Hepatocellular Carcinoma and Liver Transplantation TTS Key Opinion Leaders Meeting Montreal, April 2007 Mazen Hassanain MBBS, FRCS(C) Assistant Professor of Surgery McGill University Health Centre

Schwartz, Liver Transplantation for Hepatocellular Carcinoma, Gastroenterology. 2004: 127 S

Improving survival over time Yoo et al. Journal of Clinical Oncology. 2003:

Milan Criteria Mazzafero 1996 Mazzafero 1996 Single tumour less than 5 cm Single tumour less than 5 cm Up to three tumour nodules each 3cm or less Up to three tumour nodules each 3cm or less Mazzaferro, et.al. NEJM1996;334:

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

UCSF 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 :1394

UCSF criteria Yao et al. Liver Transplantation. 2002: 8(9)

UCSF vs Milan Schwartz, Liver Transplantation for Hepatocellular Carcinoma, Gastroenterology. 2004: 127 S

Vascular Invasion Khakhar et al. Survival after Liver Transplantation for Hepatocellular Carcinoma. Transplantation Proceedings. 2003:

Vascular Invasion Hemming et al. Liver Transplantation for Hepatocellular Carcinoma. Annals of Surgery. 2001: 233(5)

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

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

HCV and HCC Bassanello et al. Adjuvant chemotherapy for transplanted hepatocellular carcinoma patients: impact on survival or HCV recurrence timing.Transplantation Proceedings. 2003:

McGill Protocol Tumours exceeding Milan criteria Tumours exceeding Milan criteria Receive 3 TACE treatments at 6 week intervals Receive 3 TACE treatments at 6 week intervals Lipiodol,carboplatinum, gelfoam Lipiodol,carboplatinum, gelfoam If patients respond (AFP decreases or tumours shrink, then go on to Tx, otherwise continue care) If patients respond (AFP decreases or tumours shrink, then go on to Tx, otherwise continue care)

McGill Experience January 1992 to December 2005 January 1992 to December OLTx 496 OLTx 1/3 for HCV 1/3 for HCV 99 for HCC 99 for HCC 33 outside Milan criteria 33 outside Milan criteria

McGill Experience

No hepatocellular carcinoma Milan 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 Log scale of  -FP values (ng/ml) Initiation of TACE sessions Recurrence-free alive Recurrence-free dead OLT OLT or Drop-off Declining Serum  FP during TACE AB Duration of TACE Treatments Non Milan Hepatocellular Carcinoma

Pre-TACE αFP Post-TACE αFP Pre-TACE αFP Post-TACE αFP No vascular invasion Vascular invasion Slope -1 Non Milan Tumours receiving TACE Linear regression based on 4 or more alpha fetoprotein levels pre-transplantation P = (95%CI -9.1 to -1.6) Linear regression slope

Conclusions 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 transplant (LDLT) Initial experience in LDLT for HCC very promising. Initial experience in LDLT for HCC very promising. Survival comparable to DDLT Survival comparable to DDLT Schwartz et al. Adult living donor liver transplantation for patients with hepatocellular carcinoma. Annals of Surgery2004:239(2) Lo et al. The role and limitations of living donor liver transplantation for hepatocellular carcinoma. Liver Transplantation. 2004;10:440-7

Northwestern group experience Northwestern group experience –Stage for stage higher recurrence rate after LDLT Live donor liver transplant (LDLT) Kulik and Abecassis. Living donor liver transplantation for hepatocellular carcinoma. Gastroenterology. 2004;127:S277. Axelrod et al. Living donor liver transplant for malignancy. Transplantation. 2005;79(3):363-6

A2ALL data A2ALL data Confirms higher stage for stage recurrence rate. Confirms higher stage for stage recurrence rate. Higher recurrence rate recently also confirmed by Hong Kong group Higher recurrence rate recently also confirmed by Hong Kong group Live donor liver transplant (LDLT) A2ALL Study Group. A comparison of adult iving donor (LDLT) to deceased donor liver transplant (DDLT) for hepatocellular carcinoma: data from the A2ALL study. Hepatology. 2005;42(4) 199a (AASLD abstract) 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” Regeneration Regeneration Surgical technique Surgical technique Live donor liver transplant (LDLT)

18 FDG-PET PET not widely used for HCC PET not widely used for HCC –Availability –Relatively high false negative rate Early data suggested that visualization varied with degree of differentiation. Early data suggested that visualization varied with degree of differentiation.

18 FDG-PET Korean study of 18 FDG-PET in HCC Korean study of 18 FDG-PET in HCC PET positive tumours significantly more PET positive tumours significantly more –Vascular invasion –Higher grade (II, IV) –AFP >200ng/mL No association with No association with –Size 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,

18 FDG-PET

TACE TACE improves survival of unresectable HCC TACE improves survival of unresectable HCC –Llovet et al. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatlogy 2003; 37: Improved long-term survival for T2-T3 HCC when used pre-Tx Improved long-term survival for T2-T3 HCC when used pre-Tx –Yao et al. The Impact of Pre-Operative Loco-Regional Therapy on Outcome after Liver Transplantation for Hepatocellular Carcinoma. American Journal of Transplantation. 2005;5:

TACE Despite widespread use of TACE as a bridge to transplantation data is meager Despite widespread use of TACE as a bridge to transplantation data is meager Recent systematic review showed no survival benefit and minimal wait list benefit. Recent systematic review showed no survival benefit and minimal 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 directions Better patient selection!! Better patient selection!! Criteria that are more flexible than Milan/UCSF Criteria that are more flexible than Milan/UCSF Criteria that are better surrogates for vascular invasion Criteria that are better surrogates for vascular invasion –Potential role for pre-operative biopsy Adjuvant treatment for HCV Adjuvant treatment for HCV

18 FDG-PET and histologic data need prospective correlation 18 FDG-PET and histologic data need prospective correlation Role of LDLT and criteria for selection need to be defined Role of LDLT and criteria for selection need to be defined Prospective definition/evaluation of pre-transplant therapies Prospective definition/evaluation of pre-transplant therapies –TACE, RFA, Theraspheres and/or combinations of these

Acknowledgements Peter Metrakos Peter Metrakos Jeffery Barkun Jeffery Barkun Jean Tchervenkov Jean Tchervenkov Steve Paraskevas Steve Paraskevas Michael Abecassis Michael Abecassis Laura Kulik Laura Kulik Alan Koffron Alan Koffron Peter Horton Peter Horton John Martinie John Martinie George Tzimas George Tzimas Myriam Fernandez Myriam Fernandez MUHC Transplant Team MUHC Transplant Team

Montreal Hepatoma Treatment Algorithm ResectionTransplantPEI/RFA/RTxTACETherasphereNew Agents Symptomatic Tx HCC Stage A PST 0, CTP A, Okuda 1 Very early Single < 2 cm Portal Press/Bili Normal 3 nodules < 3 cm Associated disease increased noyes Stage B,C,D PST 0-2, CTP A-B, Okuda 1-2 Early stage B Single < 5 cm, PST 0 Intermediate stage C Multi-nodules, PST 0 CTP ACTP B Decreasing a-FP Advanced Stage D Portal Vein invasion, N1,M1, PST 1-2 Portal vein invasion, N1, M1 No Yes Stage E PST>2,CTP C,Okuda 3 Terminal Stage D