Natural History and Staging System for HCC Child–Pugh scoring system Points 1 2 3 Encephalopathy (grade) None 1–2 3–4 Ascites None Slight Moderate Albumin (g/dL) Prothrombin time prolonged (sec) or INR >3.5 <4 <1.7 2.8–3.5 4–6 1.7-2.3 <2.8 >6 >2.3 <2 2–3 >3 <4 4–10 >10 Bilirubin (mg/dL) for primary biliary cirrhosis 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 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 Natural history and prognostic indicators for survival in Cirrhotic Patients Compensated cirrhosis n=806 75 80 60 40 20 0 1 yr 2 yr 1 yr 2 yr 1 yr 2 yr Child–Pugh A Child–Pugh B Child–Pugh C 50 100 25 Decompensated cirrhosis n=843 Survival (%) Probability of survival (%) 100 Survival (%) 100 80 60 40 0 0 12 24 36 48 60 72 84 96 108 120 20 1 yr Months 2 yr Compensated 1 yr 2 yr 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 Decompensated Compensated 8–12% 10–20% 4–6% No varices varices 1% STAGE 1 5–8% Varices Varices 6–15% 3–5% STAGE 2 7–10% Bleeding Bleeding Ascites Ascites 10–15% STAGE 3 Ascites Ascites Bleeding Bleeding ~30% DEATH 26% STAGE 4 STAGE 5 Sepsis Sepsis Renal Renal failure failure N%= expected 1-year outcome rates STAGE 6 ? 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: – – – 1. Cabibbo G et al. Hepatology 2010:51:1274-1283; 2. Cabibbo G et al. Hep Med Evidence Res2010:2;163-73. Impaired PS CP-B or -C Presence of PVT 6 The TNM staging system Stage Tumor Node Metastases I T1 N0 M0 II T2 N0 M0 IIIA T3 N0 M0 IIIB T4 N0 M0 IIIC Any T N1 M0 IV Any T 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. 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 0 1 2 Child-Pugh score A B C Uninodular and extension ≤ 50% Multinodular and extension ≤ 50% Massive or extension > 50% < 400 ≥ 400 No Yes Tumor morphology AFP (ng/dL) Portal vein thrombosis Median survival Combined score 0: Combined score 2: Combined score 4-6: 35.7 months 8.5 months 3.2 months Modified from The CLIP investigators. Hepatology 2000; 31: 840-845 Survival according to the CLIP scoring system CLIP 0 (n = 229) Survival rate (%) (n = 722) CLIP 1 (n = 241) p < 0.01 CLIP 2 (n = 136) 0 1 p < 0.0001 p < 0.0001 2 CLIP 3 (n = 70) NS 4 CLIP 4 (n = 31) 3 NS 5 CLIP 5 (n = 8) 6 0 CLIP 6 (n = 7) 2 4 6 8 NS 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. The Barcelona Clinic Liver Cancer (BCLC) staging classification for HCC BCLC stage Performance status Tumor volume, number and invasiveness 0 Very early 0 Single < 2 cm Carcinoma in situ A A Early 0 Single or 3 nodules < 3 cm A–B B Intermediate 0 Multinodular A–B C Advanced 1–2 Portal invasion N1M1 A–B D Terminal >2 Any of above C Child-Pugh Llovet JM et al. J Gastroenterol 2005; 40: 225-235 Prognosis of newly diagnosed HCC patients (1999 2005) by BCLC class % S u r v i v a l Log-rank P A vs B P=0.0002 B vs C P<0.0001 C vs D P=0.057 A B C D Months Cammà et al. Aliment Pharmacol Ther 2008; 28: 62-75 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 No Tumor greater or less than 50% of cross-sectional area of liver No No. of nodules, tumor size, presence of PVT and metastasis Staging System TNM No No No CLIP CTP < 400 or ≥ 400 ng/mL No No. of nodules, tumor greater or less than 50% area of liver, PVT CUPI Ascites Bilirubin, AP < 500 or ≥ 500 ng/mL Symptoms TNM CTP No No TNM Bilirubin AP < 35 or ≥ 35 μg/mL Yes PVT JIS GRETCH 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 System Tumour features Histol. grade TNM1 Okuda2 JIS3 CLIP4 GRETCH5 BCLC6 CUPI7 Spread AFP Liver Vascular invasion Metastases ChildPugh Bilirubin Symptoms AP Ascites Cancer symptoms 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. 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 ChildPugh Liver GRETCH6 Okuda7 CLIP8 JIS9 TNM 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. Prospective validation of the BCLC staging system Assessment of BCLC discrimination in the 195 HCC patients 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 Log-likelihood LHR 2 test (p value) AIC 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 Univariate model (All patients n = 195) Multivariate model All patients (n = 195) 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. AASLD PRACTICE GUIDELINES 2011: Staging and treatment of HCC HCC Stage 0 Stage A–C Stage D PST 0, Child–Pugh A PST 0–2, Child–Pugh A–B PST >2, Child–Pugh C Very early stage (0) Early stage (A) single <2cm Carcinoma in situ 1 HCC or 3 nodules <3cm, PST 0 Portal pressure/ bilirubin Increased Resection Multinodular, PST 0 Portal invasion, N1, M1, PST 1–2 3 nodules ≤3cm 1 HCC Normal Intermediate stage (B) Advanced stage (C) End stage (D) Associated diseases No Liver transplantation Curative treatments Yes RFA TACE Sorafenib Palliative treatments Symptomatic treatment Llovet JM, et al. J Natl Cancer Inst. 2008; 100: 698–711 HCC presentation and survival by BCLC stage in untreated patients from randomized trials HCC Stage 0 PS 0, Child-Pugh A Very early stage (0) Single <2 cm carcinoma in situ Stage A–C Okuda 1–2, PS 0–2, Child-Pugh A–B Early stage (A) 1–3 nodules <3 cm, PS 0 30% of pts at presentation3 Intermediate stage (B) Multinodular, PS 0 Stage D PS >2, Child-Pugh C Advanced stage (C) Portal invasion, N1, M1, PS 1–2 50% of pts at presentation3 End stage (D) 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;35:51924; 4. Cottone M et al. Gastroenterology 1989; 96:1566-71; 5. Cabibbo G et al. Hepatology 2010:51:1274-1283. 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 Change in tumour volume Months No or very slow initial growth (DT > 200 days); subsequent increasing growth rate (n=10) Declining growth rate over time (n=9) Almost constant growth rate (n=8) 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% • 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. 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.