LA Liver Tx.ppt - American College of Gastroenterologys3.gi.org/wp-content/uploads/2013/01/13ACG_Western_Regional_0028.… · Transarterial Chemoembolization (TACE) SorafenibSorafenib

Fredric D. Gordon, MD

WhatWhat’’s New in Transplant?s New in Transplant?

Fredric D. Gordon, MDFredric D. Gordon, MD

Medical Director of Liver TransplantationMedical Director of Liver Transplantation

Director of HepatologyDirector of Hepatology

LaheyLahey Hospital and Medical CenterHospital and Medical CenterLaheyLahey Hospital and Medical CenterHospital and Medical Center

Associate Professor of MedicineAssociate Professor of Medicine

Tufts University School of MedicineTufts University School of Medicine

AgendaAgenda

•• Organ allocationOrgan allocation

•• Transplantation in HCCTransplantation in HCC

•• Live donor liver transplantationLive donor liver transplantation

•• Hepatitis C treatment in liver transplant Hepatitis C treatment in liver transplant recipientsrecipients

ACG Regional Postgraduate Course - Los Angeles, CA Copyright 2013 American College of Gastroenterology

1


New Look at an Old Problem:New Look at an Old Problem:Regional Disparity

Mean MELD Match Score 2009D d D N E tiDeceased Donor, No Exceptions

ELD

Sco

reM

E

Region

Median months to liver transplant for adult patients transplanted in

2009

1

29

3

118

67

5

10

34


2


Evolving Concepts in Allocation:Mortality Rates by MELD – “Transplant Benefit”Evolving Concepts in Allocation:Mortality Rates by MELD – “Transplant Benefit”

1000010000WaitlistWaitlist

100100

10001000TransplantTransplant

Mortality rate per 1000 patients

Mortality rate per 1000 patients

HR=3.64P<0.001

HR=2.35P<0.001

HR=1.21P=0.41

HR=0.62P<0.01

HR=0.38P<0.001

HR=0.22P<0.001

HR=0.18P<0.001

HR=0.07P<0.001

HR=0.04 P<0.001

11

1010

6-116-11 12-1412-14 15-1715-17 17-2017-20 21-2321-23

MELDMELD

24-2624-26 27-2927-29 30-3930-39 40+40+

HR=hazard ratioHR=hazard ratioMerion, et al. Am J Transpl, 2005;5:307-13

Organ AllocationOrgan AllocationChange from Regional to National Share 15Change from Regional to National Share 15

•• ““Livers from adult deceased donors will be offered to Livers from adult deceased donors will be offered to did t h li t d St t 1A 1B h hdid t h li t d St t 1A 1B h hcandidates who are listed as a Status 1A or 1B or who have a candidates who are listed as a Status 1A or 1B or who have a

MELD or PELD score of 15 or higher at the local, regional and MELD or PELD score of 15 or higher at the local, regional and national levels before they are offered to any candidates of national levels before they are offered to any candidates of lesser urgency within the local service area of the donor lesser urgency within the local service area of the donor hospital.hospital.””

•• Mortality rates were 6.3% for those with MELD scores of <15.Mortality rates were 6.3% for those with MELD scores of <15.

•• Implementation of National Share 15 would result in a Implementation of National Share 15 would result in a decrease of 25 deaths per year nationally when compared to decrease of 25 deaths per year nationally when compared to the current policy.the current policy.

UNOS Concept Document: Next Steps Towards Improving Liver Distribution, Jan 4, 2011


3


Organ AllocationOrgan AllocationRegional Share 35Regional Share 35

•• ““Livers from adult deceased donors will be Livers from adult deceased donors will be id d f did t ith MELDid d f did t ith MELDconsidered for candidates with a MELD or considered for candidates with a MELD or

PELD score of 35 or higher at the local PELD score of 35 or higher at the local and regional level before being offered to and regional level before being offered to any candidate with a lower score.any candidate with a lower score.””

•• Facilitates transplantation for the most Facilitates transplantation for the most urgent patients.urgent patients.

UNOS Concept Document: Next Steps Towards Improving Liver Distribution, Jan 4, 2011

UNOS Regional Map Redrawn


4


Impact of Hepatocellular

Carcinoma on Liver Allocation

Impact of Hepatocellular

Carcinoma on Liver AllocationAllocationAllocation

Anticipated that the number of HCV related tumors Anticipated that the number of HCV related tumors will double over the next 20 yearswill double over the next 20 years

The Milan Criteria set the stage for The Milan Criteria set the stage for orthotopicorthotopic liver liver transplantation to be widely accepted as a curative transplantation to be widely accepted as a curative

Anticipated that the number of HCV related tumors Anticipated that the number of HCV related tumors will double over the next 20 yearswill double over the next 20 years

The Milan Criteria set the stage for The Milan Criteria set the stage for orthotopicorthotopic liver liver transplantation to be widely accepted as a curative transplantation to be widely accepted as a curative treatment for early stage HCCtreatment for early stage HCC

Multiple treatments available but liver transplantation Multiple treatments available but liver transplantation offers a potential cure for both the HCC and offers a potential cure for both the HCC and underlying liver diseaseunderlying liver disease

treatment for early stage HCCtreatment for early stage HCC

Multiple treatments available but liver transplantation Multiple treatments available but liver transplantation offers a potential cure for both the HCC and offers a potential cure for both the HCC and underlying liver diseaseunderlying liver disease

Adult Non-Status 1 DDLTJanuary 1, 2009 - June 30, 2012

~40%~20%


5


22 25 28 29 31 33 35 etc.22 25 28 29 31 33 35 etc.

Problems With Current MELD Problems With Current MELD HCC AllocationHCC Allocation

HCC priority too high relative to nonHCC priority too high relative to non--HCCsHCCsStudies of drop-out rates (Washburn, Segev)

High % of transplants for HCC

HCC scores at transplant vary across the HCC scores at transplant vary across the countrycountry

HCC scores driving up all MELD/PELD HCC scores driving up all MELD/PELD scoresscores

TREATMENT OPTIONS FOR HCC

SURGERYSURGERYResectionResectionTransplantationTransplantation

ABLATIONABLATIONABLATIONABLATIONPercutaneous Ethanol Injection (PEI)Percutaneous Ethanol Injection (PEI)Radiofrequency Hyperthermia (RFA)Radiofrequency Hyperthermia (RFA)

CHEMOTHERAPYCHEMOTHERAPYTransarterial Chemoembolization (TACE) Transarterial Chemoembolization (TACE) SorafenibSorafenib

RADIATION THERAPYRADIATION THERAPYRadiation TherapyRadiation TherapyRadiation TherapyRadiation TherapyRadioactive Microspheres (Y90)Radioactive Microspheres (Y90)

Multidisciplinary HCC Review BoardMultidisciplinary HCC Review BoardHBP & Transplant Surgeons, Hepatologists, Interventional Radiologists, HBP & Transplant Surgeons, Hepatologists, Interventional Radiologists,

Medical Oncologists, Radiation Oncologists, traineesMedical Oncologists, Radiation Oncologists, traineesWeekly review of protocols, new cases, and ongoing therapyWeekly review of protocols, new cases, and ongoing therapyProvide consistent approach to HCCProvide consistent approach to HCC


6


Survival Following Resection for HCC in Survival Following Resection for HCC in ChildChild’’s A Cirrhoticss A Cirrhotics

Summary of Reported Series Since 2008

Author Country nStudy

DesignSURVIVAL (%)

1 year 3 year 5 year

Hiraoka, 2008 Japan 59 OBS 88 59

Guglielmi, 2008 Italy 69 OBS 90 72 57

Santabrogio, 2009 Italy 78 OBS 93 85 54

Abu-Hilal, 2008 UK 34 OBS 91 56

Ueno, 2009 Japan 123 OBS 99 92 80

H 2010 Chi 75 RCT 96 79 71Huang, 2010 China 75 RCT 96 79 71

Kagawa, 2010 Japan 55 OBS 93 83 77

Hung, 2011 Taiwan 229 OBS 97 88 79

TOTALS 722 94 84 67

21.723.225

% Dropout within 12 Months: HCC and Non-HCC Candidates by Region

Candidates Added 7/1/08 – 6/30/11

4.8

13.912

17.7

5

10

15

20

% D

ropo

ut

0

5

1 2 3 4 5 6 7 8 9 10 11 US

RegionHCC (Standard) Non-HCC


7


92.4

66 367.88090

100d

% Transplanted within 12 Months: HCC and Non-HCC Candidates by Region

Candidates Added 7/1/08 – 6/30/11

39.4

66.367.8

25.5

39.1

10203040506070

% T

rans

plan

te

01 2 3 4 5 6 7 8 9 10 11 US

RegionHCC (Standard) Non-HCC

HCC Drop Out RatesHCC Drop Out Rates

> 3 cm +> 3 cm +

≤ 3 cm

Yao, et al, Liver Transplantation 2003 9:684-92


8


Hepatocellular CancerHepatocellular CancerChanges in MELD PrioritizationChanges in MELD Prioritization

OriginalOriginal April 2003April 2003 Jan 2004Jan 2004 Jan 2005Jan 2005

Stage IStage I

1 tumor < 2cm1 tumor < 2cm

15% Risk 15% Risk =MELD 24=MELD 24


0 Risk 0 Risk =MELD =MELD calculatedcalculated

0 Risk 0 Risk =MELD =MELD calculatedcalculated

Stage IIStage II1 tumor 1 tumor ≥≥ 2CM 2CM but ≤ 5 cm or 2but ≤ 5 cm or 2--3 tumors 3 tumors largest < 3 CMlargest < 3 CM


15%Risk 15%Risk =MELD 24=MELD 24



HCC Consensus Conference, 2008HCC Consensus Conference, 2008

HCC ALLOCATION POLICY: HCC ALLOCATION POLICY: Where Are We Today?Where Are We Today?

RecommendationsRecommendations Imaging Criteria

Pathology Form

Revise HCC allocation policy: “Allocation policy should result in similar risks of removal from the

waiting list and similar transplant rates for HCC and non-HCCwaiting list and similar transplant rates for HCC and non-HCC candidates.”

“Similar post-transplant outcomes for HCC and non-HCC recipients.”

“Development of a calculated continuous HCC priority score”

Downstaging, Expansion of Milan, LRT – on hold


9


MELD Policy Principles Applied to HCC

• Use objective risk factors associated with drop-out.

MELD• MELD• Maximum tumor size• Tumor number• AFP

• Use time from diagnosis (meeting criteria) as selection for less aggressive biologygg gy

• Continuous scale• Use continuous score, “HCC MELD”

6008000

T

Live Donor Liver Transplant Live Donor Liver Transplant TrendTrend

200

300

400

500

3000

4000

5000

6000

7000

of d

ecea

sed

dono

r LT

# of

live

don

or L

T

0

100

200

0

1000

2000

1 3 5 7 9 11 13 15 17 19 21 23 25

# o

19

88

19

90

19

92

19

94

19

96

19

98

20

00

20

02

20

04

20

06

20

08

20

10


10


Should Living Donors Be Used for Should Living Donors Be Used for Patients with Hepatocellular Carcinoma?Patients with Hepatocellular Carcinoma?

Pre-MELD Post-MELD

, 2012


11


Freedom From RecurrenceFreedom From Recurrence

DDLT(%

)

LDLT

HR=2.35, p=0.0408

dom

from

Rec

urre

nce

(

Recurrence

LDLT: 38% DDLT: 11%

Kulik et al. American Journal of Transplantation Nov 2012

Fre

ed

Years from Transplant

LDLT: 38%, DDLT: 11%

• Even in countries with adequate access to DDLT, that live liver donation is appropriate due to organ shortages.

• Organ allocation policies prioritizing pts with HCC within MC do not apply

Ethical Considerations

Organ allocation policies prioritizing pts with HCC within MC do not apply to LDLT since the needs of the other candidates without HCC are not being disadvantaged.

• Donor safety is of paramount importance in living donor liver transplantation and yet living donor complications and deaths occur even in the most experienced hands (0.1%-0.5% mortality, 10%-38% morbidity)morbidity)

• “Vancouver Forum” (2008) established practice principles for LDLT: – Live liver donation should only be performed if the risk to the donor

is justified by the expectation of an acceptable outcome in the recipient.


12


Liver Transplantation and Treatment of Hepatitis C

• HCV is a major cause of morbidity and mortality after liver transplantation

• Significant resource utilization

O’Leary et al., Liver Transpl 2009:15:360-8

EVR

Peginterferon alfa-2b and Ribavirin for Hepatitis C Recurrence Post–Orthotopic Liver Transplantation (OLT)

HCV RNAEVR

HCV RNA

PEGPEG--IFN alfaIFN alfa--2b 1.5 2b 1.5 µg/kg/wk +µg/kg/wk +RBV 400RBV 400--1200 mg/day1200 mg/day

48 weeks48 weeks

FollowFollow--upup24 weeks24 weeks

ScreeningScreening

RVRHCV RNA HCV RNA

Day 1

Bas

elin

eB

asel

ine

Treatment week 1–2: RBV 400 mg/dayTreatment week 3–4: RBV 800 mg/dayTreatment week 5–48: RBV dose increased to maximum of 1200 mg/day

(weight based) if well tolerated

Wk 24Wk 4 Wk 12 Wk 48


13


Sustained Virologic ResponseITT Analysis

70

80

2924

55

30

40

50

60

70S

VR

, %

0

10

20

All Patients Genotype 1 Genotype 2/3

36/125 25/105 11/20

Sustained Virologic ResponseStudy Completion Analysis*

69

80

5550

30

40

50

60

70

SV

R, %

ITT: ITT: 29%29% ITT: ITT:

24%24%

ITT: ITT: 55%55%

0

10

20

All Patients Genotype 1 Genotype 2/3

•28

36/66 25/50 11/16

*Patients who completed 48 weeks of treatment and 24 weeks of follow-up.


14


Safety

All Patients(N = 125),

n (%)Adverse Event

Treatment-emergent adverse events 125 (100)

Adverse events leading to study drug discontinuation 38 (30)

Serious adverse events 32 (26)

Severe/life-threatening treatment-related adverse 44 (35)

•29

gevents

44 (35)

Rejection episodes 4 (3)

Treatment-emergent infections 50 (40)

Protease inhibitorsProtease inhibitors

A Multicenter Study of Protease Inhibitor-Triple Therapy in HCV-Infected Liver Transplant Recipients:

Report From The CRUSH-C Group

LILI Triple Triple TherapyTherapy P+RP+RLI <90 days: 29

(N=87)

Protease inhibitors Protease inhibitors available midavailable mid--20112011Median Median

Days LIDays LIMedian Days Median Days

Total TreatmentTotal Treatment

154

Time

LILI Triple Triple TherapyTherapy P+RP+RLI ≥90 days: 189

(N=14)398

101 patients from 5 centersBurton JR, et al., AASLD Oct 2012, Boston


15


HCV RNA <LOD at Weeks 4-12 of Triple Therapy

The median time to HCV RNA <LOD: Start of P+R LI = 54 days (IQR: 46-84)

V R

NA

<LO

D

Start of P+R LI = 54 days (IQR: 46-84)Start of PI = 23 days (IQR: 13-34)

% H

CV

N=83 N=68 N=69

*HCV RNA negative at 4 and 12 weeks; missing week 4 (N=1), missing week 12 (N=15)

N=71

Early Discontinuation of Triple Therapy

• 12% had virologic breakthrough– LI <90 days: 10%

– LI ≥90 days: 21%

• 14% had AE leading to early D/CLI <90 days: 11% (data missing in 11)– LI <90 days: 11% (data missing in 11)

– LI ≥90 days: 40% (data missing in 4)

Burton JR, et al., AASLD Oct 2012, Boston


16


Immunosuppression Dosing after PIm

g

mg75%

reduction 90% reduction


Adverse EventsBlood transfusions 49%

# units in 1st 16 weeks, median (IQR) 2.5 (2.0-6.5)( ) ( )Use of growth factors 86%

G-CSFErythropoietin

44%79%

Dose reduction during triple therapyPeginterferon 27%Ribavirin*Both

78%23%

*Median (IQR) ribavirin dose (mg):Max dose = 800 (600-1000)Reduction in dose during triple therapy = 400 (200-600)


17


Adverse Events

Creatinine >0.5mg/dL from baseline 32%Max Δ creat from baseline median (IQR) 0 4 (0 2 0 7)Max Δ creat from baseline, median (IQR) 0.4 (0.2-0.7)

Rash* 6%Treated rejection (1-transition off PI, 1- late) 2%Hospitalization due to AE 21%

Indication for hospitalization: AnemiaInfection

7%4%Infection 4%

Deaths (1-sepsis, 1-HRS) 2%

*Requiring more than topical therapy


ConclusionsConclusions

•• Organ allocation disparity remains a major Organ allocation disparity remains a major problem on a national levelproblem on a national levelpp

•• HCC is the indication for transplantation in HCC is the indication for transplantation in a high percentage of patientsa high percentage of patients

•• Live donor liver transplantation is Live donor liver transplantation is diminishing in frequency but may have diminishing in frequency but may have

t ti l f b d li tit ti l f b d li tipotential for broader applicationpotential for broader application

•• Treatment of HCV with triple therapy after Treatment of HCV with triple therapy after transplantation will likely have less transplantation will likely have less success than in nonsuccess than in non--transplant patientstransplant patients


18

Documents

LA Liver Tx.ppt - American College of Gastroenterologys3.gi.org/wp-content/uploads/2013/01/13ACG_Western_Regional_0028.… · Transarterial Chemoembolization (TACE) SorafenibSorafenib