 91 74-6 86 69-12 73 71 AFP only ALT levels 15 25 35 50 100 200 10 2.2% 3.7% 5.6% 4.0% 4.1% 5.1% 13.7% 15 2.7% 4.7% 9.4% 6.0% 6.1% 7.3% 14.1% 20 3.2% 5.6% 13.3% 8.1% 8.0% 8.7% 14.4% 25 3.7% 6.5% 17.1% 10.0% 9.9% 9.7% 14.6% 30 4.1% 7.3% 20.7% 11.9% 11.7% 10.6% 14.8% 50 5.5% 10.0% 32.6% 18.8% 17.6% 13.0% 15.2% AFP 75 7.0% 12.8% 42.7% 25.6% 23.3% 14.9% 15.5% 100 8.2% 15.1% 49.5% 31.0% 27.9% 16.3% 15.8% 150 12.4% 35.2% 67.3% 52.2% 47.5% 24.6% 18.4% 200 19.7% 66.4% 80.7% 69.9% 70.9% 44.3% 27.1% 250 26.9% 80.6% 87.1% 75.7% 79.8% 58.0% 37.8% 500 54.5% 97.1% 97.0% 84.7% 91.0% 72.1% 65.4% 1000 82.1% 99.8% 99.1% 91.5% 96.5% 77.5% 72.6% 2000 94.9% 100.0% 99.8% 95.7% 98.6% 82.3% 74.3% 4000 98.8% 100.0% 99.9% 97.7% 99.5% 86.6% 75.9% Richardson P et al CGH 2012 October 2012 8
Sensitivity of Ultrasound Surveillance in Early HCC: Systematic Review Study Sensitivity (95%CI) % Weight Pateron 1994 0.58 (0.37,0.84) 6.45 Kobayashi 1985 0.40(0.31,0.78) 0 5.10 Arrigoni 1988 0.69 (0.49,0.89) 9.60 Oka 1990 0.68 (0.54,0.81) 11.56 Cottone 1994 0.87 (0.77,0.96) 12.81 Zoli 1996 0.91 (0.84, 0.98) 13.41 Tradati 1998 0.33 (-0.11,0.78) 4.30 Henrion 2000 0.67 (0.38, 0.96) 7.16 Bolondi 2001 0.82 (0.73, 0.91) 13.03 Tong 2001 0.58 (0.41, 0.75) 10.47 Santa 2003 0.25 (0.62, 0.82) 4.93 Subtotal 0.63 (0.52, 0.82) 87.27 (I2=76.7%, p<0.0001) Singal A, et al. APT 2009 0 1.0 AFP improve detection to 70% Every 6 months significantly better than 12 months Ultrasound surveillance of HCC in cirrhosis: a randomized trial comparing 3- and 6-month Multicenter randomized trial in France and Belgium 1,278 Patients with compensated cirrhosis were randomized into US every 6 or 3 months At least one focal lesion was detected in 358 patients (28%) but HCC was confirmed in only 123 (9.6%) (uninodular 58.5%, 5% 30 mm in diameter 74%). US surveillance, performed every 3 months, detects more small focal lesions than US every 6 months, but does not improve detection of small HCC. Trinchet et al.; Hepatology 2011. October 2012 9
CT Scan, MRI for HCC Surveillance No evidence Pros: less operator dependent, more sensitive and specific for HCC diagnosis Cons: expensive, e, limited teda avaialbility, aab radiation, false positive, still operator/reader dependent Performance of Golgi Protein-73 Marrero JA, et al. J Hepatology 2005 October 2012 10
Identification of Osteopontin in HCC: HCV Shang S, et al. HEPATOLOGY 2012;55:483-490 Screening for HCC: AASLD Recommendations Surveillance for HCC should be performed with ultrasonography (level II) Screening should occur every 6 months intervals (level II) The surveillance interval does not need to be shortened for patients at higher risk of HCC (level III) Bruix J, et al. Hepatology 2010 October 2012 11
HCC Surveillance Recommendations The target population for surveillance are those with liver cirrhosis (and HBV-infected patients without cirrhosis Keep in AFP special in addition circumstances) to the US based surveillance US and AFP are the recommended screening tests for HCC in Only patients RCT at the used highest AFP risk + US Only US is central population based cohort used AFP Not Most AFP alone of the current community-based surveillance is AFP Premature to recommend dropping AFP AASLD Diagnostic Criteria for HCC Mass on surveillance ultrasound (US) in a cirrhotic liver <1 cm 1-2 cm >2 cm Repeat US every 3-4 mo Two dynamic imaging studies One dynamic imaging technique Stable >18-24 mo Enlarging Return to surveillance every 6-12 mo Proceed according to lesion size Coincidental typical vascular pattern Typical vascular pattern with 1 technique Diagnostic of HCC + Atypical vascular pattern with both techniques Biopsy Nondiagnostic of HCC Repeat biopsy or imaging i follow-up Change in size/profile Repeat imaging and/or biopsy Treat as HCC Adapted from Bruix J and Sherman M. Hepatology. 2005; 42(5):1208 Atypical vascular pattern Other diagnosis - Typical vascular pattern on dynamic imaging or AFP >200 ng/ml October 2012 12
Imaging criteria applied for confirming HCC in patients with cirrhosis and a nodule detected by ultrasound Lesion has nodular configuration Lesion is at least 1 cm in longest diameter* Lesion shows arterial hypervascularization: hyper-enhanced nodule in the arterial phase by two imaging techniques** hyper-enhanced nodule in the arterial phase and as hypoenhanced nodule in the portal venous or delayed phase by one imaging i technique** * Apply to lesions emerged during US surveillance. For lesions detected at first imaging examination, lesion diameter should be at least 2 cm to allow non-invasive diagnosis of HCC. ** Imaging techniques include: contrast-enhanced US, contrast-enhanced spiral CT, and gadolinium-enhanced MRI Washout in HCC Arterial phase 2-min delayed Arterial phase 5-min delayed October 2012 13
Prevention of HCC (HCC Surveillance) Efficacy in Clinical Trials and Research Centers Effectiveness in Community Practice El-Serag HB. et al. Gastroenterology. 2007;132:8-10. Efficacy x Access x Correct Diagnosis x Recommendation x Acceptance x Adherence Efficacy and Effectiveness A Demonstration of the Multiplicative Effect of Factors Example 1: Example 2: Example 3: Rx X Rx Y Rx X Modified Efficacy of Rx X 60% Efficacy of Rx X 80% Efficacy of Rx X 60% Access x 80% Correct diagnosis x 85% Access x 80% Correct diagnosis x 85% Access x 90% Correct diagnosis x 90% Recommend x 85% Acceptance x 85% Adherence x 70% Recommend x 85% Acceptance x 85% Adherence x 70% Recommend x 90% Acceptance x 90% Adherence x 80% Effectiveness of Rx X = 21% Effectiveness of Rx Y = 28% Effectiveness of Rx X modified = 32% El-Serag HB. Gastroenterology. 2007;132:8-10. October 2012 14
HCC Surveillance in 14,837 HCV- Infected Veterans with Cirrhosis (1997-2007) AFP or ultrasound tests for n (%) HCC surveillance Routine surveillance 12.0 Inconsistent surveillance 55.9 No surveillance 32.1 1-year following cirrhosis diagnosis date 42.0 2-years 33.8 3-years 34.7 4-years 35.6 Davila J, et al. Ann Intern Med; 2011 HCC Screening in Non VA SEER-Medicare 3,903 Medicare patients with HCC (1998-2005) 57% received at least one screening test during the 3-years prior to HCC diagnosis - 65% AFP only, 22% US only, 13% both 6.6% received regular screening 1 screening test per year during 2 or the 3 years prior to HCC screening More likey to be done by specialists Davila J, et al. Hepatology 2010 October 2012 15
Is HCC Screening Effective? The pieces are present: Increasing fatal disease HCV mainly, insulin resistance?future High risk population: liver cirrhosis (and HBV-infected patients) OK tests: US and AFP Recall strategy available (imaging, biopsy) Treatment available: curative and palliative The whole thing? Is HCC Surveillance Effective? Where it Breaks Down Identification of high risk groups Cirrhosis is missed in PC Counseling for Surveillance Patient agreement Contraindications Performing Surveillance More than once Recall strategy Diagnosis and Treatment October 2012 16
HCC Surveillance: Performance Measure Performance Measure Possible but not likely (intermediate evidence) Numerator: ultrasound in the past one year Denominator: patients with risk factors Exceptions: patient refusal, Child C not candidate for transplant Summary What Should be Done What is Being Done Why? What Could be Done How? October 2012 17