UCSF Transplant 2016: Building Bridges to Excellence OVERVIEW Liver Transplant for Hepatocellular Carcinoma (HCC): What is New? Neil Mehta, MD 9/29/16 UCSF Division of Gastroenterology and Hepatology Current state of liver transplantation (LT) for HCC Let s push past the Milan criteria Refining selection criteria for LT Updates in down-staging outcomes Proposed UNOS policy changes Risk factors for post-lt HCC recurrence How often to perform surveillance? LIVER TRANSPLANTATION FOR HCC MILAN CRITERIA LIVER TRANSPLANTATION FOR HCC T1 and T2 CRITERIA 1 lesion 5 cm 2 to 3, none > 3 cm 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 + Absence of Macroscopic Vascular Invasion Absence of Extra-hepatic Spread Mazzaferro, et al. N Engl J Med 1996;334:693-699 1
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 2006 15 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 2006 15 72 LT for HCC in 2015 47 0 05 06 07 08 09 10 11 12 13 14 15 Year 0 05 06 07 08 09 10 11 12 13 14 15 Year LIVER TRANSPLANT FOR HCC: PROBLEMS & CHALLENGES HCC misdiagnosis Outcome after liver transplant for HCC still slightly worse than that for non-hcc indications 1 HCC patients receiving unfair advantage for donors compared to non-hcc patients 2,3 1. Ioannou GN, et al. Gastroenterology 2008; 134:1342-1351 2. Washburn K, et al. Am J Transpl 2010;10:1652-7 3. Goldberg D, et al. Liver Transpl 2012;18:434-443 OUTCOME OF LIVER TRANSPLANT FOR HCC IN THE MELD ERA (2002-2007) 2002-2007 N Adjusted * Patient Survival () HR (95 CI) 1 yr 2 yr 3 yr 4 yr No HCC 14351 1 88.3 83.8 80.8 78.0 HCC, no exception 592 1.58 (1.3-1.9) 83.5 72.6 67.8 67.8 HCC, MELD 4453 1.27 (1.1-1.4) 89.0 81.4 76.5 72.7 exception HCC, MELD 3595 1.33 (1.2-1.5) 88.3 80.4 74.8 70.7 exception (> 2 cm) *Adjusted for MELD score, underlying liver disease, age, gender, race/ethnicity, BMI and donor age (+ other donor factors) Ioannou GN, et al. Gastroenterology 2008; 134:1342-1351 2
WAITLIST DROPOUT OR DEATH: HCC VS NON-HCC 25 Too sick Died 20 P<0.001 15 P<0.001 10 P< 0.001 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 5 0 HCC Non-HCC MELD 22 MELD 21-23 HCC Non-HCC MELD 25 MELD 24-26 HCC Non-HCC MELD 28 MELD 27-29 Goldberg D, et al. Liver Transpl 2012;18:434-443 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 LI-RADS 5: Definite HCC LI-RADS 4: Probable HCC LI-RADS 3: Indeterminate 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 1-1.9 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 3
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 1-1.9 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) 0 108.7 30.1 3 months 65.0 32.5 Do poorly after transplant 6 months 44.2 33.9 9 months 33.6 34.8 Moving past one-size fits all Heimbach J, et al. Hepatology 2015;61:1643-1650 Mehta N, and Yao FY. Liver Transpl 2013;19:1055-1088 4
- Local regional therapy - Observation period/ Wait time - Local regional therapy - Observation period/ Wait time Do poorly after transplant Do poorly after transplant Tumor Down-staging Do poorly after transplant 20 Do poorly after transplant (or less urgent) 5
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 SUBGROUP WITH LOW DROPOUT RISK Criteria for low dropout risk 1 lesion 2-3 cm Complete response to 1 st treatment AFPafter1 st treatment < 20 ng/ml Cumulative dropout risks of 1.3 at 1 year, and 1.6 at 2 years. Accounts for 20 of entire cohort Mehta N, et al. Liver Transpl 2013;19:1343-1353 Mehta N, et al. Liver Transpl 2013;19:1343-1353 PROPOSED UNOS POLICY CHANGE Cumulative Incidence 10 20 30 21.6 26.5 All other patients (n=254) 1 lesion 2-3 cm, complete 1 st treatment response, AFP < 20 (n= 63) Single Small Lesion Criteria Candidates who initially present w/ single 2-3 cm lesion must be treated with local-regional therapy (LRT) in order to be eligible for automatic MELD exception If the lesion is completely treated after 1+ LRTs, the candidate is not eligible for MELD exception until lesion recurs or develops a new lesion 1.3 1.6 Months after listing If the lesion persists or recurs after 1+ LRTs, the candidate is eligible for MELD exception Mehta N, et al. Liver Transpl 2013;19:1343-1353 6
OPTIMIZING SELECTION CRITERIA OPTIMIZING SELECTION CRITERIA Scenario: Your patient with a 3.5 cm HCC is at the top of the wait list and is expecting a liver offer at any time. Today in clinic he asks you what his expected outcomes are after transplant. Scenario: Your patient with a 3.5 cm HCC is at the top of the wait list and is expecting a liver offer at any time. Today in clinic he asks you what his expected outcomes are after transplant. 5 yr post-lt survival: 75-80 5 yr HCC recurrence: ~15 OPTIMIZING SELECTION CRITERIA Scenario: Your patient with a 3.5 cm HCC is at the top of the wait list and is expecting a liver offer at any time. Today in clinic he asks you what his expected outcomes are after transplant. Do poorly after transplant?? 10-20 Do poorly after transplant 5 yr post-lt survival:??? 5 yr HCC recurrence:??? 7
OPTIMIZING SELECTION CRITERIA OPTIMIZING SELECTION CRITERIA AFP Response to LRT Response to LRT 3.5 cm 3.5 cm OPTIMIZING SELECTION CRITERIA OPTIMIZING SELECTION CRITERIA AFP AFP Response to LRT 7.5 cm Response to LRT 7.5 cm 3.5 cm 3.5 cm 5 yr post-lt survival: 5 yr HCC recurrence: 8
DOWNSTAGING 7.5 cm DOWN-STAGING Down-staging: Reduction in the size of tumor(s) using LRT to meet acceptable LT criteria Tumor response to down-staging treatment is based on radiographic measurement of the size of viable tumors 3.5 cm 5 yr post-lt survival: 5 yr HCC recurrence: Yao FY, et al, Liver Transpl 2011; Ravaioli et al. Am J Transpl 2008; Pomfret et al. Liver Transplant 2010; Bruix, J et al EASL Practice Guidelines, J Hepatology 2012 UCSF 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 Candidates can undergo LDLT 3 months after down-staging if within UCSF criteria* *1 lesion <6.5cm or 2-3 lesions <4.5cm with total tumor diameter <8cm Yao et al. Hepatology 2008;48:819-827 UCSF DOWN-STAGING 122 consecutive patients with HCC treated under UCSF down-staging protocol from 2002-11 Endpoint of down-staging: Residual tumor(s) within Milan criteria Down-staging group compared w/ 488 consecutive patients with initial HCC meeting T2 criteria listed for LT over same time period Median time from 1 st down-staging to LT 10 months Yao et al. Hepatology 2015; 1968-77 9
Patient Proportion Survival without death 100 75 50 0 POST-TRANSPLANT SURVIVAL Control down-staging Kaplan-Meier plot of Time to death By group P=0.87 Milan (T2) group (n= 332) 81 80 Down-staging group (n= 68) Cont r ol : 332 273 228 184 136 100 Median post-transplant follow-up 4.0 yrs 25 Down- st agi ng: 68 58 50 42 34 29 0 1 2 3 4 5 Years Years from after the date Liver of Transplant liver transplant Log-Rank 228 Test P-Value is 0.8733 184 332 273 136 100 68 58 50 42 34 29 Proportion without recurrence Recurrence-free probability 100 75 50 25 0 RECURRENCE-FREE PROBABILITY Control down-staging Kaplan-Meier plot of Time to recurrence By group Down-staging group (n= 68) P=0.31 Cont r ol : 309 255 213 167 126 95 Down- st agi ng: 68 56 48 40 33 28 0 1 2 3 4 5 Years Years from after the date Liver of Transplant liver transplant Milan (T2) group (n= 332) 91 88 Log-Rank 213 Test P-Value is 0.3097 167 332 265 126 95 68 56 48 40 33 28 MULTI-CENTER DOWN-STAGING The UCSF down-staging protocol has been adopted by the rest of Region 5 Were our single center findings reproducible? REGION 5 DOWN-STAGING RESULTS 187 patients at UCSF, CPMC, and Scripps Successful down-staging: residual tumor(s) within Milan criteria 58 underwent LT a median of 13 months from 1 st down-staging procedure Favorable explant characteristics 81 within Milan 6 microvascular invasion 1 poorly differentiated tumor grade Mehta N et al. Hepatology 2014; 60 (Suppl):253A (AASLD 2014) 10
POST-TRANSPLANT SURVIVAL RECURRENCE-FREE PROBABILITY Probability of Survival 1.0 0.8 0.6 0.4 0.2 84.0 95 Median post-lt follow-up period 4 years 80 56.2 Recurrence Free Probability 1.0 0.8 0.6 0.4 0.2 95 87 0.0 0 1 2 3 4 5 Years Post-Transplant 85 119 101 70 187 109 150 98 83 56 56 46 0.0 0 1 2 3 4 5 Years Post-Transplant 109 95 83 68 55 44 Mehta et al. AASLD 2014 PROPOSED UNOS POLICY CHANGES Downstaging Candidates that meet the UCSF/Region 5 downstaging protocol and then complete LRT must be successfully down-staged into Milan criteria to receive a MELD exception AFP AFP 3.5 cm 5 yr post-lt survival: 5 yr HCC recurrence: 11
AFP and Post-transplant Outcome- France AFP and Post-transplant Outcome - UCSF 100 Survival rate () 80 60 40 20 P < 0.001 68 51 39 n=387 n=109 n=61 AFP <100 AFP 100-1000 AFP >1000 AFP <1000 AFP >1000 p = 0.03 80 52 0 0 12 24 36 48 60 72 84 96 Months after Liver Transplantation y Duvoux et al. Gastroenterology 2012;143:986-94 Hameed B. et al. Liver Transplantation 2014; 945-951 AFP AND POST-LT HCC SURVIVAL UNOS Database from 2002-11 (n=45,267) AFP AND POST-LT HCC SURVIVAL UNOS Database from 2002-11 (n=45,267) Berry et al. Liver Transplantation 2013; 634-45 Berry et al. Liver Transplantation 2013; 634-45 12
PROPOSED UNOS POLICY CHANGES High AFP Threshold Candidates with lesions meeting T2 criteria but with an AFP >1000 are not eligible for a standardized MELD exception If these lesions fall <500 after LRT, the candidate is eligible for a standardized MELD exception Candidates with an AFP level 500 at any time point following LRT will be referred to the review board OPTIMIZING SELECTION CRITERIA Response to LRT 3.5 cm 5 yr post-lt survival: 5 yr HCC recurrence: RESPONSE TO LOCAL-REGIONAL THERAPY AS PROGNOSTIC FACTOR Recurrence Rate () 18 5 Recurrence Free Survival () Risk factors - Radiologic tumor progression - AFP slope > 15 ng/ml/month, no risk factors Beyond Milan, no risk factors, (+) risk factors Beyond Milan, (+) risk factors Months after liver transplantation Kim DJ, et al. Am J Transpl 2014; 1383-90 Lai Q, et al. Liver Transpl 2013;19:1108-1118 13
Recurrence Free Survival () 90 Risk factors - Radiologic tumor progression - AFP slope > 15 ng/ml/month, no risk factors Beyond Milan, no risk factors, (+) risk factors Beyond Milan, (+) risk factors Recurrence Free Survival () 90 68 42 Risk factors - Radiologic tumor progression - AFP slope > 15 ng/ml/month, no risk factors Beyond Milan, no risk factors, (+) risk factors Beyond Milan, (+) risk factors Months after liver transplantation Months after liver transplantation Lai Q, et al. Liver Transpl 2013;19:1108-1118 Lai Q, et al. Liver Transpl 2013;19:1108-1118 OVERVIEW Current state of liver transplantation (LT) for HCC Let s push past the Milan criteria Refining selection criteria for LT Updates in down-staging outcomes Proposed UNOS policy changes DEVELOPMENT AND VALIDATION COHORTS Development cohort: 721 consecutive adult patients with HCC within Milan criteria who underwent LT from 2002-12 (UCSF, Mayo Roch, Mayo Jax) Validation cohort: 340 patients who underwent LT with same inclusion criteria at University of Toronto Risk factors for post-lt HCC recurrence How often to perform surveillance? 14
RECURRENCE RISK SCORE RETREAT Risk Estimation of Tumor REcurrence After Transplant RETREAT SCORE Predictor Points AFP at LT 21-99 1 100-999 2 >1000 3 Micro-vascular Invasion Yes 2 Largest Viable Tumor Size (cm) + Number of Viable Lesions 1-4.9 1 5-9.9 2 >10 3 No RETREAT points scored for: AFP 0-20, no microvascular invasion, and explant pathology stage score of 0 RETREAT SCORE: 1 YR RECURRENCE 50 40 30 20 10 0 Risk Estimation of Tumor REcurrence After Transplant (1 year) 1.0 C Concordance Statistic 0.77 2.9 4.0 5.1 11.4 39.3 0 1 2 3 4 >5 _ RETREAT Score N= 149 220 155 73 45 47 RETREAT SCORE: 5 YR RECURRENCE 80 60 40 20 0 Risk Estimation of Tumor REcurrence After Transplant (5 years) C Concordance Statistic 0.77 28.7 13.7 10.8 8.0 2.9 75.2 0 1 2 3 4 >5 _ RETREAT Score N= 149 220 155 73 45 47 15
VALIDATION OF RETREAT SCORE RETREAT score predicted recurrence in validation cohort better than Milan: RETREAT C index of 0.82 (95 CI 0.77-0.86) Milan C index of 0.70 (95 CI 0.63-0.76) 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 16
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 Do poorly after transplant?? 10-20 Do poorly after transplant Surveillance should be performed w/ multiphasic abdominal CT or MRI, chest CT, and AFP at the recommended interval. Do poorly after transplant?? 10-20 1) High AFP 2) Poor response to LRT Do poorly after transplant 20 (or less urgent)?? 17
1) Single 2-3 cm lesion 2) Complete response to LRT 3) AFP <20 : IS THERE A PLACE FOR DOWN-STAGING? 20 Successful Down-staging (or less urgent)?? UCSF Transplant 2016: Building Bridges to Excellence THANKS! Special thanks to Dr. Francis Yao Questions? Neil.mehta@ucsf.edu 18