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Epatocarcinoma: nulla di nuovo sotto il sole - Gastrolearning®
The document discusses hepatocellular carcinoma (HCC), emphasizing its association with chronic liver disease and environmental risk factors like HBV and HCV. It covers various treatment approaches, staging classifications including the Barcelona Clinic Liver Cancer (BCLC) criteria, and outcomes related to surgical resection, radiofrequency ablation, and systemic therapies such as sorafenib. Additionally, the document provides financial disclosures of the presenter and outlines evolving concepts in the management of HCC.
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Epatocarcinoma: nulla di nuovo sotto il sole - Gastrolearning®
- 1. Gastro-learning 2014 Milano,13 ottobre 2014 Epatocarcinoma: nulla di nuovo sotto il sole Prof. Massimo Colombo Chairman Department of Liver, Kidney, Lung and Bone Marrow Units and Organ Transplant Head Division of Gastroenterology and Hepatology Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico University of Milan Milan, Italy
- 2. Financial Disclosures Grantand research support: BMS, Gilead Science Advisory committees: Merck, Roche, Novartis, Bayer, BMS, Gilead Science, Tibotec, Vertex, Janssen Cilag, Achillion, Lundbeck, GSK, GenSpera, AbbVie Speaking and teaching: Tibotec, Roche, Novartis, Bayer, BMS, Gilead Science, Vertex, Merck, Janssen
- 3. Hepatocellular Carcinoma: DistinctFeatures 1. The tumor develops in the context of well-known environmental risk factors. The dominant role of HBV and HCV. 2. The tumor is strictly associated with chronic liver disease, mainly cirrhosis. Long phase of intrahepatic growth. 3. One of the few cancers not requiring histology for diagnosis in all cases. Radiological diagnosis possible in cirrhotics and HBV patients. 4. The sole solid cancer treatable by organ transplantation
- 4. European Mean Age-standardised5-year Relative Survival For Adult Patients With Cancer Diagnosed In 2000–2007 De Angelis et al, Lancet Oncology 2014;15:23-34
- 5. Evolving Concepts inthe Clinical Management of Hepatocellular Carcinoma www.aasld.org 2001 EASL 2005 AASLD 2010 APASL 2011 AASLD 2012 EASL
- 6. The Barcelona ClinicLiver Cancer (BCLC) Staging Classification for Hepatocellular Carcinoma BCLC stage 0 Very early A Early B Intermediate C Advanced D End-stage Performance status 0 0 0 1-2 3-4 Tumor volume,number and invasiveness ≤ 2 cm vaguely nodular Single < 5 cm or 3 nodes < 3 cm each Large/multinodular Vascular invasion and/or extrahepatic spread Any of the above Child-Pugh A A & B A & B A & B C Forner et al, Sem liver Dis 2010;30:61-74
- 7. The Barcelona ClinicLiver Cancer (BCLC) Staging Classification for Hepatocellular Carcinoma BCLC stage 0 Very early A Early B Intermediate C Advanced D End-stage Performance status 0 0 0 1-2 3-4 Tumor volume,number and invasiveness ≤ 2 cm vaguely nodular Single < 5 cm or 3 nodes < 3 cm each Large/multinodular Vascular invasion and/or extrahepatic spread Any of the above Child-Pugh A A & B A & B A & B C Forner et al, Sem liver Dis 2010;30:61-74
- 8. Early HCC: Survivalafter Resection Is Influenced by Portal Hypertension and Bilirubin Best candidates for resection : Solitary HCC ≤ 5 cm Child-Pugh A: Low portal hypertension Normal bilirubin 100 80 74% 50% 25% Survival (%) months 60 40 20 0 Log Rank 0.00001 0 12 24 36 48 60 72 84 96 < 10 mmHg HVPG (n= 35) ≥ 10 mmHg HVPG and normal bilirubin (n=15) ≥ 10 mmHg HVPG and Bilirubin >1 mg/dL (n=27) Llovet JM et al, Hepatology 1999;30:1434-40
- 9. Portal Hypertension andHepatic Resection for Small HCC A Meta-analysis, 5-year Mortality Berzigotti et al, Hepatology in press
- 10. Radiofrequency Ablation inChild Pugh A Cirrhosis The Importance of Tumor Number and Size Tumor N Survival (%) 1 yr 5 yr 10 yr Median (yr) Solitary 685 97.2 64.6 32.0 7.0 P=0.0003 2-3 395 95.7 54.4 19.9 5.6 ≥ 4 90 96.5 53.6 17.6 5.3 ≤ 3cm 889 97.2 65.1 30.7 6.7 P<0.0001 > 3cm 281 94.8 46.5 18.6 4.6 Shiina et al Am J Gastroenterol 2012;107:569-577
- 11. Local Tumor Progressionof 1462 HCCs after RFA as a First Line Therapy Kim et al, J Hepatol 2013;58:89-97
- 12. RCT of Resectionvs Radiofrequency as First Line Treatment of HCC in Compensated Cirrhosis Outline & outcomes Chen 2006 Huang 2010 Feng 2012 SR RFA SR RFA SR RFA Number patients 90 71 115 115 84 84 Max tumor size (cm) 5 5 5 5 4 4 Single tumor (%) 100 100 100 100 62 57 Overall Survival (%) 3-yr 73 71 92 70 75 67 4-yr 68 64 83 66 - - 5-yr - - 76 55* - - *P=0.001 Chen Ann Surg 2006;243:321-8. Huang et al Ann Surg 2010;252:903. Feng J Hepatol 2012;57:794
- 13. Overall Survival FollowingResection vs RFA vs PEI in Very Early HCC Five-year OS: Resection 71.1% vs Ablation 61.1%, P=0.0001 Hasegawa et al, J Hepatol 2013;58:724-729
- 14. Review Three-yr SurvivalFollowing Resection or RFA of HCC in Child Pugh A Cirrhosis Radiofrequency more cost-effective than resection in very early HCC and 2-3 nodules 3 cm ≤ Cucchetti et al, J Hepatol 2013;59:300-7
- 15. STORM RCT ofAdjuvant Sorafenib after Curative Resection or Ablation Outcomes Sorafenib Placebo Hazard ratio (95% CI) P-value Recurrence free survival, mos 33.4 33.8 0.940 (0.780-1.134) 0.26 Time to progression, mos 38.6 35.8 0.891 (0.735-1.081) 0.12 Overall survival, mos NR NR 0.995 (0.761-1.300) 0.48 Tx-related Adverse events, % All grade 98 90 Serious 40 42 Bruix et al, ASCO 2014 Chicago
- 16. Selection Criteria InLiver Transplantation For HCC Criteria Definition Milan (MC) Single nodule ≤ 5 cm Up to 3 nodules ≤ 3 cm No macrovascular invasion UCSF Single ≤ 6.5 cm Up to three nodules ≤ 4.5 cm Sum of tumor diameter ≤ 8 cm Up-to-7 Sum of size (cm) and number of HCC nodules ≤ 7 No mVI TTV+AFP Any nodule up to TTV ≤115 cm3 AFP ≤400 ng/mL Milan + AFP Score system based on number of nodules, size of the largest nodule, AFP at listing (<100; 100–1000; >1000 ng/mL) Bruix J et al, Gut. 2014;63:844-55 TTV, total tumor volume
- 17. Predicting Survival afterLiver Transplantation in Patients with HCC beyond Milan Criteria No. of Patients (n=1556) Mazzaferro V et al, Lancet Oncol 2009;10:35-43 Milan in (n=444) Milan out (n=1112) P-value No. tumors Median (range) 3 (1-20) 1 (1-3) 4 (1-20) <0.0001 Max tumor size, mm Median (range) 35 (1-200) 20 (1-50) 40 (4-200) <0.0001 Vascular invasion, n No Yes 977 (66.2%) 498 (33.8%) 361 (89.1%) 44 (10.9%) 616 (57.6%) 454 (42.4%) <0.0001 Overall survival (95% CI) at 10 years 46.8% (43.0-50.5) 69.6% (63.7-74.8) 38.7% (34.2-43.1) <0.0001
- 18. The Founders ofBCLC: Staging and Treatment Strategy Very early (0) Early (A) Intermediate (B) Advanced (C) Terminal(D) Potential candidate for liver transplantation Single Three nodules ≤3 cm Portal pressure, bilirubin No Yes Normal Increased Associated diseases Forner et al, Lancet 2012;379:1245-55 No Yes Ablation Resection OLT Ablation TAC E Sorafenib BSC
- 19. TACE/RFA Down-Staging ofHCC Prior to Liver Transplantation. An ITT Analysis Yao et al, Hepatology 2008;48:819-827
- 20. Salvage Liver TransplantationAfter Primary Hepatic Resection for HCC, Milan (±) A review of 16 comparative/cohort studies N=319 Patients SLT Complications Biliary 8% Tumor size 2.5-3.4 cm Infection 11% Micro vs macrovascular: 28% vs 4% Bleeding 8% 18-29% Major hepatectomy (0-6% deaths) Vascular 7% 27-80% Tumor recurrence Deaths 6% 16-65% Salvage Liver Transplantation (SLT) Five-yr survival 62% (41-89) Chan et al, J Gastroenterol Hepatol 2014;29:31-34
- 21. The Barcelona ClinicLiver Cancer (BCLC) Staging Classification for Hepatocellular Carcinoma BCLC stage 0 Very early A Early B Intermediate C Advanced D End-stage Performance status 0 0 0 1-2 3-4 Tumor volume,number and invasiveness ≤ 2 cm vaguely nodular Single < 5 cm or 3 nodes < 3 cm each Large/multinodular Vascular invasion and/or extrahepatic spread Any of the above Child-Pugh A A & B A & B A & B C Forner et al, Sem liver Dis 2010;30:61-74
- 22. Intermediate HCC: TheOutcome of Chemoembolization Author,Journal year Patients Lin , Gastroenterology 1988 63 GRETCH, NEJM 1995 96 Bruix , Hepatology 1998 80 Pelletier, J Hepatol 1998 70 Lo, Hepatology 2002 79 Llovet, Lancet 2002 112 Overall 503 Heterogeneity: Q:7.73 P=0.14 Bruix J et al, Gastroenterology 2004;127:S179-88 Random effects model (DerSimonian & Laird). OR (95% IC) 0.01 0.1 0.5 1 2 10 100 p=0.017 Favors treatment Favors control Improved survival: from 16 to 20 months
- 23. Survival of Patientswith Hepatocellular Carcinoma Treated by TACE Using DC-beads Overall survival BCLC-A Overall survival BCLC-B Burrel et al, J Hepatol 2012;56:1330-5
- 24. Uncontrolled Studies: Y-90Radioembolization (RE) in HCC BCLC B Patients Adapted from Sangro et al, J Hepatol 2012;56:464-7 Salem 2011 Wang 2008 Chen 2009 Hilgard 2010 Salem 2010 Sangro 2011
- 25. Transarterial Chemoembolization inCombination with Local Therapies for HCC: A Meta-Analysis Three-yr survival Yao et al, PlosOne 2013 e68453
- 26. The Barcelona ClinicLiver Cancer (BCLC) Staging Classification for Hepatocellular Carcinoma BCLC stage 0 Very early A Early B Intermediate C Advanced D End-stage Performance status 0 0 0 1-2 3-4 Tumor volume,number and invasiveness ≤ 2 cm vaguely nodular Single < 5 cm or 3 nodes < 3 cm each Large/multinodular Vascular invasion and/or extrahepatic spread Any of the above Child-Pugh A A & B A & B A & B C Forner et al, Sem liver Dis 2010;30:61-74
- 27. Randomized Controlled Trialsof Sorafenib in Advanced Hepatocellular Carcinoma Study Characteristics SHARP Study1 Asia Study2 Median age 65 yrs 51 yrs BCLC-B stage 18% 4% Previous treatments 67% na HBV etiology of cirrhosis 19% 71% TTP (control) 5.5 mo (2.8 mo) 2.8 mo (1.4 mo) Median survival (control) 10.7 mo (7.9 mo) 6.5 mo (4.2 mo) Grade 3/4 toxicity 30% 24% 1. Llovet JM, et al. N Eng J Med. 2008;359(4):378-390; 2. Cheng A et al. Lancet Oncol. 2009;10(1):25-34.
- 28. Overall Survival Accordingto the Prevalent Dose of Sorafenib in the SOFIA Study (296 Patients) Total patients: 296 •97 (40%) discontinued without previous dose reduction •122 with half dose for <70% of the treatment period •77 patients with half dose for ≥70% of the treatment period Iavarone M et al. Hepatology 2011;54:2055-63 Predictors of mortality HR (95% CI) ECOG Performance Status 1.9 (1.5 – 2.5) Macroscopic vascular invasion 1.9 (1.4 – 2.6) Extrahepatic spread 1.4 (1.1 – 1.9) Early radiological progression 1.4 (1.1 – 2.1) Full dosing 1.8 (1.4-2.4)
- 29. Cost-effectiveness Analyses ofSorafenib Therapy for HCC Treatment Strategies Cammà et al, Hepatology. 2013;57:1046-54 Costs in 2012 euros QAL Y ICER/QALY base-case analysis (2012 euros) Best supportive care 4,142 - - BCLC B+C Full dose 16,081 0.16 69,344 Dose-adjusted 19,944 0.44 34,534 BCLC B Full dose 24,224 0.32 57,385 Dose-adjusted 26,914 0.38 54,881 BCLC C Full dose 14,841 0.16 65,551 Dose-adjusted 16,625 0.44 27,916 Willingness to pay for 1 ICER/Quality = 34,000€
- 30. Multimodal Treatment ofHCC: How Field Practice Complies with AASLD Recommendations Reasons for withdrawing from recommendations Total (No.370) BCLC A (No. 251) BCLC B (No. 66) BCLC C (No. 53) Impaired liver function 17 (5%) 0 7 (11%) 10 (19%) Strategic localization and/or vascular invasion 53 (14%) 19 (8%) 21 (32%) 7 (13%) Co-morbidities 33 (9%) 28 (11%) 2 (3%) 9 (17%) Sangiovanni et al submitted
- 31. Multimodal Treatment ofHCC: How Field Practice Complies with AASLD Recommendations Sangiovanni et al submitted A (AASLD+) B (AASLD-) p = 0.0042
- 32. Multimodality Treatment ofHCC: How Field Practice Complies with AASLD Recommendations TREATMENT Total (No. 370) BCLC A (No. 251) BCLC B (No. 66) BCLC C (No. 53) OLT 29 (8%) 26 (10%) 3 (4%) 0 Resection 59 (16%) 52 (21%) 6 (9%) 1 (2%) Local ablation 146 (40%) 126 (50%) 13 (21%) 7 (13%) Chemoembolization 90 (24%) 45 (18%) 36 (54%) 9 (17%) Sorafenib 34 (9%) 1 (0.5%) 6 (9%) 27 (51%) Best supportive care 12 (3%) 1 (0.5%) 2 (3%) 9 (17%) Sangiovanni et al submitted
- 33. Post-progression Survival ofPatients with Advanced HCC. Rationale for Second Line Trial Design BCLCp C1: Patients BCLC-C under sorafenib treatment with progression due to growth of existing nodules or new intra-hepatic sites. BCLCp C2: Patients BCLC-C under sorafenib treatment with progression due to new extra-hepatic lesion and/or vascular invasion. Reig M et al, Hepatology. 2013;58:2023-31.
- 34. Association of Multidisciplinary(MDC) HCC Clinic with Clinical Outcome 105 patients diagnosed after the MDC clinic (2010) vs 209 patients diagnosed in the 3 previous years 1. Received treatment 56% vs 44% P=0.04 2. Time to treatment (mo.) 2.2 vs 4.7 P=0.001 3. Survival time (mo.) 15.2 vs 4.7 P=0.002 4. One-year survival 64% vs 47% P=0.001* *after excluding BCLC-D patients Yopp et al, Journal of Clinical Oncology 2013;31 suppl:332