Surveillance for HCC

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 ALT = alanineaminotransferase; HBV = hepatitis B virus; HCV = hepatitisC virus; LT = liver transplantation. 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.

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

6. Rationale for surveillance in HCC • 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 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.

7. Surveillance and mortality in HCC • 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 screening control 600 Cumulative mortality (per 100,000) 400 200 0 0 1 2 3 4 5 AFP = alfa-fetoprotein; HBV = hepatitis B virus; RCT = randomized controlled trial; US = ultrasound. Time (years) • Zhang BH, et al. J Cancer Res Clin Oncol. 2004;130:417-22.

8. Meta-analyses: ultrasound as a screening tool for HCC Specificity Sensitivity Sensitivity (95%CI) Specificity (95%CI) Study (year) Study (year) Sangiovanni 2006 Sangiovanni 2006 0.99 (0.92–1.00) 0.90 (0.84–0.95) Sangiovanni 2004 Sangiovanni 2004 0.98 (0.94–1.00) 0.85 (0.81–0.89) Bolondi 2001 Bolondi 2001 0.93 (0.84–0.98) 0.95 (0.91–0.97) Pateron 1994 Pateron 1994 0.79 (0.49–0.95) 0.96 (0.90–0.99) 0.75 (0.35–0.97) Kobayashi 1985 Kobayashi 1985 0.98 (0.92–1.00) 0.94 (0.83–0.98) Combined Combined 0.94 (0.89–0.97) Q = 25.48;df = 4.00;p = 0.0 Q = 29.72;df = 4.00;p = 0.0 I2 = 84.30 (71.63–96.98) I2 = 86.54 (76.09–96.99) 0.3 1.0 0.8 1.0 Specificity Sensitivity Singal A, et al. Aliment Pharmacol Ther. 2009:30;37-47.

9. Meta-analyses: ultrasound as a screening tool for HCC Sensitivity of ultrasound when only early HCCs were considered Sensitivity (95%CI) Study (year) Sangiovanni 2006 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) Sangiovanni 2004 Santagostino 2003 Bolondi 2001 Henrion 2000 Tradati 1998 Zoli 1996 Cottone 1994 Pateron 1994 Oka 1990 Arrigoni 1988 Kobayashi 1998 0.63 (0.49–0.76) Combined 0.0 1.0 Sensitivity Singal A, et al. Aliment Pharmacol Ther. 2009:30;37-47.

10. Diagnostic sensitivity of ultrasound in the early diagnosis of HCC in cirrhosis Ultrasound alone Ultrasound + AFP Study (year) Study (year) Sensitivity (95%CI) Sensitivity (95%CI) Sangiovanni 2006 Sangiovanni 2006 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) 0.50 (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) Sangiovanni 2004 Sangiovanni 2004 Santagostino 2003 Santagostino 2003 Bolondi 2001 Bolondi 2001 Henrion 2000 Henrion 2000 Tradati 1998 Tradati 1998 Zoli 1996 Zoli 1996 Cottone 1994 Cottone 1994 Pateron 1994 Pateron 1994 Oka 1990 Oka 1990 Arrigoni 1988 Arrigoni 1988 Kobayashi 1998 Kobayashi 1998 Combined 0.63 (0.49–0.76) Combined 0.69 (0.53–0.81) 0.0 1.0 0.0 1.0 Sensitivity Sensitivity AFP = alfa-fetoprotein. Singal A, et al. Aliment Pharmacol Ther. 2009:30;37-47.

11. Alfa-fetoprotein (AFP): a screening test for HCC: considerations • Combined use of AFP and ultrasound increases detection rates, but also increased costs and false-positive rates2 • AFP-only surveillance had a 5.0% false-positive rate, ultrasound alone had a 2.9% false-positive rate2 • In combination the false-positive rate was 7.5%2 • AFP is still considered an inadequate screening test for HCC1,3–5 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 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 declines2 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. Conclusions • Patients at risk of HCC – and amendable to treatment if the tumor develops – must be under regular surveillance1 • Recommeneded that surveillance is based on periodic ultrasound1 • Recommended that time interval is 6 months1 • Alfa-fetoprotein is still considered an inadequate screening test for HCC 2-4 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.