chung mau lo 2

8/14/2019 Chung Mau Lo 2

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Living Donor Liver Transplantation

for Hepatocellular Carcinoma

Chung-Mau Lo

Chin Lan Hong Professor of Hepatobiliary Surgery

Department of Surgery

The University of Hong Kong Medical Center

Queen Mary Hospital

Hong Kong, China


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Pros:

Widest resection

Removes multicentric tumor/intrahepatic metastasis

Prevents metachronous disease

Cures underling liver disease

Prevents liver failure

Most accurate pathologic staging

Cons:

Transplant-related morbidity

Need for immunosuppression

Recurrence under immunosuppression

Cost

Limited organ supply

HEPATOCELLULAR CARCINOMA

Liver Transplantation


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Selection Criteria for Transplantation

Criteria n long-term survival

Milan solitary 5 cm 48 75%

(NEJM 1996) 1-3 lesions, 3 cm

USCF solitary 6.5 cm 70 72.4%

(Hepatology 2001) 1-3 lesions, 4.5 cm

total diameter 8 cm

Expected 5-year survival >70%


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Limited availability

restricted candidacy

Prolonged waiting timetumor progression and dissemination

Unpredictable timingimpossible to plan neoadjuvant treatmentinaccurate assessment of tumor status


Liver Transplantation: Deceased Donor Graft


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Liver Transplantation: Intention-to-treat Analysis

Survival(%)no. of patients drop out 1 years 3 years 5 years

Llovet et al 1999

Partial hepatectomy 77 / 85 62 51

Liver transplant 87 8 (9%) 82 69 69

Yao et al 2002

Liver transplant 46 11 (23%) 92 73 /


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Liver Transplantation


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Living Donor Liver Transplantation


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Deceased donor Living donor

Availability

Source Limited Unlimited

Candidacy Maximal benefit Risk/benefit analysis

Allocation Objective criteria Dedicated gift

Waiting time Long Short

Timing Unpredictable Planned


Liver Transplantation: Deceased Vs Living Donor


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0 12 24 36 48 60

Months

0

10

20

30

40

50

60

70

80

90

100

Patie

ntsurvival(%)

LDLTCDLT

no transplant


Deceased Donor Vs Living Donor- Decision Analysis

Cheng et al, Transplantation 2001

86%

71%

63%

8%

42%

68%

Hypothetical cohort of patients:

unresectable HCC of 3.5 cm with cirrhosis


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Ignores the risks of living donors

Wrong assumptions Living donor readily available

Comparable outcome between deceased and living donor transplants


Limitation of Decision Analysis


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Wrong assumptions Living donor readily available



Limitation of Decision Analysis (I)


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Location Number Total

Asia Japan 1 5

Hong Kong 1

Singapore 1

India 2

Europe Germany 2 4

France 1

Unknown 1N. America USA 3 3

S. America Brazil 1 1

Africa Egypt 1 1

Total 14

LIVING DONOR LIVER TRANSPLANTATIONDonor Deaths

Search in medical and lay literature

Trotter, Adam and Lo Liver Transplantation 2006


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Wrong assumptions

Living donor readily available

donor voluntarism

donor selection criteria



Limitation of Decision Analysis (II)


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Selection Criteria

Recipients (n=51)

65 years old

unresectable HCC, Milan/UCSF criteria Donors

voluntarism and informed consent

60 years old

ABO compatibility

negative hepatitis serology and normal liver function

no extra operative risk

graft size >40% of recipients standard liver weight

liver remnant >30% of donors standard liver weight


Are Living Donors Readily Available?

Lo et al, Liver Transplantation 2004


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Patients with HCC on

list

51

On list for CDLT

30

Voluntary donor available

25

No voluntary donor

26

Died before CDLT 19

Alive, off list 2Alive, waiting 1

CDLT oversea 2

CDLT performed

6(12%)

LDLT performed

21 (41%)

Donor not suitable 4HBsAg positive 2ABO incompatible 1Liver dysfunction 1


Results



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0 6 12 18 24 30 36 42 48

Time (months)

0

10

20

30

40

50

60

70

80

90

100

Probabilityofpatientsurvival(%)

No. at riskWith donor 25 24 23 16 13 9 7 3 3Without donor 26 22 18 14 8 7 6 5 4


Intention-to-treat Patient Survival


66%

31%

P=0.029


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Wrong assumptions

Living donor readily available

donor voluntarism

donor selection criteria


Lower graft survival

Higher risk of biliary complications

Other complications and learning curve effect

?Higher recurrence rate

Lack of waiting period for drop-out of poor risk tumors

acute-phase injury of small-for size graft with regeneration and angiogenesis

promotes recurrence


Limitation of Decision Analysis (III)


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LIVING DONOR LIVER TRANSPLANTATION

Graft Survival in Adults (US Data)

LDLT

Donor younger shorter ischemic time

Recipient

fewer retransplant lower MELD score fewer status 1 or 2a

Abt et al, Am J Transplantation 2004

A Marginal Graft!?

Adjusted HR for graft failure requiringretransplantation = 1.66 (1.30-2.11)


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0 6 12 18 24 30 36 42Time (months)

0

0.2

0.4

0.6

0.8

1

Probabilityofsurvival

RIGHT LOBE LIVER TRANSPLANTATION

Graft Survival

96%100%

74%

First 50 cases

Second 50 cases

74%78%

P=0.0015

Lo et al, Ann Surg 2004

Relative risk (95% CI) P-valueSecond 50 cases 0.13 (0.03-0.66) 0.014 Child C 2.28 (0.28-18.87) 0.443MELD >30 1.96 (0.35-11.10) 0.446ICU-bound 0.30 (0.05-1.88) 0.200Hepatorenal syndrome 0.95 (0.22-4.05) 0.947


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Kyoto (Kaihara, 2003) Mount Sinai (Gondolesi, 2004)

Number of patients 56 36

Byond Milan criteria 25 (45%) 19 (53%)

Median follow up (mths) 11 (1-39) 15.7 (


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LDLT (n=43) DDLT (n=17)

Age (yrs) 52 (11-64) 49 (38-61)

Male gender 39 (91%) 15 (88%)

MELD score 15 (6-59) 16 (12-33)

Incidental tumour in explant 3 (7%) 5 (29%)*

Recurrence after hepatectomy/RFA 10 (23%) 1 (6%)TOCE after on list 1 (2%) 4 (50%)*

AFP (ng/ml) 30 (1-15084) 19 (4-902)

* p


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Waiting time (days) 27 (1-341) 110 (7-1359)*

Graft weight (gm) 570 (330-1120) 1105 (830-1845)*

Graft weight/recipient SLW 0.45 (0.31-0.79) 0.85 (0.62-1.87)*


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Tumor no. 1 (1- >9) 1 (1- >9)

Tumor size 2.5 (1.0-7.0) 2.5 (1.2-6.5)

Vascular permeation 15 (35%) 3 (18%)

Differentiation (well/moderate/poor) 17/18/8 5//9/3

Beyond Milan criteria 11 (26%) 5 (29%)

Beyond UCSF criteria 7 (16%) 2 (12%)


Deceased Donor Vs Living Donor-Histology

Lo et al, BJS in press


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LIVER TRANSPLANTATION FOR HCC

Patient Survival

0 6 12 18 24 30 36 42 48 54 60

Time (months)

0

20

40

60

80

100

Overallpatientsurv

ival(%)

Cause of death LDLT DDLT

recurrent HCC 6 0

recurrent HCV 1 0

recurrent HBV 0 1

Others 3 0

No. at risk

Living donor graft 43 35 30 26 20 15 11 7 5 3 2

Deceased donor graft 17 15 13 13 11 10 8 7 7 6 6

LDLT (n=43)

DDLT (n=17) 94%

58%

P=0.187

Median follow-up 33 (4-120) months



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Recurrence Rate

No. at risk

Living donor graft 43 41 33 27 22 17 14 10 6 5 4

Deceased donor graft 17 16 16 13 13 13 10 8 7 7 6

LDLT (n=43)

DDLT (n=17)

29%

0%

P=0.029

Median time to recurrence 15 (6-26) months

0 6 12 18 24 30 36 42 48 54 60

Time (months)

0

20

40

Cumulativerecurrencerate(%)


All patients fulfilled radiologic UCSF criteria


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5-yr survival p-value 5-yr recurrence p-value

Incidental tumor (yes/no) 100%/64% 0.102 0%/23% 0.160

Salvage transplant (yes/no) 63%/81% 0.053 45%/14% 0.002

Graft type (LDLT/DDLT) 58%/94% 0.187 29%/0% 0.029

Graft weight/SLW ( 0.6/>0.6) 53%/96% 0.078 32%/0% 0.009

Tumor no. ( 3/> 3) 72%/67% 0.152 16%/52% 0.032

Vascular permeation (yes/no) 69%/74% 0.206 29%/16% 0.034

Beyond Milan criteria (yes/no) 71%/71% 0.412 38%/14% 0.028

Beyond UCSF criteria (yes/no) 67%/72% 0.180 50%/16% 0.047


Results-Prognostic Variables



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Time to Recurrence by Donor Type

Free

domfromR

ecurrence

(%)

100

75

25

0

50

Years from Transplant

0 1 2 3

DDLT

LDLT

Unadjusted P=0.0024

A2ALL, AASLD San Francisco 2006


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Recurrences by Stage at Explant

17/870/3117/56Total

5/240/85/16T4a or T4b

7/240/57/19T3

4/300/134/17T1 or T2

1/90/51/4No HCC

TotalDDLTLDLTStage at Explant

A2ALL, AASLD San Francisco 2006


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Orthotopic rat liver transplantation modelMale Buffalo rats (300g) as donors and recipients

Whole graft Small (50-60%) graft

Sampling at day 1, 3, 7, 14 and 21 after liver transplantation

Acute phase injury

Tumor cell (CRL1601, 2105) injection

via portal vein after reperfusion

Tumor progression

and invasion

AngiogenesisCell adhesion

and invasion

Histology

Protein expression IHC and Western blot

Gene expression - cDNA microarray


Effect of Graft Size-Animal Model


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Whole graft

Small graft

Day 14 Day 21

Larger tumor in small liver graft




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Invasive growth pattern in small liver graft (day14)

Whole graft

Small graft

Tumor Non-tumor




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Whole graft

Small graft

Venous invasion in small liver graft (day21)




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010

20

30

40

50

60

70

80

90

100

Day 14 Day 21

Whole graft

Small graft

Percent of liver occupied by tumor

*

*

0.061

0.015

4/6 (66.7%)

6/6 (100%)

0/6 (0%)

1/6 (16.7%)

Tumor growth

at day 7

by macroscopy

by microscopy

0.01210/12 (83.3%)3/12 (25%)Tumor thrombus

0.00311/12 (91.7%)3/12 (25%)Venous invasion

PSmall graftWhole graft

Tumor Invasiveness


Effect of Graft Size- Tumor Growth and Invasiveness


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Day 14 Day 21

Whole graft

Small graft

Significant tumor proliferation (Ki67) in small liver graft




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Whole graft

Small graft

Significant stellate cell activation (-SMA) in small liver graft

Da 14 Da 21




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CAKRac1

Whole graft

Small graft

Significant activation of cell invasion signals in small liver graft




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Up-regulation of ROCK and VEGF in small liver graft

T NT T NT T NT T NT

Whole graft Small graft

Actin

VEGF

ROCK I




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Distinct gene signature linking to acute phase injury and proliferation in

small liver graft - by cDNA microarray screening (day 1)

Gene names (selected)Gene names (selected) Fold ratio (S/W)Fold ratio (S/W)Wnt 4 24.25Ki67 6.06

Cell division cycle control protein (Cdc2a) 3.73

G protein coupled receptor 19 (GRP19) 3.48

IP10 2.14

IL1b 2.14IL1r2 2.14

MMP2 1.87

HSP70 0.18

Insulin-like growth factor binding protein 3 (IGFBP3) 0.41




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Acute phase injury and late phase tumor recurrenceAcute phase injury and late phase tumor recurrence

Liver transplantation using small liver graft

Portal hyperperfusion-

Shear stress

Inflammatory cascades

Angiogenesis

(VEGF , HSC activation )

Favorable environmentfor tumor growth and

metastasis

Liver regeneration

Hepatic sinusoidal injury

Microvascular barrier dysfunctionIncreased vascular permeability

Cell adhesion, migration

and invasion

(ROCK , RAC , CAK )

Tumor cell proliferation

(Ki67 )

Invasive tumor growth in small liver graft


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The benefits of LDLT over DDLT for early HCCderived from decision analysis should be interpretedwith caution

There is a risk of waiting list mortality both for organallocation in DDLT and for donor voluntarism/selectionin LDLT

Difference in selection of patients and graft size mayresult in a higher recurrence rate after LDLT for earlyHCC

The role of LDLT for HCC remains to be defined by

more clinical studies


Summary


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Figure 1


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1-a 2-a

1-b 2-b

Day 14 Day21

0

10

20

30

40

50

60

70

80

90

100

Day 14 Day 21

Whole graft

Small graft

% of liver occupied by tumor

*

*

1-a 2-a

1-b 2-b

0

200

400

600

800

1000

1200

Week 4 Week 6

Liver tumor from whole graft

Liver tumor from small graft

*

*

Tumor volume (mm3)

Week 4 Week 6

A B

3 3


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Distinct gene signature linking to tumor invasiveness in small liver graft

- by cDNA microarray screening (day21)

Gene names (selected)Gene names (selected) Fold ratio (S/W)Fold ratio (S/W)

Laminin 5 beta3 chain 4.29S100 calcium binding protein A8 (S100A8) 4.29

S100 calcium binding protein A9 (S100A9) 3.03

IL6 2.46

HSP70 3.03

MMP2 2.83

MAPK13 2.14Tissue factor 2.14

Foslike antigen1 (FOSL1) 2

Insulin-like growth factor binding protein 2 (IGFBP2) 0.38

Serine protease inhibitor (Spin2b) 0.31

Claudin-7 0.27


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Poor expected outcome

Advanced malignancy

Sickest complicated cirrhosis

Psychosocial problems e.g. alcoholism

Relative contraindications e.g. HIV positive

Minimum outcome limit

1-yr survival=50%

5-yr survival=30%


Extended Indications

Malago et al, Liver Transplantation 2001


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Liver Transplantation: Extended Indication


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LIVING DONOR LIVER TRANSPLANTATIONHepatocellular Carcinoma: Extended Indications

Multi-center study on 316 patients with HCC

49 transplant centers- one-third adopt Milan criteria

, n=137, n=172 , n=137, n=172

chung mau lo 2

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