Natural History and Staging System for HCC

Child–Pugh scoring system Points 1 2 3 Encephalopathy (grade) None 1–2 3–4 Ascites Slight Moderate Albumin (g/dL) >3.5 2.8–3.5 <2.8 Prothrombin time prolonged (sec) or INR <4 <1.7 4–6 1.7-2.3 >6 >2.3 Bilirubin (mg/dL) <2 2–3 >3 for primary biliary cirrhosis 4–10 >10 Class A: 5–6 points Class B: 7–9 points Class C: 10–15 points Pugh RN, et al. Br J Surg. 1973 ;60: 646-649; Riley TR et al. Am Fam Physician 2001; 64: 1555-60 2

Natural history and prognostic indicators for survival in Cirrhotic Patients Markedly longer survival in patients with compensated cirrhosis vs those with decompensated cirrhosis Median survival Compensated cirrhosis: > 12 years Decompensated cirrhosis: ~ 2 years 1 year risk D’Amico G, et al. J Hepatology. 2006;44:217-231 3 3

Probability of survival (%) Natural history and prognostic indicators for survival in Cirrhotic Patients 100 80 60 40 20 100 75 50 25 Compensated cirrhosis n=806 Survival (%) 1 yr 2 yr 1 yr 2 yr 1 yr 2 yr Child–Pugh A Child–Pugh B Child–Pugh C Probability of survival (%) 100 80 60 40 20 Survival (%) Decompensated cirrhosis n=843 0 12 24 36 48 60 72 84 96 108 120 1 yr 2 yr 1 yr 2 yr Months Compensated Decompensated Compensated cirrhosis: absence of jaundice, ascites, portal-systemic encephalopathy or variceal bleeding D’Amico G, et al. J Hepatology. 2006;44:217-231

Liver cirrhosis: Prognosis by stage Classification system proposed at the Baveno V workshop1 Compensated Decompensated 8–12% 10–20% 4–6% 5–8% 6–15% 7–10% Ascites Bleeding Ascites Bleeding No varices No varices Varices Varices Bleeding Bleeding Ascites Ascites DEATH DEATH ~30% 26% 10–15% 3–5% 1% STAGE 1 STAGE 1 STAGE 2 STAGE 2 STAGE 3 STAGE 3 STAGE 4 STAGE 4 STAGE 5 STAGE 5 Sepsis Renal failure Sepsis Renal failure STAGE 6 ? N% = expected 1-year outcome rates 1. de Franchis R [Editor]. Portal Hypertension V: Proceedings of the Fifth Baveno International Consensus Workshop, 5th Ed. 2010 5

Survival rates among untreated patients with unresectable HCC Meta-analysis of patients included in the placebo or no-treatment arms of 30 randomized controlled trials (n=1927) Survival rates highly heterogeneous Shorter survival for: Impaired PS CP-B or -C Presence of PVT 6 1. Cabibbo G et al. Hepatology 2010:51:1274-1283; 2. Cabibbo G et al. Hep Med Evidence Res2010:2;163-73.

The TNM staging system Advantage of TMN in HCC Stage Tumor Node Metastases I T1 N0 M0 II T2 IIIA T3 IIIB T4 IIIC Any T N1 IV Any N M1 M = metastases; N = node; T = tumor. Advantage of TMN in HCC The TNM system and the simplified TNM system are used in many cancers, and therefore there is familiarity with the system1 Commonly used in the USA in HCC patients1 Widely tested in the surgical HCC population2 1.Bruix J, Sherman M. Hepatology. 2011;53:1020-2. 2. Pons F, et al. HPB (Oxford). 2005;7:35-41. 3. Kee K, et al. Int J Cancer. 2007;120:2650-2655. 7

The TNM staging system Disadvantages of the TNM in HCC There is lack of homogeneity in outcomes for patients within certain current TNM categories1 Poor stratification of survival at intermediate stages2 Requires evidence of microvascular invasion, something that is not available except from surgical specimens3 Use is limited as it is based on pathological findings and does not consider liver function or tumors < 5 cm4 Changes to the TNM system have been proposed by several authors, but it still lacks adequate prognostic accuracy1,2,4 1. Wildi S, et al. Br J Surg. 2004;91:400-8. 2. Marrero JA, et al. Hepatology. 2005;41:707-16. 3. Bruix J, Sherman M. Hepatology. 2011;53:1020-2. 4. Pons F, et al. HPB (Oxford). 2005;7:35-41.

CLIP staging system for HCC Variable 1 2 Child-Pugh score A B C Tumor morphology Uninodular and extension ≤ 50% Multinodular and extension ≤ 50% Massive or extension > 50% AFP (ng/dL) < 400 ≥ 400 Portal vein thrombosis No Yes Median survival Combined score 0: 35.7 months Combined score 2: 8.5 months Combined score 4-6: 3.2 months Modified from The CLIP investigators. Hepatology 2000; 31: 840-845

Survival according to the CLIP scoring system 6 5 4 3 2 1 CLIP 0 (n = 229) CLIP 1 (n = 241) CLIP 2 (n = 136) CLIP 3 (n = 70) CLIP 4 (n = 31) CLIP 5 (n = 8) CLIP 6 (n = 7) p < 0.0001 p < 0.01 NS (n = 722) Survival rate (%) 2 4 6 8 10 Survival period (year) Survival at 3, 5, and 10 years, respectively, for each CLIP group was 86%, 72%, and 23% for CLIP 0 70%, 47%, and 19% for CLIP 1 53%, 37%, and 8% for CLIP 2 20%, 7%, and 0% for CLIP 3 15%, 15%, and 15% for CLIP 4 0%, 0%, and 0% for CLIP 5/6 Kudo M, et al. J Gastroenterol. 2003;38:207-15.

Tumor volume, number and invasiveness Single or 3 nodules < 3 cm The Barcelona Clinic Liver Cancer (BCLC) staging classification for HCC BCLC stage Performance status Tumor volume, number and invasiveness Child-Pugh Very early Single < 2 cm Carcinoma in situ A Early Single or 3 nodules < 3 cm A – B B Intermediate Multinodular C Advanced 1 – 2 Portal invasion N1M1 D Terminal > 2 Any of above Llovet JM et al. J Gastroenterol 2005; 40: 225-235

Prognosis of newly diagnosed HCC patients (1999  2005) by BCLC class Log-rank P A vs B P=0.0002 B vs C P<0.0001 C vs D P=0.057 A % S u r v i a l B C D Months Cammà et al. Aliment Pharmacol Ther 2008; 28: 62-75 12

Staging systems for HCC Hepatic function AFP PS Tumor staging BCLC CTP No Yes Tumor size, No. of nodules and PVT Okuda Ascites Albumin Bilirubin Tumor greater or less than 50% of cross-sectional area of liver TNM No. of nodules, tumor size, presence of PVT and metastasis CLIP < 400 or ≥ 400 ng/mL No. of nodules, tumor greater or less than 50% area of liver, PVT CUPI Bilirubin, AP < 500 or ≥ 500 ng/mL Symptoms JIS GRETCH Bilirubin AP < 35 or ≥ 35 μg/mL PVT AFP: alpha fetoprotein; AP: alcaline phosphatase; CTP: Child-Turcotte-Pugh; PS: performance status; PVT: portal vein thrombosis Marrero JA et al. Hepatology 2005; 41: 707-716

Staging of HCC: Several different systems are available Tumour Spread Liver Symptoms Tumour features Histol. grade AFP Vascular invasion Metastases Child-Pugh Bilirubin AP Ascites Cancer symptoms TNM1  Okuda2 JIS3 CLIP4 GRETCH5 BCLC6 CUPI7 AFP, alpha-fetoprotein; AP, alkaline phosphatase; BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of the Lliver Italian Program; CUPI, Chinese University Prognostic Index; GRETCH, Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire; HCC, hepatocellular carcinoma; Histol., histological; JIS, Japan Integrated Stage; TNM, tumor nodes metastases. 1. American Cancer Society. Available at: http://www.cancer.org/docroot/CRI/content/CRI_2_4_3X_How_is_liver_cancer_staged_25.asp; 2. Schafer DF, et al. Lancet 1999;353:1253-7; 3. Makuuchi M, et al. World J Gastroenterol 2006;12:828-9; 4. CLIP. Hepatology 1998;28:751-5; 5. Chevret S, et al. J Hepatol 1999;31:133-41; 6. Llovet JM, et al. Semin Liver Dis 1999;19:329-38; 7. Leung T, et al. Cancer 2002;94:1760-9. 14

HCC staging is complex and multifaceted Staging is used for prognosis and to guide treatment1 Staging HCC1 Most patients have underlying liver disease Key prognostic indicators are not clearly defined Prognostic indicators vary during the course of disease Factors affecting staging2,3 Tumour stage Liver function Health status Impact of treatment Patient ECOG PS BCLC4 CUPI5 Child- Pugh GRETCH6 TNM Okuda7 CLIP8 JIS9 Liver Tumour BCLC, Barcelona Clinic Liver Cancer; CLIP, cancer of the liver Italian program; CUPI, Chinese University Prognostic Index; ECOG PS, Eastern Cooperative Oncology Group performance status; GRETCH, Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire; HCC, hepatocellular carcinoma; JIS, Japan Integrated Stage; TNM, tumor nodes metastases. 1. Llovet JM, et al. Lancet 2003;362:1907–17; 2. Marrero JA, et al. Clin Liver Dis 2006;10:339–51; 3. Marrero JA, et al. Hepatology 2005;41:707–16; 4. Llovet JM, et al. Semin Liver Dis 1999;19:329–38; 5. Leung T, et al. Cancer 2002;94:1760–1769; 6. Chevret S, et al. J Hepatol 1999;31:133–41; 7. Schafer DF, et al. Lancet 1999;353:1253–7; 8. CLIP. Hepatology 1998;28:751–5; 9. Makuuchi M, et al. World J Gastroenterol 2006;12:828–9. 15

Prospective validation of the BCLC staging system Assessment of BCLC discrimination in the 195 HCC patients Univariate model (All patients n = 195) Linear trend 2 test LHR 2 test (p value) AIC Okuda 3.98 8.87 (0.0118) 933.06 CLIP 4.17 7.83 (0.0979) 938.10 UNOS-TNM 20.03 28.31 (0.0000) 915.62 JIS 12.45 15.77 (0.0013) 928.16 BCLC 43.01 57.94 (0.0000) 885.98 Multivariate model All patients (n = 195) Log-likelihood Full model 434.80 – 899.60 Removing Okuda 436.29 2.97 (0.2258) 898.58 Removing CLIP 436.36 3.11 (0.5385) 894.72 Removing UNOS-TNM 437.47 5.32 (0.1494) 898.94 Removing JIS 435.43 1.26 (0.7386) 896.86 Removing BCLC 449.92 48.90 (0.0000) 923.84 The BCLC staging system gives a more precise prognostic stratification in a study group treated mainly with radical therapies Cillo U, et al. J Hepatol. 2006;44:723-31. 16

AASLD PRACTICE GUIDELINES 2011: Staging and treatment of HCC Stage 0 PST 0, Child–Pugh A Stage A–C PST 0–2, Child–Pugh A–B Stage D PST >2, Child–Pugh C Very early stage (0) single <2cm Carcinoma in situ Early stage (A) 1 HCC or 3 nodules <3cm, PST 0 Intermediate stage (B) Multinodular, PST 0 Advanced stage (C) Portal invasion, N1, M1, PST 1–2 End stage (D) 1 HCC 3 nodules ≤3cm Portal pressure/ bilirubin Increased Associated diseases Normal No Yes Resection Liver transplantation RFA TACE Sorafenib Symptomatic treatment Curative treatments Palliative treatments Llovet JM, et al. J Natl Cancer Inst. 2008; 100: 698–711 17 17

HCC presentation and survival by BCLC stage in untreated patients from randomized trials Stage 0 PS 0, Child-Pugh A Stage A–C Okuda 1–2, PS 0–2, Child-Pugh A–B Stage D PS >2, Child-Pugh C Very early stage (0) Single <2 cm carcinoma in situ Early stage (A) 1–3 nodules <3 cm, PS 0 Intermediate stage (B) Multinodular, PS 0 Advanced stage (C) Portal invasion, N1, M1, PS 1–2 End stage (D) 30% of pts at presentation3 50% of pts at presentation3 20% of pts3 BCLC stage 0-A BCLC stage B BCLC stage C BCLC stage D Asymptomatic HCC: 96% 1-year survival4 50% 1-year survival5 25% 1-year survival5 11% 1-year survival5 1. Lencioni R et al. Radiol 2005; 234:961–967; 2. Llovet JM, et al. J Natl Cancer Inst 2008;100:698–7; 3. Bruix B, Llovet J. Hepatology 2002;35:51924; 4. Cottone M et al. Gastroenterology 1989; 96:1566-71; 5. Cabibbo G et al. Hepatology 2010:51:1274-1283. 18

Tumour doubling in untreated nodules 59 small HCCs in 39 patients: No correlation to initial tumour size No significant relation to cirrhosis severity (trend to faster DT if more severe) Serial tumour volume measurements over time identified different growth patterns Almost constant growth rate (n=8) Declining growth rate over time (n=9) Months Change in tumour volume No or very slow initial growth (DT > 200 days); subsequent increasing growth rate (n=10) Barbare L et al. Hepatology 1992;16:132-7.

Clinical Importance of Early Detection & Precise staging of HCC T1: Resection Ablation T2: Transplant 5-yr survival rates 50 – 70% This diagram illustrating the T stages of HCC shows the critical importance of early detection and precise staging of HCC, in terms of treatment. According to many previous studies, HCCs detected in their T1 and T2 stages have been shown to provide much better survival rates after, resection, ablation, or transplantation, than that in T3 and T4 lesions. The 5 yr survival rates of those with early detected HCCs is in the range of 50-70%. So, clearly, we need more sensitive imaging modalities to detect HCCs in its early stages. HCCs detected in T1 & T2 stages show much better survival Sensitive imaging modalities to detect HCCs in its early stages El-Serag HB, et al. Gastroenterology 2008; 134:1752-1763. 20

The natural history of HCC – a summary Common worldwide, although disease aetiology varies Often occurs in conjunction with liver cirrhosis Liver function of prognostic importance in cirrhotic patients CP-A survival > CP-B survival > CP-C survival Multitude of staging systems exist Tumour characteristics alone are unlikely to adequately predict prognosis Integrated staging systems are mandatory BCLC staging system links integrated staging and treatment strategy The natural history of intermediate/advanced stage HCC is dismal and prognosis for patients still remains very poor In fact, surgical or locoregional treatments of large tumour burden may further worsen liver function, which might be compromised already There is a pressing need for improved management strategies to improve survival HCC, hepatocellular carcinoma; CP, Child-Pugh. 21