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Natural History and Staging System for HCC

Natural History and Staging System for HCC. Child–Pugh scoring system. 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.

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Natural History and Staging System for HCC

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  1. Natural History andStaging System for HCC

  2. Child–Pugh scoring system Pugh RN, et al. Br J Surg. 1973 ;60: 646-649; Riley TR et al. Am Fam Physician 2001; 64: 1555-60

  3. 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

  4. Natural history and prognostic indicators for survival in Cirrhotic Patients 100 80 60 40 20 0 100 75 50 25 0 Compensated cirrhosisn=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 cirrhosisn=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

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

  6. 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.

  7. The TNMstaging system 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.

  8. The TNMstaging 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.

  9. CLIP staging system for HCC 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

  10. Survival according to the CLIP scoring system p < 0.0001 p < 0.01 CLIP 0 (n = 229) p < 0.0001 CLIP 1 (n = 241) CLIP 2 (n = 136) NS CLIP 3 (n = 70) NS CLIP 4 (n = 31) CLIP 5 (n = 8) NS 0 1 CLIP 6 (n = 7) 2 4 3 5 6 (n = 722) Survival rate (%) 0 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.

  11. The Barcelona Clinic Liver Cancer (BCLC) staging classification for HCC Llovet JM et al. J Gastroenterol 2005; 40: 225-235

  12. 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 v a l B C D Months Cammà et al. Aliment Pharmacol Ther 2008; 28: 62-75

  13. Staging systems for HCC 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

  14. Staging of HCC: Several different systems are available 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.

  15. HCC staging is complex and multifaceted Staging is used for prognosisand to guide treatment1 Staging HCC1 Most patients have underlyingliver disease Key prognostic indicatorsare 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 ECOGPS BCLC4 CUPI5 GRETCH6 Child-Pugh 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.

  16. Prospective validation of the BCLC staging system Assessment of BCLC discrimination in the 195 HCC patients 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.

  17. Symptomatictreatment AASLD PRACTICE GUIDELINES 2011: Staging and treatment of HCC HCC Stage 0PST 0, Child–Pugh A Stage A–CPST 0–2, Child–Pugh A–B Stage DPST >2, Child–Pugh C Very early stage (0) single <2cmCarcinoma 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 Curative treatments Palliative treatments Llovet JM, et al. J Natl Cancer Inst. 2008; 100: 698–711

  18. HCC presentation and survival by BCLC stage in untreated patients from randomized trials 50% of pts at presentation3 30% of pts at presentation3 20% of pts3 HCC Stage 0PS 0, Child-Pugh A Stage A–COkuda 1–2, PS 0–2, Child-Pugh A–B Stage DPS >2,Child-Pugh C Very early stage (0)Single <2 cmcarcinoma 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) 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.

  19. 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.

  20. 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.

  21. 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 The natural history of HCC – a summary There is a pressing need for improved management strategies to improve survival HCC, hepatocellular carcinoma; CP, Child-Pugh.

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