Hepatocellular Carcinoma Diagnostic and Therapeutic Strategies Faisal Sanai Consultant Hepatologist Riyadh Military Hospital 10th International Advanced Medicine Symposium

Tumor Markers for HCC Des3  carboxy prothrombin. Alpha Fetoprotein. -l-Fucosidase. 5’- nucleotide phosphodiesterase. Des3  carboxy prothrombin. CA 19-9, CA 125, ALP. Alpha Fetoprotein. Fucosylated AFP.

Alpha Fetoprotein Sensitivity and Specificity Issues GI tumors: 10 – 20%. Cirrhosis: 40%. Acute and chronic hepatitis: 20%. Pregnancy. Gonadal tumors: 80%. Ethnicity. Etiology of liver disease. Treatment of underlying liver disease. Tumor staging. Sensitivity patterns for HCC vary widely: 32 – 93% Colli A, et al. Am J Gastro 2006.

Alpha Fetoprotein Change in HCC Detection by Changing Cut-off Points Diagnostic Criteria Sensitivity (%) Specificity (%) >615 ng/ml 56.4 96.4 >445 ng/ml 94.5 >100 ng/ml 72.6 70.9 >20 ng/ml 87.1 30.9 Poon TCW, Clin Liv Dis 2001

Diagnostic Yield of U/S Sensitivity in cirrhotic liver: 60%. Specificity: 97%. Colli A, et al. Am J Gastro 2006 Sensitivity for lesions 1 - 2 cm: 13%. Sensitivity for lesions 2 - 3 cm: 20%. Dodd G, et al. AJR 1992

CT Scan for HCC Diagnosis Diagnostic procedure of choice. Arterial phase CT is vastly superior to double phase scanning. The sensitivity of CT is much greater than ultrasonography (80% vs 60%). Chalasani N, et al. Am J Gastro 1999

The CT Modality of Choice Recent lipiodol studies have shown reduced sensitivities compared to initial reports. Reduced sensitivity compared to triple phase CT. Ngan H. Br J Radiol 1990 Nakayama A, et al. Ann Surg 2001 Earlier Report Recent Report Sensitivity 93 – 97% 78%

Angiography Does the Route Make Any Difference ? 109 patients with HCC. Sensitivity of angiographic interventions studied. CT Lipoidol – 80%. CT Portography – 84.4%. CT Angiography – 91.3%. CT portography revealed additional 15% lesions that had significant therapeutic alterations. Malagari K & Hadziyannis S. Hepatogastroenterology 1999

To Biopsy or Not to Biopsy… Pre-existing cirrhosis + mass >2 cm: >95% chance of HCC. Pre-existing cirrhosis + mass <2 cm: ≈ 75% chance of HCC. Frazer C J Gastro & Hepat 1999 Horigome H, et al J Gastro & Hepatol 1999 “Only where considerable doubt exists, will a biopsy of the lesion be required.” BSG Guidelines – Ryder SD, Gut 2003.

Needle Track Seeding Incidence of 1 - 2% for each biopsy attempt. Incidence lower with FNA than tru-cut. Needle track seeding converts curative resection to palliative. False-positive clinical/radiological diagnosis about 3%. 20% in HCC <3cm and low AFP Levy I, et al. Ann Surg 2001

Biopsy The Guidelines Lesions <1 cm should not be biopsied. Lesions 1 - 2 cm should have FNA + biopsy. Conclusions of EASL 2000, J Hepatol 2001 Bruix J, et al. AASLD Guidelines 2005 Lesions >2 cm should not be biopsied in presence of diagnostic clinical criteria. Abdo A, et al. Saudi Guidelines for HCC, Ann Saudi Med 2006

Setting Diagnostic Criteria Histological diagnosis. Presence of classic appearance in one imaging modality + AFP >400 µg/L + appropriate clinical setting. Presence of normal AFP + classic (>2 cm nodule, arterial vascularity) appearance in two imaging modalities + appropriate clinical setting. Saudi Guidelines for HCC, Ann Saudi Med 2006 Conclusions of EASL 2000, J Hepatol 2001

Surveillance and Recall Strategy for HCC Cirrhotic patients (US + AFP/6 m) Liver nodule No nodule 1 cm <1 cm Increased AFP* Normal AFP <2 cm >2 cm US/3m Spiral CT FNAB AFP 400 ng/mL CT/MRI/Angiography No HCC HCC** Surveillance US + AFP/6 m *AFP levels to be defined; **Pathological confirmation or non-invasive criteria

Decision making in HCC Treatment The status of the non-tumorous liver: Underlying cirrhosis. Non-cirrhotic liver (HBV). Size and extension of the tumour: Is it ≤5 cm in size/≤3 lesions ≤ 3 cm ? Vascular involvement. General condition of patient, the age and expected life expectancy.

Liver Transplantation for HCC HCC is the curative intervention of choice Survival: 75% at 5 years. Data comparable to non-HCC LT. HCC require priority listing for LT. Living Donor LT can be offered. Milan Criteria serve as threshold for LT option (single lesion < 5 cm; ≤ 3 in number, < 3 cm). Conclusions of EASL 2000, J Hepatol 2001 Saudi Guidelines for HCC, Ann Saudi Med 2006 Bruix J, et al. AASLD Guidelines 2005

Liver Transplantation for HCC Expanding the Milan Criteria UCSF Criteria: (single lesion < 6.5 cm; ≤ 3 in number, < 4.5 cm; combined diameter < 8cm) Survival Milan Criteria 94% 88% UCSF Criteria 90% Yao et al. Hepatology 2005, 197A

The Optimal Resection Candidate All non-cirrhotic patients with no extrahepatic spread (Western 5%, Asian 40%). When cirrhosis present - 30%: Child-Pugh class ‘A’. No portal HTN. Pr. gradient >10 mmHg Oesophageal varices Splenomegaly  plats <105 Patient is not a candidate for LT treatment. Solitary lesions <5 cm.

Resections Outcome Recurrence: Survival: Decompensation: 5 years >70%. Survival: 3 years: 38 - 65%. 5 years: 33 - 44%. Decompensation: 50%. Song TJ, et al. Gastroenterology 2004

Survival: 3 years, 391 patients, 1 lesion, <5 cm Local Ablative Therapies for HCC PEI: Livraghi T, et al., J Hepatol 1995 Survival: 3 years, 391 patients, 1 lesion, <5 cm Child - A Resection 79% (p <0.001) P E I 71% (p <0.001) No Treatment 26% Child - B 40% (p <0.01) 41% (p <0.001) 13%

Local Ablative Therapies for HCC Radiofrequency Ablation (Lencioni R et al, Radiology 2003) Randomized trial: RFA vs PEI. Child A or B in accordance with Milan criteria. Survival 1 year 2 years RFA 100% 98% p = 0.138 PEI 96% 88% 1 Year 89% 3 years 62% 5 years 33% Buscarini L et al., Eur Radiol 2001

Rationale for Embolization Therapy HCC blood supply >90% from hepatic artery. Normal liver 70 - 80% blood supply from portal vein. Breedis et al, Am J Pathol 1954 Occlusion of blood supply may cause tumor necrosis in up to 95% of lesion. Higuchi et al, Cancer 1994

Improved Survival with TACE Systematic review of 7 RCT comprising 545 patients. Llovet & Bruix, Hepatology 2003 (Chemo)embolization vs no treatment. Significant improvement in 2 year survival. Subanalysis showed significant benefit with chemoembolization but not with bland emolization. Small tumors, good liver reserve: TACE: 63% Bland: 50% Control: 27% Llovet et al, Lancet 2002

Guidelines Recommendation for TACE “The evidence for a survival benefit with TACE is sound and that this useful procedure should be used more often in the right clinical setting.” Saudi Guidelines for HCC, Ann Saudi Med 2006 “TACE is recommended as first line non-curative therapy for non-surgical patients with large/multifocal HCC who do not have vascular invasion or extrahepatic spread”. AASLD Practice Guidelines: HCC; Hepatology 2005

Approach in Non-Cirrhotic Patient No Cirrhosis Resection candidate Normal bilirubin No portal HTN No extra-hepatic spread Technically resectable Not Resection candidate Multifocal (>3) Lesion >4 cm Less than 3 lesions Smaller than 3 cm Resection TACE TACE Local ablation Saudi HCC Guidelines. Ann Saudi Med 2006

Approach in Child-Pugh ‘A’ Cirrhotic Child-Pugh Class A Timely transplant available Yes No ≤3 lesions each <3 cm 1 lesion <5 cm No extra hepatic spread Resection candidate Normal bilirubin No portal HTN No extra-hepatic spread Technically resectable Not Resection candidate Transplant Multifocal (>3) Lesion >4 cm Less than 3 lesions Smaller than 3 cm Resection TACE TACE Local ablation Local ablative therapy or TACE may be used while awaiting liver transplant Saudi HCC Guidelines. Ann Saudi Med 2006

Approach in Child-Pugh ‘B’ Cirrhotic Child-Pugh Class B Timely transplant available Yes No ≤3 lesions each <3 cm 1 lesion <5 cm No extra hepatic spread Multifocal (>3) Lesion >4 cm Less than 3 lesions Smaller than 3 cm Transplant TACE TACE Local ablation therapy Saudi HCC Guidelines. Ann Saudi Med 2006

Approach in Child-Pugh ‘C’ Cirrhotic Child-Pugh Class C Timely transplant available Yes No ≤3 lesions each <3 cm 1 lesion <5 cm No extra hepatic spread Good performance status <50 years old Poor performance status >50 years old Transplant Cirrhosis complication management Consider enrollment in systemic chemotherapy trials Cirrhosis complication management Palliative symptomatic treatment Saudi HCC Guidelines. Ann Saudi Med 2006

Summary HCC is essentially diagnosed by non-invasive criteria which is a combination of serology and imaging means. Liver biopsy is to be performed only where considerable doubt exists for the diagnosis Recent advances in ablative therapy (RFA) and improved survival with TACE are encouraging; that these should be used more frequently. LT remains the curative treatment of choice.

Saudi Gastroenterology Association Guidelines Diagnosis & Management of HCC Technical Review & Practice Recommendations www.saudiannals.net/SGAHCCguidelines/