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Stefan Breitenstein
Department of Visceral and Transplantation Surgery
University Hospital Zurich
SASL Tag der Leber 2012
KSSG, 30. August 2012
Lebertransplantation bei HCC
Male patient
24 y
Family, 2 children
Hep B
Cirrhosis with HCC
AFP 220
MELD 8
Listed for Liver TPL
Case 1
Radiology, MRI:
Male patient
24 y
Family, 2 children
Hep B
Cirrhosis with HCC
AFP 220
MELD 8
Listed for Liver TPL
Case 1
1. Escape from the list, no
transplantation
2. Transplantation
3. Bridging (TACE, RF,…) and
Transplantation
Question: What to do?
Case 2
Male patient
59 y
Family, 2 children
Hep C
Cirrhosis with HCC
AFP 14
MELD 25
Radiology, MRI
1. No transplantation, ablative
treatment (TACT, RF, …)
2. Transplantation
3. Bridging (TACE, RF,
resection) and
Transplantation
4. other
Question: What to do?
HCC: Therapeutic Options
Radiofrequency /
Microwave Ablation
Resection
?
Cryo-Surgery
Chemoembolization
Transplantation
Chemo-, Immunotherapy
Radioembolization
Zurich, Switzerland
2-4 December 2010
Recommendations for
Liver Transplantation
for HCC:
an International
Consensus Conference Report
• To establish the State of the Art
regarding indications for OLT in patients
with HCC
• To provide internationally accepted
statements & guidelines
Aim
Endorsing Societies
European HepatoPancreatoBiliary Association
American Association for the Study of Liver Disease
American Society of Transplant Surgeons
European Association for the Study of the Liver
European Liver and Intestine Transplant Association
International HepatoPancreatoBiliary Association
International Liver Cancer Association
International Liver Transplantation Society
Liver and Gastrointestinal Disease Foundation
The Transplantation Society
Methods
Organizing
Committee
Danish Model
Working Groups
of Experts Jury
Finest
available knowledge
WELL IN ADVANCE
Recommendations
Preparatory Meetings Boston Oct 2009Vienna Apr 2010Boston Oct 2010
Strength of recommendations
GRADE SystemGrading of Recommendations Assessment, Development and Evaluation
BMJ 2008; 337: 327-30
Liver TPL for HCC: Rational
• Multifocal diseases
• Best oncologic resection
• Treatment of cirrhosis
• Restores normal hepatic function
Liver TPL for HCC: History
Indications in the 80s/ 90s
• Easier
• Assumption of cure
• No other options
Authors years Mortality 3yr Survival
Ringe 1989 34% 20%
Iwatsuki 1991 15% 52%
O ’Grady 1988 31% 32%
Bismuth 1993 5% 49%
Liver TPL for HCC: History
MILAN Criteria
Liver TPL für HCC:
• Single tumor < 5 cm
• Two-three tumors < 3 cm
• No vascular invasion
Mazzaferro et al., N Engl J Med 1996
MILAN Criteria: Outcome
Authors years Mortality 3yr Survival
Ringe 1989 34% 20%
Iwatsuki 1991 15% 52%
O ’Grady 1988 31% 32%
Bismuth 1993 5% 49%
Mazzaferro 1996 6% 83%
Figueras 1997 - 75%
Llovet 1998 13% 74%
Bismuth 1999 3% 68%
Herrero 2001 - 76%
Hemming 2001 15% 63%
Beaujon 2001 10% 73%
Ravaioli 2004 - 82%
Milan CriteriaMilan Criteria
Extended Criteria: UCSF
Criteria: Solitary Tumor < 6.5 cm
< 3 nodules with largest lesion < 4.5 cm
Yao et al, Am J Transplantation 2007.
Validation of University of California, San Francisco (UCSF) criteria.
n = 168 patients with liver transplantation
38 patients exceeding Milan but meeting UCSF criteria
Extended Criteria: UCSF
Criteria: Solitary Tumor < 6.5 cm
< 3 nodules with largest lesion < 4.5 cm
Yao et al, Am J Transplantation 2007.
Validation of University of California, San Francisco (UCSF) criteria.
5-year recurrence-free probability
UCSF 93%
Milan 90%
What are the criteria for OLT?
• LT within the Milan criteria (1 tumor <5cm or 3 < 3cm) achieves similar results than LT for non HCC patients: >70% 5-yr survival
• UCSF criteria (1 tumor ≤ 6.5cm, ≤ 3 with the largest ≤ 4.5 cm and total tumour Ø ≤ 8 cm) : same outcome in retrospective studies
What are the criteria for OLT?
Recommendation Level of evidence
Strength
1. The Milan Criteria are currently the benchmark, and the basis for comparison with other suggested criteria. 2b Strong
2. A modest expansion of the number of potential candidates may be considered on the basis of several studies showing comparable survival for patients outside the Milan criteria.
3b Weak
3. Patients with worse prognosis may be considered for OLT outside the Milan criteria if the dynamics of the waiting list allow it without undue prejudice to other recipients with a better prognosis.
Ø Weak
Negative risk factors of survival for HCC
• Multifocal tumor
• Size of tumor
• Poor differentiation
• Lympho/ vascular invasion
• AFP > 400 – 1000 ng/ml
Allocation for Liver TPL
Model for End-stage Liver Diseases:
MELD Score
2002 «United Network for Organ Sharing» (UNOS):
To grade patients on the waiting list according to
the severity of liver disease
• Serum Creatinine (mg/dl)
• Bilirubin (mg/dl)
• INR
Score 6 - 40
Wiesner R et al., Gastroenterology, 2003Kamath PS et al, Hepatology 2001
10 x (0.957 (Serum Crea) + 0.378 (Bilirubin) + 1.12 (INR) + 0.643)
Allocation for Liver TPL
Model for End-stage Liver Diseases:
MELD Score
Highly predictive of the risk of
dying from liver disease for
patients on the waiting list
Switzerland: Allocation
according to MELD since 2007
Allocation: Problem HCC - MELD
• Patients with HCC often have low MELD score
• Long waiting time for Liver TPL
Extra points
• T1(< 2 cm) +0 pts 33% OLT without HCC !
• T2 (2-5 cm) 22 pts
• T3 – T4: +0 pts negative prognostic
UNOS Eurotx• Minimum 22
• Upgrade 10% MELD
equivalent (3 months)
Swisstx• MEDIAN of the MELD score
of all liver-patients of the
month before: 14
•1pt in addition every month
on the waiting list
Allocation: Problem HCC - MELD
• Tumor progression
Tumor growth
Risk of Drop-out (2-4% / mt)
Loss of benefit of TPL
TransplantationTPL Decision
Vascular invasion
• CH: waiting time: 7 - 9 months for HCC patients
Allocation: Problem HCC - MELD
Contrast imaging every 3 mt (MRI)
Consequences of long waiting time:
1. Monitoring
- Trans-Arterial-Chemoembolization (TACE)
- Percutaneous treatment (RFA)
- Resection
2. Bridging
Trans-Arterial-Chemoembolisation as Bridge
AUTHOR YEAR n Conclusions
Maddala 2004 54 No survival advantage after LT
Perez 2005 46 No survival advantage after LT
Decaens 2005 200 No survival advantage after LT
Yao 2005 168 Survival advantage for T2/T3
Porret 2006 64 No survival advantage after LT
Kim et al., JACS, 2007
Only retrospective studies!
Trans-Arterial-Chemoembolisation as Bridge
• Improvement of long-term survival: unclear
• No increase of post-operative complications
• Insufficient evidence about TACE benefits
• Impact of hyperselective TACE ?
Lesurtel et al, Am. J. Transplant. 2006
Radiofrequency Ablation as Bridge
• No randomized studies
• Controversial results
• Morbidity 2,2%, mortality 0,3%
• Good option for Child A-B patients with expected
waiting time >6 months
Kim et al, JACS, 2007
Lau et al, Ann Surg 2009
Resection as Bridge
Belghiti J et al., Ann Surg 2003; 238: 885-893
Primary OLT Secondary OLT after liver resection
n = 70 n = 18
Morbidity
Mortality
36 (51%)
4 (6%)
10 (56%)
1 (6%)
(Within Milan)
Resection as Bridge
“OLT after liver resection is associated with an increased risk of
recurrence and poorer outcome than primary OLT“
1.0
0.8
0.6
0.4
0.2
00 1 2 3 4 5
Years
Dis
ease
-fre
e su
rviv
al
Primary LT (n=195)LT after resection (n=17)
29% 29%
64%58%
p=0.003
Adam R et al. Ann Surg,2003
Resection as Bridge
61 Resection of HCC within the Milan criteriaMean follow-up 4.3 years
Recurrence present 31 (51%)
Salvage LT possible:24 out of 31 (77%)
Cherqui D et al., Ann Surg 2009
5-year survival: 85%
Is treatment of HCC on the waiting list necessary?
Recommendation Level of evidenc
e
Strength
1. Based on current absence of evidence, no recommendation can be made on bridging therapy in patients with UNOS T1 (<2cm) HCC.
Ø None
2. In patients with UNOS T2 HCC (1 nodule 2-5cm or ≤3 nodules each ≤3cm) and a likely waiting time longer than 6 months, loco-regional treatment may be appropriate.
4 Weak
3. No recommendation can be made for preferring any type of loco-regional therapy over others. Ø None
Does a patient qualify for OLT after downstaging?
Recommendation Level of evidence
Strength
1. Transplantation may be considered after successful downstaging. 5 Weak
2. Criteria for successful downstaging should include tumor size and number of viable tumors. AFP may add additional information.
4 Strong/Weak
3. LT after successful downstaging should achieve a 5yr survival comparable to that of HCC patients who meet the criteria for LT without requiring downstaging. 5 Strong
4. Based on existing evidence, no recommendation can be made for preferring a specific locoregional treatment for downstaging over others.
Ø None
Contraindications for Liver TPL
Cirrhosis, HCC:
• Tumor specific factors
• Age > 60 – 70
• Protal vein occlusion
• Hypertension A. pulmonalis
Liver TPL: Current problem
Shortage of organs
Increase of donor rates
Living Related Liver Transplantation
Split Liver Transplantation
Extend donor criteria (marginal organs)
Living Related Liver Transplantation
Advantages
• Shorten waiting time
• < 2 - 4 weeks
• High quality graft
• > 95 % 1yr survival
• Positive impact on pool of organs
Living Related Liver Transplantation
Disadvantages
• Donor Mortality : 0,2%
• Donor Morbidity: 16%
• Technically more demanding
Living Related Liver Transplantation
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
0
200
400
600
US : source :2006 OPTN/SRTR Annual Report (www.optn.org)
ELTR : data analysis booklet 05/1968 -12/2007 (www.eltr.org)n
um
ber
of
tran
spla
nts
Clavien et al., J Hep, 2009
Conclusions
• Milan criteria is the standard to select cirrhotic patients
with HCC for liver TPL
• Survival after Liver TPL (HCC and other patients): 85%
1y, >70% 5y
• Allocation of Donor organs base on MELD score of
recepients
• Resection/ Ablation and Transplantation should be
associated rather than opposed
• Living related liver transplantation is one option to
reduce shortage of organs
Male patient
24 y
Family, 2 children
Hep B
Cirrhosis with HCC
AFP 220
MELD 8
Listed for Liver TPL
Case 1
Radiology, MRI: