9/10/2018. Liver Transplant for Hepatocellular Carcinoma (HCC): What is New? DISCLOSURES

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1 UCSF Transplant 2018: Pioneering Advances in Transplantation DISCLOSURES Liver Transplant for Hepatocellular Carcinoma (HCC): What is New? I have no relevant commercial interests or relationships to report Neil Mehta, MD 9/20/18 UCSF Division of Gastroenterology and Hepatology OVERVIEW Current state of liver transplantation (LT) for HCC Refining selection criteria for LT Updates in down-staging and allcomers outcomes Novel biomarkers Assessing individualized post-transplant HCC recurrence risk Novel risk scores using explant pathology LIVER TRANSPLANTATION FOR HCC MILAN CRITERIA 1 lesion 5 cm 2 to 3, none > 3 cm + Absence of Macroscopic Vascular Invasion Absence of Extra-hepatic Spread Mazzaferro, et al. N Engl J Med 1996;334:

2 LIVER TRANSPLANTATION FOR HCC T1 and T2 CRITERIA LT FOR HCC: EXPANDED CRITERIA T1: 1 lesion < 2 cm T2: 1 lesion 2-5 cm or 2 to 3 lesions, none >3cm + Absence of Macroscopic Vascular Invasion Absence of Extra-hepatic Spread Sapisochin, G. & Bruix, J Nat. Rev. Gastroenterol. Hepatol. LT FOR HCC: EXPANDED CRITERIA Extended Toronto Criteria XX XX XX XX 5-yr post-transplant survival 68% ETC; 78% Milan Milan >Milan 5-yr recurrence probability 30% ETC; 13% Milan >Milan Milan Sapisochin G et al. Hepatology 2016;64: Sapisochin, G. & Bruix, J Nat. Rev. Gastroenterol. Hepatol. 2

3 LT FOR HCC: EXPANDED CRITERIA XX XX XX XX Extended Criteria & FDG PET/CT The National Cancer Korea Criteria Total tumor diameter < 10 cm Negative 18 F-FDG PET/ CT 84% 85% Within NCCK Within NCCK > NCCK > NCCK Preoperative P < Pathology P < Lee SD, et al. World J Transpl 2016;6: Sapisochin, G. & Bruix, J Nat. Rev. Gastroenterol. Hepatol. % of adult LT done for HCC RISING INCIDENCE OF LT FOR HCC UCSF DATA 60% 50% 40% 30% 20% 10% 22 LT for HCC in % % of adult LT done for HCC RISING INCIDENCE OF LT FOR HCC UCSF DATA 60% 50% 40% 30% 20% 10% 22 LT for HCC in % 84 LT for HCC in % 0% Year 0% Year 3

4 LIVER TRANSPLANT FOR HCC: RECENT CHANGES Uniform diagnostic criteria (OPTN/ LIRADS) + standardized reporting Only pts w/ T2 HCC and LI-RADS 5 lesions are eligible to receive priority listing LIVER IMAGING REPORTING AND DATA SYSTEM (LI-RAD) MAJOR DIAGNOSTIC CRITERIA Arterial phase hyper-enhancement Delayed phase washout Pseudo-capsule Interval growth 50% diameter within 6 mo Different diagnostic criteria for lesion 2 cm versus < 2 cm HCC RADIOLOGIC DIAGNOSIS HCC RADIOLOGIC DIAGNOSIS Arterial Phase Portal Venous phase Arterial Phase Portal Venous phase pseudo-capsule Hyper-enhancement washout Hyper-enhancement washout 4

5 LIVER IMAGING REPORTING AND DATA SYSTEM (LI-RADS) LIVER IMAGING REPORTING AND DATA SYSTEM (LI-RADS) Diagnostic Criteria Arterial phase hypo- or Isoenhancement LIVER MASS Arterial phase hyperenhancement < 2 cm 2 cm < 1 cm cm 2 cm Washout None LIRADS 3 LIRADS 3 LIRADS 3 LIRADS 3 LIRADS 4 Capsule One LIRADS 3 LIRADS 4 LIRADS 4 LIRADS 4 LIRADS 5 Threshold growth Two LIRADS 4 LIRADS 4 LIRADs 4 LIRADS 5 LIRADS 5 Diagnostic Criteria Arterial phase hypo- or Isoenhancement LIVER MASS Arterial phase hyperenhancement < 2 cm 2 cm < 1 cm cm 2 cm Washout None LIRADS 3 LIRADS 3 LIRADS 3 LIRADS 3 LIRADS 4 Capsule One LIRADS 3 LIRADS 4 LIRADS 4 LIRADS 4 LIRADS 5 Threshold growth Two LIRADS 4 LIRADS 4 LIRADs 4 LIRADS 5 LIRADS 5 LIVER TRANSPLANT FOR HCC: RECENT CHANGES Uniform diagnostic criteria (OPTN/ LIRADS) + standardized reporting 6-month mandatory waiting period before MELD exception of 28 Cap at MELD of 34 DELAYED HCC-MELD EXCEPTION SCORE Delays in HCC-MELD exception HCC Transplant rates (per 100 person-years) Non-HCC Transplant rates (per 100 person-years) months months months Heimbach J, et al. Hepatology 2015;61:

6 LIVER TRANSPLANT FOR HCC: RECENT CHANGES Uniform diagnostic criteria (OPTN/ LIRADS) + standardized reporting 6-month mandatory waiting period before MELD exception of 28 Cap at MELD of 34 Regional variation in access to LT for HCC still exists PROBABILITY OF WAITLIST DROPOUT BY WAIT TIME REGION AND LISTING PERIOD LWTR, % 29% Long wait time (LWTR) is regions 1, 5, and 9 Mid wait time (MWTR) is regions 2, , 6, 7, and 8 and Short wait time (SWTR) is regions 3, 10, and 11 86% 90% % % MWTR, % 20% % LWTR, MWTR, % SWTR, % 6% p<0.001 SWTR, p<0.001 Mehta N et al, Liver Transplantation 2018 LIVER TRANSPLANT FOR HCC: UPCOMING CHANGES 6-month mandatory waiting period before MELD exception of 28 Cap at MELD of 34 Regional variation in access to LT for HCC still exists To overcome regional disparities: median MELD at LT minus 3 points will be awarded to HCC pts after 6 month wait time (estimated to start Jan 2019) DECIDING WHO SHOULD BE TRANSPLANTED IN THE NEW MELD ERA FOR HCC Within Milan Within Milan Moving past one-size fits all Transplant would benefit Transplant not needed Do poorly after transplant Mehta N, and Yao FY. Liver Transpl 2013;19:

7 DECIDING WHO SHOULD BE TRANSPLANTED IN THE NEW MELD ERA FOR HCC DECIDING WHO SHOULD BE TRANSPLANTED IN THE NEW MELD ERA FOR HCC Within Milan Within Milan - Local regional therapy - Observation period/ Wait time Within Milan Within Milan - Local regional therapy - Observation period/ Wait time Transplant would benefit Transplant not needed Do poorly after transplant Transplant would benefit Transplant not needed Do poorly after transplant Tumor Down-staging DECIDING WHO SHOULD BE TRANSPLANTED IN THE NEW MELD ERA FOR HCC Within Milan SUBGROUP WITH LOW DROPOUT RISK Criteria for low dropout risk 1 lesion 2-3 cm Complete response to 1 st treatment AFP after 1 st treatment < 20 ng/ml 20% Transplant would benefit Transplant not needed Do poorly after transplant Transplant not needed (or less urgent) Mehta N, et al. Liver Transpl 2013;19:

8 SUBGROUP WITH LOW DROPOUT RISK Cumulative Incidence % 21.6% 1.3% 26.5% All other patients (n=254) 1 lesion 2-3 cm, complete 1 st treatment response, AFP < 20 (n= 63) 1.6% Months after listing Criteria for low dropout risk 1 lesion 2-3 cm Complete response to 1 st treatment AFP after 1 st treatment < 20 ng/ml For now these HCC patients are still awarded same MELD exception points as other T2 HCC patients though policy being considered to change this Mehta N, et al. Liver Transpl 2013;19: Mehta N, et al. Liver Transpl 2013;19: OVERVIEW Current state of liver transplantation (LT) for HCC Refining selection criteria for LT Updates in down-staging and allcomers outcomes Novel biomarkers Assessing individualized post-transplant HCC recurrence risk Novel risk scores using explant pathology CASE PRESENTATION 55 year-old man with alcoholic cirrhosis, found on screeningu/stohavea6cmlesionintherightlobe. Quadphase CT abdomen showed a 6.5 cm arterial enhancing lesion in the right lobe with washout along with mild ascites. Examination showed no spider nevi. Spleen tip palpable. No alcohol in 3 years Dx: LI-RADS 5 HCC per Tumor Board review Laboratory evaluation showed bilirubin 1.7, ALT 28, AST 42, albumin 3.5, INR 1.3, platelets 85,000, AFP 36. 8

9 Down-staging of HCC for Transplant Definition: Reduction in the size of tumor using local regional therapy to meet acceptable criteria for liver transplant 1 Tumor response: Based on radiographic measurement of the size of all viable tumors, not including the area of necrosis from local regional therapy 2 A selection tool for tumors with more favorable biology that respond to down-staging treatment and also do well after liver transplant 1 1. Yao & Fidelman. Hepatology 2016;63: EASL Guidelines - Briux J. et al. J Hepatol 2001;35: LOCAL REGIONAL THERAPIES FOR HCC CHEMOEMBOLIZATION Transarterial (TACE) ABLATIONS CHEMICAL Percutaneous ethanol injection (PEI) THERMAL Radiofrequency ablation (RFA) (Laparoscopic, percutaneous or open) Microwave/ Cryo- ablation RADIOEMBOLIZATION (YITTRIUM - 90) & EXTERNAL BEAM IRRADIATION (SBRT) Y-90 RADIOEMBOLIZATION 56M with HCV and large HCC TheraSphere (glass microspheres) SIR-Spheres (resin microspheres) Radiographic response up to 90% Survival benefit unknown Risks of radiation damage Advanced tumor stage and preserved liver function (bilirubin < 2mg/dl) Radioembolization with TheraSphere/Y-90 9

10 56M with HCV and large HCC SIRT (Y-90) versus TACE (PREMIERE) Time to Progression (TTP) Y-90 P= C-TACE Pre-treatment 1 mo after Y-90 #1 1 mo after Y-90 #2 4 mo after Y-90 #1 Salem R, et al. Gastroenterology 2016;151: SIRT (Y-90) versus TACE (PREMIERE) Intention-to-treat Survival ctace --- Y90 POTENTIAL ROLES OF PRE-TRANSPLANT LOCAL REGIONAL THERAPY? To slow tumor progression and reduce risk of dropout from the waiting list bridge to liver transplant ctace Y Salem R, et al. Gastroenterology 2016;151:

11 POTENTIAL ROLES OF PRE-TRANSPLANT LOCAL REGIONAL THERAPY? To slow tumor progression and reduce risk of dropout from the waiting list bridge to liver transplant To reduce risk of post-transplant HCC recurrence Selection criterion tool; those who have a good response to LRT have better outcomes after LT POTENTIAL ROLES OF PRE-TRANSPLANT LOCAL REGIONAL THERAPY? To slow tumor progression and reduce risk of dropout from the waiting list bridge to liver transplant To reduce risk of post-transplant HCC recurrence Selection criterion tool; those who have a good response to LRT have better outcomes after LT Down-staging of HCC initially exceeding conventional or acceptable criteria Tumor Down-staging Before Liver Transplant Beyond Milan Within Milan Complete necrosis REGION 5 DOWN-STAGING PROTOCOL Inclusion criteria - 1 lesion > 5 cm and 8 cm - 2 or 3 lesions 5 cm w/ total tumor diameter 8 cm - 4 or 5 lesions 3 cm w/ total tumor diameter 8 cm - No vascular invasion on imaging Candidates can undergo deceased-donor LT 3 months after down-staging if within Milan criteria EASL and mrecist Yao & Fidelman. Hepatology 2016;63: Yao et al. Hepatology 2008;48:

12 Region 5 D/S Multi-center Study: Post-LT Survival Treatment Failure: AFP and Child s Class Probability of Survival % 95% 80% 56.2% 100% 2 Risk Factors 1 Risk Factor 0 Risk Factors Risk factors - Pre-treatment AFP > Child-Pugh B/C p= % 33% Years Post-Transplant Mehta N et al. Clinical Gastroenterology and Hepatology 2017 Mehta N et al. Clin Gastroenterol Hepatol 2018;16: Dropout UCSF/ Region 5 Down-staging criteria End-point of Down-staging = Milan Criteria Dropout Liver Transplant LRT for tumor down-staging Observation period > 3 months LRT for maintaining tumors within LT listing criteria 5-yr survival same as Milan criteria without down-staging CASE PRESENTATION 55 year-old man with alcoholic cirrhosis, found on screeningu/stohavea9cmlesionintherightlobe. Quadphase CT abdomen showed a 9 cm arterial enhancing lesion in the right lobe with washout along with mild ascites. Examination showed no spider nevi. Spleen tip palpable. No alcohol in 3 years. Dx: LI-RADS 5 HCC per Tumor Board review Laboratory evaluation showed bilirubin 1.7, ALT 28, AST 42, albumin 3.5, INR 1.3, platelets 85,000, AFP 36. UCSF/ Region 5 Down-staging protocol recently accepted as national policy 12

13 HCC Transplant UCSF Probability of Downstaging by Initial Tumor Burden Number of Lesions + Largest Tumor Diameter 68% 57% 47% MILAN CRITERIA DOWNSTAGING CRITERIA ALL-COMERS CRITERIA 38% 1 lesion < 5 cm 2-3 lesions < 3 cm No extra-hepatic dz 1 lesion 5.1-8cm 2-3 lesions 5 cm 4-5 lesions 3 cm TTD 8 cm No extra-hepatic dz Any number of tumors Total tumor burden beyond DS criteria No extra-hepatic dz Rassiwala J et al. AASLD 2016 Probability of Downstaging by Initial Tumor Burden HCC Recurrence (All-comers group) Number of Lesions + Largest Tumor Diameter 68% 57% 47% Meeting All-Comer Criteria (N = 74) Down-staged to Milan (N = 48) 38% Rassiwala J et al. AASLD 2016 Underwent LT (N = 10) Median 21.4 months from LT to recurrence Post LT Recurrence (N = 3) 13

14 Intention-to-Treat Survival UCSF-DS 56% All-Comers 21% P < CASE PRESENTATION 55 year-old man with alcoholic cirrhosis, found on screeningu/stohavea9cmlesionintherightlobe. Quadphase CT abdomen showed a 9 cm arterial enhancing lesion in the right lobe with washout along with mild ascites. Examination showed no spider nevi. Spleen tip palpable. No alcohol in 3 years. An upper limit in tumor burden probably exists beyond which successful LT after down-staging becomes an unrealistic goal Patients with tumor burden exceeding the Region 5 down-staging criteria must be very carefully selected for consideration of LT OVERVIEW Current state of liver transplantation (LT) for HCC Refining selection criteria for LT Updates in down-staging and allcomers outcomes Biomarkers Assessing individualized post-transplant HCC recurrence risk Novel risk scores using explant pathology Survival rate (%) AFP and Post-transplant Outcome- France P < French Multi center Study 68% 51% 39% n=387 n=109 n= Months after Liver Transplantation AFP <100 AFP AFP >1000 Duvoux et al. Gastroenterology 2012;143:

15 AFP and Post-transplant Outcome - UCSF AFP AND POST-LT HCC SURVIVAL AFP <1000 AFP > % 52% UNOS Database from (n=45,267) p = 0.03 y Hameed B. et al. Liver Transplantation 2014; Berry et al. Liver Transplantation 2013; AFP AND POST-LT HCC SURVIVAL UNOS Database from (n=45,267) LT FOR HCC: METROTICKET 2.0 HCC Specific Survival Berry et al. Liver Transplantation 2013; Mazzaferro V et al. Gastroenterology

16 REDUCING HIGH AFP PRIOR TO LT UNOS POLICY CHANGE High AFP Threshold Candidates with lesions meeting T2 criteria but with an AFP >1000 are not eligible for a standardized MELD exception If AFP falls <500 after LRT, the candidate is eligible for a standardized MELD exception Yao F. et al. AASLD 2017 UNOS POLICY CHANGE High AFP Threshold Candidates with lesions meeting T2 criteria but with an AFP >1000 are not eligible for a standardized MELD exception If AFP falls <500 after LRT, the candidate is eligible for a standardized MELD exception However, AFP reduction to <100 after LRT is ideal DCP and Post Transplant Outcome 5 Yr RFS 3 Yr RFS % 94% 90 84% % 50% 50 N=87 N=66 N= N=29 N= <=100 >100 <=400 >400 <300 >= 300 Fujiki 2009 Taketomi 2007 Fujiki et al. Am J Transpl 2009;9: Taketomi et al. Transplantation 2009;87:

17 DCP + AFP + AFP-L3 (Mayo Clinic) NLR + AFP (Pre-MORAL Risk Score) Factors predicting HCC Recurrence HR (p value) C statistic Milan 0.63 Among tumors within Milan AFP > (p=0.01) 0.68 DCP > (p<0.001) 0.7 AFP L3% > (p<0.001) 0.7 Absolute AFP L3 > (p=0.001) 0.68 Factors (Multivariate) HR (p value) Pre MORAL Score Pre MORAL NLR (p <0.0001) 6 AFP > (p <0.0001) 4 Largest tumor >3cm 3.0 (p < 0.001) 3 Pre MORAL Risk Score Risk category 0 2 Low risk 3 6 Medium risk 7 10 High risk >10 Veryhigh risk Chaiteerakij et al. Liver Transpl 2015; 21: Halazun KJ, et al. Ann Surg 2017;265: NLR + AFP (Pre-MORAL Risk Score) Within Milan, no risk factors Recurrence-free survival High risk Low risk Medium risk Very low risk Recurrence Free Survival (%) Risk factors - Radiologic tumor progression - AFP slope > 15 ng/ml/month Beyond Milan, no risk factors Within Milan, (+) risk factors Beyond Milan, (+) risk factors Months after liver transplantation Months after liver transplantation Halazun KJ, et al. Ann Surg 2017;265: Lai Q, et al. Liver Transpl 2013;19:

18 Recurrence Free Survival (%) 90% Risk factors - Radiologic tumor progression - AFP slope > 15 ng/ml/month Within Milan, no risk factors Beyond Milan, no risk factors Within Milan, (+) risk factors Beyond Milan, (+) risk factors Recurrence Free Survival (%) 90% 68% 42% Risk factors - Radiologic tumor progression - AFP slope > 15 ng/ml/month Within Milan, no risk factors Beyond Milan, no risk factors Within Milan, (+) risk factors Beyond Milan, (+) risk factors Months after liver transplantation Months after liver transplantation Lai Q, et al. Liver Transpl 2013;19: Lai Q, et al. Liver Transpl 2013;19: OVERVIEW Current state of liver transplantation (LT) for HCC Refining selection criteria for LT Updates in down-staging and allcomers outcomes Novel biomarkers RECURRENCE RISK SCORE RETREAT Risk Estimation of Tumor REcurrence After Transplant Assessing individualized post-transplant HCC recurrence risk Novel risk scores using explant pathology 18

19 RETREAT SCORE Predictor Points AFP at LT > Micro-vascular Invasion Yes 2 Largest Viable Tumor Size (cm) + Number of Viable Lesions >10 3 No RETREAT points scored for: AFP 0-20, no microvascular invasion, and explant pathology stage score of 0 Mehta N, et al. JAMA Oncology 2017 RETREAT SCORE: 1 YR RECURRENCE % % % % % 0% Risk Estimation of Tumor REcurrence After Transplant (1 year) 1.0% C Concordance Statistic % 4.0% 5.1% 11.4% 39.3% >5 _ RETREAT Score N= RETREAT SCORE: 5 YR RECURRENCE % % % % % Risk Estimation of Tumor REcurrence After Transplant (5 years) 75.2% RETREAT score predicted recurrence in validation cohort better than Milan: C Concordance Statistic 0.77 RETREAT C index of 0.82 (95% CI ) Milan C index of 0.70 (95% CI ) 2.9% 8.0% 10.8% 13.7% 28.7% >5 _ RETREAT Score N= VALIDATION OF RETREAT SCORE 19

20 USING RETREAT FOR HCC SURVEILLANCE AT UCSF RETREAT Proposed surveillance regimen 0 No surveillance (20% of the cohort) USING RETREAT FOR HCC SURVEILLANCE AT UCSF RETREAT Proposed surveillance regimen 0 No surveillance (20% of the cohort) 1-3 HCC surveillance every 6 months for 2 years 4 HCC surveillance every 6 months for 5 years USING RETREAT FOR HCC SURVEILLANCE AT UCSF RETREAT Proposed surveillance regimen 0 No surveillance (20% of the cohort) 1-3 HCC surveillance every 6 months for 2 years 4 HCC surveillance every 6 months for 5 years 5+ HCC surveillance every 3 months for 2 years; then every 6 months for years 2-5 USING RETREAT FOR HCC SURVEILLANCE AT UCSF RETREAT Proposed surveillance regimen 0 No surveillance (20% of the cohort) 1-3 HCC surveillance every 6 months for 2 years 4 HCC surveillance every 6 months for 5 years 5+ HCC surveillance every 3 months for 2 years; then every 6 months for years 2-5 Surveillance should be performed w/ multiphasic abdominal CT or MRI, chest CT, and AFP at the recommended interval. 20

21 RETREAT VALIDATION IN UNOS (N=3392) POST-LT IMS: CNIs C Statistic 0.75 for HCC recurrence prediction in UNOS Standard post-lt IMS is CNI (e.g tacrolimus) w/ mycophenolate and prednisone Postulated that CNIs may increase HCC recurrence risk Log-rank p<0.001 RETREAT Mehta N, et al. Am J Transplant 2017 Rodriguez-Peralvarez et al. J Hepatology 2013 POST-LT IMS: mtori mtor regulates cell growth, proliferation, metabolism, and aging SILVER TRIAL Prospective phase 3, multi-center international RCT mtor inhibitors have shown anticancer properties in in vitro and animal models Prevents angiogenesis by interfering with VEGF-mediated pathways, thus potentially limiting tumor growth Induces extensive microthrombi, thus potentially inhibiting tumor growth mtor pathway frequently up-regulated in HCC Many LT centers have shifted to using mtor based IMS in HCC pts undergoing LT Matter MS et al J Hepatology 2014 Geissler EK et al, Transplantation

22 SILVER TRIAL: RFS Prospective phase 3, multi-center international RCT SILVER TRIAL: OVERALL SURVIVAL Sirolimus Sirolimus No SIR No SIR Geissler EK et al, Transplantation 2016 Geissler EK et al, Transplantation 2016 POST-LT IMS Consider moving away from studying mtor inhibitors in all HCC LT recipients, but focus on those most likely to benefit UCSF Transplant 2018: Pioneering Advances in Transplantation THANKS! Questions? Specifically target those with up-regulation of mtor pathways, which occurs in ~50% of HCC pts Molecular subtyping of explant tumor may prove important, especially w/ 2nd generation mtor inhibitors that more widely block downstream targets At UCSF, pts w/ RETREAT score >4 are converted to MTOR based IMS at 4-12 wks post LT Mehta N et al, Liver Txp 2016; Matter MS et al J Hepatology