1. Surveillance for HCC

2. Surveillance in cancer Definition: Repeated application of a test over time with the aim of reducing disease-specific mortality Criteria: 1. Common disease with substantial morbidity and mortality 2. Identification of the target population 3. An acceptable screening test with low morbidity and high diagnostic accuracy 4. Well-defined recall strategy 5. Effective therapy at diagnosis Bruix J, Sherman M. Hepatology. 2011;53:1020-2. Prorok PC. Am J Pediatr Hematol Oncol. 1992;14:117-28.

3. Groups of patients for whom surveillance Is recommended GuidelinesChronic hepatitis B or C Cirrhosis EASL 1 HBV: not specified HCV: histological transition to cirrhosis Child–Pugh A & B Child–Pugh C if LT available AASLD 2 HBV: ALT + DNA + HBV carriers: males > 40 y Asian females > 50 y family history of HCC African/North American Blacks >20 y All etiologies JSH 3 Increasing risk: sex, age, alcohol Very high risk: HBV/HCV 1. Bruix J. et al J Hepatol. 2001;35:421-30. 2. Bruix J, Sherman M. Hepatology. 2010. 2011;53:1020-2. 3. JSH Clinical Practice Guidelines for HCC: Makuuchi M, et al. Hepatol Res. 2008;38:37-51. ALT = alanine aminotransferase; HBV = hepatitis B virus; HCV = hepatitisC virus; LT = liver transplantation.

4. Ultrasound in HCC surveillance AASLD guidelines recommend: 1. Surveillance for HCC should be performed using ultrasound 2. Patients should be screened at 6 months interval 3. The surveillance interval does not need to be shortened for patients at higher risk of HCC Ultrasound has been reported to have a sensitivity of between 65% and 80%, and a specificity greater than 90% when used as screening test Bruix J, Sherman M. Hepatology. 2011;53:1020-2.

5. AASLD PRACTICE GUIDELINE 2011: Surveillance and diagnosis Bruix J, Sherman M. Hepatology. 2011;53:1020-2 AASLD PRACTICE GUIDELINE 2011: http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/HCCUpdate2010.pdf Arterial hypervascularity AND venous or delayed phase washout Other contrast enhanced study (CT or MRI) Arterial hypervascularity AND venous or delayed phase washout 4-phase MDCT / dynamic contrast enhanced MRI > 1 cm Biopsy No Yes HCC Suspected HCC < 1 cm Repeat US at 3 months Investigate according to size Growing / changing character Stable

6. Bruix J, Sherman M. Hepatology. 2011;53:1020-2. Arguedas MR, et al. Am J Gastroenterol. 2003;98:679-90. Sarasin FP, et al. Am J Med 1996;101:422–34. McMahon BJ, et al. Hepatology 2000;32:842–6. Wong LL, et al. Liver Transpl. 2000;6:320–5. A prerequisite of cost-effectiveness: disease frequency in the target population should be sufficiently high; annual incidence should be: –in the target population: > 0.2% –for HCC surveillance in liver cirrhosis: > 1.5% Several cost-effectiveness models for HCC have proven that HCC surveillance is cost-effective Uncontrolled studies have suggested that survival is improved after surveillance, but results are affected by lead-time and length biases –lead time bias: unless properly controlled, studies of surveillance will show enhanced survival, simply because the cancer is diagnosed at an earlier stage –length bias: is the apparent improved survival that occurs because surveillance preferentially detects slow-growing cancers More randomized, controlled trials are needed Rationale for surveillance in HCC

7. Surveillance and mortality in HCC Zhang BH, et al. J Cancer Res Clin Oncol. 2004;130:417-22. There is a single RCT of surveillance vs no surveillance 18,816 HBV-positive patients recruited in China Surveillance by US every 6 months + AFP vs no surveillance Adherence to surveillance was suboptimal (< 60%) HCC-related mortality was reduced by 37% in the surveillance arm 800 600 400 200 0 0 12345 Time (years) screening control Cumulative mortality (per 100,000) AFP = alfa-fetoprotein; HBV = hepatitis B virus; RCT = randomized controlled trial; US = ultrasound.

8. Meta-analyses: ultrasound as a screening tool for HCC Singal A, et al. Aliment Pharmacol Ther. 2009:30;37-47. Study (year) Sangiovanni 2006 Sangiovanni 2004 Bolondi 2001 Pateron 1994 Kobayashi 1985 Combined Q = 25.48;df = 4.00;p = 0.0 I 2 = 84.30 (71.63–96.98) 0.3 Sensitivity 1.0 0.94 (0.83–0.98) 0.75 (0.35–0.97) 0.79 (0.49–0.95) 0.99 (0.92–1.00) 0.93 (0.84–0.98) 0.98 (0.94–1.00) Sensitivity (95%CI) Study (year) Sangiovanni 2006 Sangiovanni 2004 Bolondi 2001 Pateron 1994 Kobayashi 1985 Combined Q = 29.72;df = 4.00;p = 0.0 I 2 = 86.54 (76.09–96.99) Specificity (95%CI) 0.90 (0.84–0.95) 0.85 (0.81–0.89) 0.95 (0.91–0.97) 0.98 (0.92–1.00) 0.96 (0.90–0.99) 0.94 (0.89–0.97) 0.8 Specificity 1.0 Sensitivity Specificity

9. Sensitivity of ultrasound when only early HCCs were considered Singal A, et al. Aliment Pharmacol Ther. 2009:30;37-47. Meta-analyses: ultrasound as a screening tool for HCC Sangiovanni 2004 Sangiovanni 2006 Santagostino 2003 Bolondi 2001 Henrion 2000 Tradati 1998 Zoli 1996 Cottone 1994 Pateron 1994 Oka 1990 Arrigoni 1988 Kobayashi 1998 Combined 0.0 Sensitivity 1.0 Study (year) Sensitivity (95%CI) 0.50 (0.38–0.62) 0.50 (0.41–0.60) 0.25 (0.03–0.65) 0.82 (0.70–0.91) 0.67 (0.22–0.96) 0.33 (0.04–0.78) 0.91 (0.76–0.98) 0.87 (0.69–0.96) 0.23 (0.05–0.54) 0.68 (0.51–0.81) 0.69 (0.41–0.89) 0.50 (0.16–0.84) 0.63 (0.49–0.76)

10. Diagnostic sensitivity of ultrasound in the early diagnosis of HCC in cirrhosis Singal A, et al. Aliment Pharmacol Ther. 2009:30;37-47. Ultrasound alone Combined Kobayashi 1998 Arrigoni 1988 Oka 1990 Henrion 2000 Pateron 1994 Cottone 1994 Zoli 1996 Tradati 1998 Bolondi 2001 Santagostino 2003 Sangiovanni 2004 Sangiovanni 2006 0.0 Study (year) 1.0 Sensitivity Sensitivity (95%CI) 0.50 (0.38–0.62) 0.50 (0.41–0.60) 0.25 (0.03–0.65) 0.82 (0.70–0.91) 0.67 (0.22–0.96) 0.33 (0.04–0.78) 0.91 (0.76–0.98) 0.87 (0.69–0.96) 0.23 (0.05–0.54) 0.68 (0.51–0.81) 0.69 (0.41–0.89) 0.50 (0.16–0.84) 0.63 (0.49–0.76) 0.01.0 Combined Kobayashi 1998 Arrigoni 1988 Oka 1990 Henrion 2000 Pateron 1994 Cottone 1994 Zoli 1996 Tradati 1998 Bolondi 2001 Santagostino 2003 Sangiovanni 2004 Sangiovanni 2006 Study (year) 0.50 (0.38–0.62) 0.50 (0.41–0.60) 0.25 (0.03–0.65) 0.82 (0.70–0.91) 1.00 (0.54–1.00) 0.33 (0.04–0.78) 0.91 (0.76–0.98) 0.87 (0.69–0.96) 0.38 (0.14–0.68) 0.80 (0.64–0.91) 0.75 (0.48–0.93) 0.50 (0.16–0.84) 0.69 (0.53–0.81) Sensitivity Sensitivity (95%CI) Ultrasound + AFP AFP = alfa-fetoprotein.

11. Combined use of AFP and ultrasound increases detection rates, but also increased costs and false-positive rates 2 AFP-only surveillance had a 5.0% false-positive rate, ultrasound alone had a 2.9% false-positive rate 2 In combination the false-positive rate was 7.5% 2 AFP is still considered an inadequate screening test for HCC 1,3–5 Alfa-fetoprotein (AFP): a screening test for HCC: considerations 1. Bruix J, Sherman M. Hepatology. 2011;53:1020-2. 2. Zhang B, Yang B. J Med Screen. 1999;6:108-110. 3. Trevisani F, et al. J Hepatol. 2001;34:570-5. 4. Sherman M. J Hepatol. 2001;34:603-5. 5. Forner A, et al. Gastroenterology. 2009;137:26-9. AFP = alfa-fetoprotein.

12. Studies comparing diagnostic accuracy and outcome of surveillance with different screening intervals StudyDesign Intervals (months) Screening outcome Santagostino 2003 1 (Milan, Italy) Multicenter comparative 559 hemophiliacs HCV+ 6 vs 12 No differences in detection of early cancer Jan 2006 2 (Taipei, Taiwan) Community-based RCT 4,180 with mixed risks 6 vs 12 No differences in early cancer detection and mortality rates Trinchet 2007 3 (Bondy, France) Multicenter RCT 1,190 cirrhotics HCV/EtoH 3 vs 6No differences in detection. More false-positives in the 3-month arm 1. Santogostino E, et al. Blood. 2003;102:78-82. 2. Jan CF. J Hepatol. 2006;44(suppl 2):S4. 3. Trinchet J-C, et al. Presented at ILCA 2007, Barcelona 5–7 October. HCV = hepatitis C virus; RCT = randomized controlled trial.

13. Surveillance challenges Over-diagnosis: detection of cancers that would not have come to clinical attention in the patient’s lifetime had surveillance not taken place (pseudo-disease) 1 Treatment applicability and results decrease as liver function declines 2 1. Black WC, et al. N Engl J Med. 1993;328:1237-43. 2. Trevisani F, et al. Am J Gastroenterol. 2002;97:734-44.

14. Patients at risk of HCC – and amendable to treatment if the tumor develops – must be under regular surveillance 1 Recommeneded that surveillance is based on periodic ultrasound 1 Recommended that time interval is 6 months 1 Alfa-fetoprotein is still considered an inadequate screening test for HCC 2-4 Conclusions 1. Bruix J, Sherman M. Hepatology. 2010. 2011;53:1020-2. 2. Trevisani F, et al. J Hepatol. 2001;34:570-5. 3. Sherman M. J Hepatol. 2001;34:603-5. 4. Forner A, et al. Gastroenterology. 2009;137:26-9.