Stefan Breitenstein Department of Visceral and Transplantation Surgery University Hospital Zurich

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:


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?

Dutkowski, Clavien, Gastroenterology, 2010

Survival after Liver TPL in Europe

Dutkowski, Clavien, Gastroenterology, 2010

Survival after Liver TPL in Europe

5 yr survival: > 70%

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 2009 Vienna Apr 2010 Boston Oct 2010

E S S E N T I A L R U L E

The members of the Jury

draw the recommendations

NOT the experts

Methods

Level of Evidence

Oxford Centre for Evidence-based Medicine

Strength of recommendations

GRADE System Grading of Recommendations Assessment, Development and Evaluation

BMJ 2008; 337: 327-30

Publication

Lancet Oncol. 2012 Jan;13(1)

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

Mazzaferro et al., N Engl J Med 1996

MILAN Criteria

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 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%

Challenge of Milan Criteria

Challenge of Milan Criteria

Yao F et al, Am J Transpl, 2008

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, 2003 Kamath 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


• Tumor progression

Tumor growth

Risk of Drop-out (2-4% / mt)

Loss of benefit of TPL

Transplantation TPL Decision

Vascular invasion

• CH: waiting time: 7 - 9 months for HCC patients


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!


• 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

Salvage OLT

Without recurrence

With recurrence

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

0 0 1 2 3 4 5 Years

Dis

ease

-free

sur

viva

l

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 criteria Mean 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)



Donor



Recepient Donor


Advantages

• Shorten waiting time

• < 2 - 4 weeks

• High quality graft

• > 95 % 1yr survival

• Positive impact on pool of organs


Disadvantages

• Donor Mortality : 0,2%

• Donor Morbidity: 16%

• Technically more demanding


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)nu

mbe

r of t

rans

plan

ts

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


Case 1

Radiology, MRI:

Case 1

2y Follow up: uneventful

Case 2

Male patient 59 y Family, 2 children Hep c Cirrhosis with HCC AFP 14 MELD 25

Radiology, MRI

Case 2

Tumor recurrence after 6 mt

Death after 8 mt

Documents

Stefan Breitenstein Department of Visceral and Transplantation Surgery University Hospital Zurich