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Risk assessment for outcomes following potentially curative treatments for HCC

Explore risks and outcomes in liver cancer treatments. Guidelines, predictors, and recurrence patterns after surgery discussed. Patients' candidacy for surgery or transplant evaluated.

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Risk assessment for outcomes following potentially curative treatments for HCC

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  1. Risk assessment for outcomes following potentially curative treatments for HCC Francis Yao, M.D Professor of Clinical Medicine and Surgery Director, Hepatology Medical Director, Liver Transplantation University of California, San Francisco

  2. Potentially curative treatments for HCC

  3. EASL 2018 algorithm for curative treatments of HCC Early stage HCC Single or 2-3 nodules <3 cm Preserved liver function, PS 0 Very early stage HCC Single < 2 cm Preserved liver function, PS 0 2-3 nodules Solitary - Child’s class - MELD score - portal hypertension - Residual liver Optimal surgical candidate Transplant candidate No Yes No Yes Ablation Ablation Resection Liver Transplant EASL Clinical Practice Guidelines. J Hepatol 2018;69:182-236

  4. Liver Resection: Assessing risks of liver decompensation Portal Hypertension Extent of hepatectomy Extent of hepatectomy Minor (< 3 segment) Minor (< 3 segment) Major (> 3 segment) Major (> 3 segment) MELD score < 10 > 10 Low risk 5% risk of liver decompensation Liver related morality 0.5% Intermediate risk <30% risk of liver decompensation Liver related morality 9% High risk >30% risk of liver decompensation Liver related morality 25% Citterio D et al. JAMA Surg 2016;15:846-853

  5. Liver Resection: Assessing risks of liver decompensation • Indocyanine green (ICG) routinely used in the East in clinical practice since criteria proposed by Makuuchi et al.1 • ICG remains an important factor in risk stratification of post-operative liver decompensation in the East.2 Liver Cancer Study Group of Japan 1. Makuuchi M et al. SemSurgOncol 1993;9:298-304 2. Kudo M et al. Dig Dis 2011;29:339-364

  6. Predictors of early HCC recurrence < 2 years of resection ERASL-pre ERASL-pre low Intermediate high 1.00 0.75 0.50 0.25 0.0 ERASL-pre Gender ALBI grade AFP Tumor size Tumor number 0 5 10 15 20 25 Recurrence-free survival (months) ERASL-post ERASL-post low Intermediate high 1.00 0.75 0.50 0.25 0.0 ERASL-pre Gender ALBI grade Microvascular invasion AFP Tumor size Tumor number 0 5 10 15 20 25 Recurrence-free survival (months) Chan AWH et al. J Hepatol2018;69:1284-1293

  7. Pattern and risk of HCC recurrence after resection No recurrence Recurrence > Milan or (+) metastasis resection What % of HCC recurrence? Recurrence within Milan “Salvage” liver transplant

  8. Resection and salvage transplant: Risk of HCC recurrence > Milan 0.0 0.2 0.4 0.6 0.8 1.0 Total of 304 patients, median follow-up 47 months Pre-op Milan (n=94) – 19% HCC recurrence > Milan Pre-op > Milan (n=210) – 46% HCC recurrence > Milan CRS O CRS 1 CRS 2 CRS 3 Cumulative Incidence 0 1 2 3 4 5 6 7 Years Lee SY et al. HPB 2014;16:943-953

  9. Pattern and risk of HCC recurrence after resection No recurrence “preemptive” liver transplant Recurrence > Milan or (+) metastasis resection What % of HCC recurrence? Recurrence within Milan “Salvage” liver transplant

  10. Preemptive transplant after resection in high risk patients • Microvascular invasion in resection specimen: • 17/37 high risk patients underwent LT (10 of 17 before HCC recurrence), with reported 5-year post-transplant survival of 82%.1 • At least 3 high risk factors for HCC recurrence > Milan.2 • Cirrhosis present • Poorly differentiated grade • Microvascular invasion • Tumor diameter > 3 cm • Satellite nodules 1. Ferrer-Fabrega J, et al. Hepatology 2016;63:839-849 2. Fuks D, et al. Hepatology 2012;55:132-140

  11. Liver resection: Minimally invasive/ laparoscopic • EASL recommendations: Liver resection via minimally invasive/ laparoscopic approach may be considered in properly trained centers, especially for tumors located in anterolateral and superficial locations.1 • No differences between laparoscopic versus open approaches in overall survival and disease-free survival.2-4 • Whether laparoscopic approach reduce incidence of hepatic decompensation and perioperative morbidity has not yet been established.2-4 • A multi-center Japanese study reported shorter hospital stay and lower complication rate with laparoscopic approach.5 • EASL Clinical Practice Guidelines. J Hepatol2018;69:182-236 • Parks KR, et al. HPB (Oxford) 2014;16:109-118 • Kasai M, et al. Surgery 2018;163:985-995 • Abu Hilal M, et al. Ann Surg 2018;268:11-18 • Takahara T, et al. J Hepatobiliary PancreatSci 2015;22721-727

  12. Randomized controlled trials of resection versus RFA Chen MS et al. Ann Surg 2006;243:321-328 2. Huang J et al. Ann Surg2010;252:903-912 Feng K et al. J Hepatol 2012;57:794-802 4. Fang Y et al. J GastroenterolHepatol 2014;29:193-200 5. Ng KKC et al. Br J Surg2017;104:1775-1784

  13. Randomized controlled trial of resection versus RFA All Patients; 1 lesion ≤5 cm Overall Survival Disease-free Survival P = 0.072 P = 0.531 Resection RFA Resection RFA Ng KKC et al. Br J Surg 2017;104:1775-1784

  14. Randomized controlled trial of resection versus RFA Very early HCC; 1 lesion ≤2 cm Overall Survival Disease-free Survival P = 0.95 P = 0.90 Resection RFA Resection RFA Ng KKC et al. Br J Surg 2017;104:1775-1784

  15. Ablation: Factors in outcome assessment RFA Tumor Diameter 3 cm vs 3-5 cm ≤ Tumor Location AFP

  16. Ablation: Factors in outcome assessment RFA Tumor Diameter 3 cm vs 3-5 cm ≤ Tumor Location AFP • Procedure-related complications • Liver function • Coagulopathy • Thrombocytopenia • Ascites • Tumor location

  17. Thermal Ablation: Very early HCC Single Tumor <2 cm • A multi-center study on 218 patients with single lesion <2cm, median follow-up 31 months. • Sustained complete response in 97% after 1 (86%) or 2 (12%) sessions. • 5-year survival 55%, perioperative mortality 0% and major complication rate 1.8%. • 5-year disease free survival rate 26%. Livraghi T, et al. Hepatology 2008;47:82-89

  18. Thermal Ablation: Very early HCC Single Tumor <2 cm • Systematic review and meta-analysis of 17 studies (3996 treated with resection and 4424 with ablation), with cost-effectiveness using a Markov model. • Very early HCC < 2 cm in Child’s class A patients: RFA provides similar life expectancy and quality-adjusted life expectancy at a lower cost compared to resection. Cucchetti A, et al. J Hepatol 2013;59:300-307

  19. Thermal Ablation for HCC > 3 cm ≤3 cm versus > 3 cm • Treatment response rate 70-95% for lesions < 3 cm versus around 50% for lesions > 3 cm • In lesions > 3 cm, overall 5-year survival 30-35%, 5-year recurrence rate up to 80%. Sala M, et al. Hepatology 2004;40:1352-60 Lencioni R, et al. Radiology 2005;234:961-7 N’Kontchou G, et al. Hepatology 2009;50:1465-83 Santambrogio R, et al. Ann SurgOncol 2009;16:3289-98

  20. Resection vs ablation for HCC Well compensated cirrhosis, no portal hypertension * Resection may be preferred over RFA for high alpha-fetoprotein

  21. Survival outcome after RFA for HCC ≤ 3 cm Overall Survival Recurrence-free Survival v HCC > 2 & ≤ 3 cm HCC ≤ 2 cm HCC > 2 & ≤ 3 cm HCC ≤ 2 cm HCC > 2 & ≤ 3 cm HCC ≤ 2 cm Cumulative probabilities Recurrence-free Survival Overall Survival 79% 71% P = 0.01 P < 0.001 P = 0.001 Doyle A, et al. J Hepatol 2019;70:866-873

  22. HCC recurrence pattern after RFA for HCC ≤ 3 cm Doyle A, et al. J Hepatol 2019;70:866-873

  23. HCC recurrence pattern after RFA for HCC ≤ 3 cm HCC Recurrence > Milan Criteria v HCC > 2 & ≤ 3 cm HCC ≤ 2 cm Cumulative probabilities HCC > 2 & ≤ 3 cm HCC ≤ 2 cm Recurrence-free Survival P < 0.001 P = 0.01 Doyle A, et al. J Hepatol 2019;70:866-873

  24. Liver Transplant: Outcome risk assessment Immuno-suppression and complications Liver disease Psycho-social issues Liver Transplant Outcome HCC Tumor burden + others factors Medical Co-morbidities Donor factors

  25. Liver Transplant: Outcome risk assessment Immuno-suppression and complications Liver disease Psycho-social issues Liver Transplant Outcome HCC Tumor burden + others factors Selection Criteria Medical Co-morbidities Donor factors

  26. The HCC “Metro-ticket” – Tumor Size and Number HCC Forecast Chart: Survey of 1112 patients > Milan (Pathology) Number of nodules Size of the largest nodule (in mm) Courtesy of Dr. VincencoMazzaferro, with permission Mazzaferro et al. Lancet Oncology 2009;10:35-43

  27. The HCC “Metro-ticket” – Tumor Size and Number HCC Forecast Chart: Survey of 1112 patients > Milan (Pathology) Number of nodules Milan Criteria Size of the largest nodule (in mm) Courtesy of Dr. VincencoMazzaferro, with permission Mazzaferro et al. Lancet Oncology 2009;10:35-43

  28. Liver Transplant for HCC Changing views on Selection Criteria “Morphology” Size Number Volume “Biology” Response to LRT? Biomarkers? Other surrogates?

  29. French AFP Model - Tumor size, number and AFP Variables Points Largest tumor diameter, cm ≤ 3 0 3-6 1 > 6 4 Number of tumor nodules 1-3 0 ≥ 4 2 AFP level, ng/mL • ≤ 100 0 • 100-1000 2 • > 1000 3 Duvoux C et al. Gastroenterology 2012;143:986-94

  30. French AFP Model - Tumor size, number and AFP Variables Points Largest tumor diameter, cm ≤ 3 0 3-6 1 > 6 4 Number of tumor nodules 1-3 0 ≥ 4 2 AFP level, ng/mL • ≤ 100 0 • 100-1000 2 • > 1000 3 Low risk ≤ 2 points Within Milan butAFP > 1000 = High risk Some HCC > Milan but AFP ≤ 100 =Low risk national policy in France Duvoux C et al. Gastroenterology 2012;143:986-94

  31. Metro-ticket 2.0: AFP + Tumor Burden Mazzaferro et al. Gastroenterology 2018;154:128-139

  32. AFP and Liver Transplant (UNOS) 100 AFP > 1000 <100 80 88% Survival rate (%) AFP > 1000 101- 499 60 67% P < 0.0001 AFP > 1000 49% 40 UNOS data 2005-2015 Within Milan or UCSF Down-staging 20 P = 0.09 for AFP 101-499 vs AFP < 100 0 0 1 2 3 4 5 Years after liver transplant < 100 58 54 48 39 33 28 101-500 39 37 31 27 24 19 >1000 293 216 165 145 114 96 Mehta N et al. Hepatology 2019;69:1193-1205

  33. HCC-HALT: AFP, Tumor Burden score, MELD-Na (1·27 × Tumer Burden Score (TBS)) + (1·85 × lnAFP) + (0·26 × MELD-Na)  AUROC 0.61 79 75 72 62 Sasaki et al. Lancet GastroenterolHepatol 2017;2:595-603

  34. UCSF Down-staging protocol for liver transplant Minimum observation 3 months Meeting Milan criteria (n=41) Median f/u 3.8 years Dropout - 5 HCC recurrence (8%) - 78% 5-yr survival post-transplant - 91% 5-yr recurrence free probability - 56% 5-yr intention- to-treat survival Transplant Down-staging (n=64) (n=118) Inclusion Criteria for Down-staging 1 tumor ≤ 8 cm 2-3 tumor ≤ 5 cm + total diameter ≤ 8 cm 4-5 tumor ≤ 3 cm + total diameter ≤ 8 cm US national policy Yao FY et al. Hepatology 2015;61:1968-1977

  35. Post-transplant survival after tumor down-staging - - - Milan group 81% Down-staged group 78% p=0.69 Yao FY, et al. Hepatology 2015;61:1968-1977

  36. Predictors of Treatment Failure: Multivariable Analysis Treatment failuredefined as dropout due to tumor progression, liver-related death without LT, or post-LT HCC recurrence * Before 1st down-staging procedure Mehta N et al.ClinGastroenterolHepatol 2018;16:955-964

  37. Down-staging treatment failure: AFP and Child’s Class 100% Risk factors - Pre-treatment AFP > 1000 - Child-Pugh B/C 2 Risk Factors 46% 1 Risk Factor 33% 0 Risk Factors p=0.001 Mehta N et al.ClinGastroenterolHepatol 2018;16:955-964

  38. Post-transplant survival after down-staging The effects of initial tumor burden 100 Post-transplant Survival (%) 83% 79% 71% 80 Milan (n=3276) UNOS-DS (n=422) >UNOS-DS or “All-comers” (n=121) 60 UNOS-DS vs Milan, p=0.17 >UNOS-DS vs Milan, p=0.04 40 20 0 0 6 12 18 24 30 36 Months after Transplant UCSF/ UNOS-down-staging Inclusion Criteria 1 tumor ≤ 8 cm 2-3 tumor ≤ 5 cm + total diameter ≤ 8 cm 4-5 tumor ≤ 3 cm + total diameter ≤ 8 cm Mehta N, et al. Hepatology [Epub]

  39. Pre-transplant Prognostic Models (selected) 1. Yao FY, et al. Hepatology 2015;61:1968-1977 2. Hameed B. et al. Liver Transpl2014;20:945-951 3. Duvouxet al. Gastroenterology 2012;143:986-94 4. Mazzaferroet al. Gastroenterology 2018;154:128-139 5. Sasaki et al. Lancet GastroenterolHepatol 2017; 2:595-603 6. Toso et al. Hepatology2015;62:158-165 7. Halazun KJ, et al. Ann Surg 2017;265:557-564 *Include MELD-Na

  40. Post-transplant Prognostic Models 1. Agopian VG. et al. J Am CollSurg 2015;220:416-427 2. Mehta N. et al. JAMA Oncol 2017;3:493-500 3. Halazun KJ, et al. Ann Surg2017;265:557-564

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