hepatocellular carcinoma and liver transplantation tts key opinion leaders meeting montreal, april...

Hepatocellular Hepatocellular Carcinoma and Liver Carcinoma and Liver TransplantationTransplantation

TTS Key Opinion Leaders TTS Key Opinion Leaders MeetingMeetingMontreal, April 2007Montreal, April 2007

Mazen Hassanain MBBS, FRCS(C)Mazen Hassanain MBBS, FRCS(C)Assistant Professor of SurgeryAssistant Professor of SurgeryMcGill University Health CentreMcGill University Health Centre

Schwartz, Liver Transplantation for Hepatocellular Carcinoma, Gastroenterology. 2004: 127 S268-276.

Improving survival Improving survival over timeover time

Yoo et al. Journal of Clinical Oncology. 2003: 21 4329-4335.

Milan CriteriaMilan Criteria

Mazzafero 1996Mazzafero 1996 Single tumour less than 5 cmSingle tumour less than 5 cm Up to three tumour nodules each Up to three tumour nodules each

3cm or less3cm or less

Mazzaferro, et.al. NEJM1996;334:693-699

Milan CriteriaMilan Criteria

Regalia et al. Liver Transplantation for small hepatocellular carcinoma in cirrhosis: analysis of our experience. Transplantation Proceedings, 33, 1442–1444 (2001)

UCSF CriteriaUCSF Criteria

Patients with HCC meeting the following criteria: – Solitary tumor < 6.5 cm, – or < 3 nodules with the largest

lesion < 4.5 cm – and total tumor diameter < 8 cm

Yao et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001 33:1394

UCSF criteriaUCSF criteria

Yao et al. Liver Transplantation. 2002: 8(9) 765-774

UCSF vs MilanUCSF vs Milan

Schwartz, Liver Transplantation for Hepatocellular Carcinoma, Gastroenterology. 2004: 127 S268-276.

Vascular InvasionVascular Invasion

Khakhar et al. Survival after Liver Transplantation for Hepatocellular Carcinoma. Transplantation Proceedings. 2003: 35 2438-2441


Hemming et al. Liver Transplantation for Hepatocellular Carcinoma. Annals of Surgery. 2001: 233(5) 652-659


Jonas et al. Vascular invasion and histologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 2001;33:1080-1086.

Histologic GradeHistologic Grade

Jonas et al. Vascular invasion and histologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 2001;33:1080-1086.

HCV and HCCHCV and HCC

Bassanello et al. Adjuvant chemotherapy for transplanted hepatocellular carcinoma patients: impact on survival or HCV recurrence timing.Transplantation Proceedings. 2003: 35 2991-2994

McGill ProtocolMcGill Protocol

Tumours exceeding Milan criteriaTumours exceeding Milan criteria Receive 3 TACE treatments at 6 Receive 3 TACE treatments at 6

week intervalsweek intervals Lipiodol,carboplatinum, gelfoamLipiodol,carboplatinum, gelfoam If patients respond (AFP decreases If patients respond (AFP decreases

or tumours shrink, then go on to or tumours shrink, then go on to Tx, otherwise continue care)Tx, otherwise continue care)

McGill ExperienceMcGill Experience

January 1992 to December 2005January 1992 to December 2005 496 OLTx496 OLTx 1/3 for HCV1/3 for HCV 99 for HCC99 for HCC 33 outside Milan criteria33 outside Milan criteria


0.00

0.25

0.50

0.75

1.00

0 1 2 3 4 5Time (years)

No HCC HCC

HCC vs No HCCOverall Patient Survival


0.00

0.25

0.50

0.75

1.00

0 1 2 3 4 5Time (years)

No HCC Milan HCC

No HCC vs Milan HCCSurvival of Patients with Milan HCC


0.00

0.25

0.50

0.75

1.00

0 1 2 3 4 5Time (years)

No HCC Beyond Milan HCC

Milan HCC

No HCC vs Non-Milan HCC vs Milan HCCSurvival of Patients with HCC

No hepatocellular carcinomaMilan criteria hepatocellular carcinoma Non-Milan criteria tumours: No vascular invasion Non-Milan criteria tumours: Vascular invasion

Chi-squared = 4.97

DF = 2

P = 0.08

Patient Survival Non Milan Hepatocellular

Carcinoma Vascular Invasion vs No Vascular Invasion

Dead with Recurrence

Alive with Recurrence

Rising Serum FP during TACE

Log scale of -FP values(ng/ml)

Initiation of TACE sessions

1

10

100

1000

10000

1 2 3 4 5 6 7

1

10

100

1000

10000

1 2 3 4 5 6 7 8 9 10

Log scale of-FP values(ng/ml)

Initiation of TACE sessions

Recurrence-free alive

Recurrence-free deadOLTOLT or

Drop-off

Declining Serum FP during TACE

A B

Duration of TACE Treatments Duration of TACE Treatments

Non Milan Hepatocellular Carcinoma

-10

-5

0

5

10

15

Pre-TACE αFP Post-TACE αFP Pre-TACE αFP Post-TACE αFP

No vascular invasion Vascular invasion

Slope -1

Non Milan Tumours receiving TACELinear regression based on 4 or more alpha fetoprotein levels

pre-transplantation

P = 0.008 (95%CI -9.1 to -1.6)

Linear regression slope

ConclusionsConclusions

Changes in AFP following TACE predicted who would have vascular invasion on explant histology and which patients would have recurrent disease post-transplantation.

AFP levels >64ng/ml pre-TACE were more likely to be associated with vascular invasion.

When the AFP level was > 10ng/ml pre-TACE, a positive AFP slope following TACE predicted vascular invasion (p<0.01).

Live donor liver Live donor liver transplant (LDLT)transplant (LDLT)

Initial experience in LDLT for HCC Initial experience in LDLT for HCC very promising.very promising.

Survival comparable to DDLTSurvival comparable to DDLT

Schwartz et al. Adult living donor liver transplantation for patients with hepatocellular carcinoma. Annals of Surgery2004:239(2) 142-9

Lo et al. The role and limitations of living donor liver transplantation for hepatocellular carcinoma. Liver Transplantation. 2004;10:440-7

Northwestern group experienceNorthwestern group experience– Stage for stage higher recurrence Stage for stage higher recurrence

rate after LDLTrate after LDLT


Kulik and Abecassis. Living donor liver Kulik and Abecassis. Living donor liver transplantation for hepatocellular carcinoma. transplantation for hepatocellular carcinoma. Gastroenterology.Gastroenterology. 2004;127:S277. 2004;127:S277.

Axelrod et al. Living donor liver transplant for Axelrod et al. Living donor liver transplant for malignancy. malignancy. Transplantation. Transplantation. 2005;79(3):363-6 2005;79(3):363-6

A2ALL dataA2ALL data Confirms higher stage for stage Confirms higher stage for stage

recurrence rate.recurrence rate.

Higher recurrence rate recently also Higher recurrence rate recently also confirmed by Hong Kong groupconfirmed by Hong Kong group


A2ALL Study Group. A comparison of adult iving donor A2ALL Study Group. A comparison of adult iving donor (LDLT) to deceased donor liver transplant (DDLT) for (LDLT) to deceased donor liver transplant (DDLT) for hepatocellular carcinoma: data from the A2ALL study. hepatocellular carcinoma: data from the A2ALL study. HepatologyHepatology. 2005;42(4) 199a (AASLD abstract). 2005;42(4) 199a (AASLD abstract)

A2ALL Study Group. Personal communication.A2ALL Study Group. Personal communication.

Wong et al. Living donor versus deceased donor liver transplantation for early irresectable hepatocellular carcinoma. British Journal of Surgery 1007; 94:78-86.

““Fast-tracking”Fast-tracking” RegenerationRegeneration Surgical techniqueSurgical technique


1818FDG-PETFDG-PET

PET not widely used for HCC PET not widely used for HCC – AvailabilityAvailability– Relatively high false negative rateRelatively high false negative rate

Early data suggested that Early data suggested that visualization varied with degree visualization varied with degree of differentiation.of differentiation.

1818FDG-PETFDG-PET

Korean study of Korean study of 1818FDG-PET in HCCFDG-PET in HCC PET positive tumours significantly PET positive tumours significantly

moremore– Vascular invasionVascular invasion– Higher grade (II, IV)Higher grade (II, IV)– AFP >200ng/mLAFP >200ng/mL

No association with No association with – Size or number of tumoursSize or number of tumours

Yang et al. The role of 18-F FDG-PET Imaging for the Selection of Liver Transplantation candidates among Hepatocellular Carcinoma Patients. Liver Transplantation. 2006, 12 1655-1660.

1818FDG-PETFDG-PET

TACETACE

TACE improves survival of unresectable TACE improves survival of unresectable HCCHCC

– Llovet et al. Systematic review of randomized trials Llovet et al. Systematic review of randomized trials for unresectable hepatocellular carcinoma: for unresectable hepatocellular carcinoma: chemoembolization improves survival. chemoembolization improves survival. HepatlogyHepatlogy 2003; 37:429-4422003; 37:429-442

Improved long-term survival for T2-T3 Improved long-term survival for T2-T3 HCC when used pre-TxHCC when used pre-Tx

– Yao et al. The Impact of Pre-Operative Loco-Regional Yao et al. The Impact of Pre-Operative Loco-Regional Therapy on Outcome after Liver Transplantation for Therapy on Outcome after Liver Transplantation for Hepatocellular Carcinoma. Hepatocellular Carcinoma. American Journal of American Journal of Transplantation.Transplantation. 2005;5:795-804. 2005;5:795-804.

TACETACE

Despite widespread use of TACE Despite widespread use of TACE as a bridge to transplantation as a bridge to transplantation data is meagerdata is meager

Recent systematic review showed Recent systematic review showed no survival benefit and minimal no survival benefit and minimal wait list benefit.wait list benefit.

Clavien et al. Transarterial chemoembolization as a bridge to liver transplantation for hepatocellular ccarcinoma: an evidence-based analysis. American Journal of Transplantation. 2006: 6:2644

Future directionsFuture directions

Better patient selection!!Better patient selection!! Criteria that are more flexible Criteria that are more flexible

than Milan/UCSFthan Milan/UCSF Criteria that are better surrogates Criteria that are better surrogates

for vascular invasionfor vascular invasion– Potential role for pre-operative Potential role for pre-operative

biopsybiopsy Adjuvant treatment for HCVAdjuvant treatment for HCV

1818FDG-PET and histologic data FDG-PET and histologic data need prospective correlationneed prospective correlation

Role of LDLT and criteria for Role of LDLT and criteria for selection need to be definedselection need to be defined

Prospective definition/evaluation Prospective definition/evaluation of pre-transplant therapiesof pre-transplant therapies– TACE, RFA, Theraspheres and/or TACE, RFA, Theraspheres and/or

combinations of thesecombinations of these

AcknowledgementsAcknowledgements

Peter MetrakosPeter Metrakos Jeffery BarkunJeffery Barkun Jean TchervenkovJean Tchervenkov Steve ParaskevasSteve Paraskevas Michael AbecassisMichael Abecassis Laura KulikLaura Kulik Alan KoffronAlan Koffron Peter HortonPeter Horton John MartinieJohn Martinie George TzimasGeorge Tzimas

Myriam FernandezMyriam Fernandez MUHC Transplant MUHC Transplant

TeamTeam

Montreal Hepatoma Treatment AlgorithmMontreal Hepatoma Treatment Algorithm

Resection Transplant PEI/RFA/RTx TACE Therasphere New AgentsSymptomatic

Tx

HCC

Stage APST 0, CTP A, Okuda 1

Very earlySingle < 2 cm

Portal Press/Bili

Normal

3 nodules< 3 cm

Associated disease

increased

no yes

Stage B,C,DPST 0-2, CTP A-B, Okuda 1-2

Early stage BSingle < 5 cm, PST 0

Intermediate stage CMulti-nodules, PST 0

CTP A CTP B

Decreasing a-FP

Advanced Stage DPortal Vein invasion,N1,M1, PST 1-2

Portal vein invasion,N1, M1

No

Yes

Stage EPST>2,CTP C,Okuda 3

Terminal Stage D

hepatocellular carcinoma and liver transplantation tts key opinion leaders meeting montreal, april...

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