SAMO, Friday 15th April 2011 Workshop on Primary liver tumors HCC surgical approach: resection and transplantation indications and outcome Gilles Mentha University Hospital of Geneva
Hepatocellular Carcinoma (HCC) Frequent disease 80% on cirrhotic patients 10% in non-cirrhotic chronic liver disease 10% on normal liver (usually tumor > 10 cm) Evolution different from a patient to another Evolution different in the same patient over the years studies are difficult!
Hepatocellular cancer in the non-cirrhotic liver Less than 20% of HCC develops in non-cirrhotic liver AFP is often normal Due to late symptoms, it is usually diagnosed at a more advanced stage large tumor Average age of onset is lower than for HCC on cirrhosis R0 resection has a 5-year OS > 50% Alkofer B., Lepennec V., Chiche L. J Visc Surg 2011; 148: 3-11
Liver transplantation for unresectable HCC in patients without liver cirrhosis Partial liver resection is the treatment of choice (expected 40-70% survival at 5-year) But because of advanced stage at the time of diagnosis, for some patients the tumor has turned already as unresectable Is there a place for liver transplantation in these usually large tumors? Mergental H., Porte RJ. Transplant International 2010; 23: 662-667
single HCC 5 cm 3 HCC 3 cm Mazzaferro et al. NEJM 1996 ; 334: 693-99
Liver transplantation for unresectable HCC in patients without liver cirrhosis 150 patients transplanted for NC - HCC during the last 15 years (ELTR) 5-year survival rate about 50% and 70% in wellselected patients Macrovascular invasion, lymph node involvement, rescue therapy for intra-hepatic recurrence (<12 months) after partial liver resection are poor pronostic factors Median tumor size was 8cm tumor diameter was not identified as an independant determinant of survival after OLT Mergental H., Porte RJ. Transplant International 2010; 23: 662-667
By way of illustration Clinical case 19 year-old girl Hospitalisation for mental anorexia (BMI 13) Routine liver tests because of medical treatment AST and ALT increased twice the normal US just in case... huge liver tumor CT scan
19 year-old girl, under medical T for anorexia Control of liver tests anormal values US..
Mrs A. G. 19 year-old: CT scan left biliary dilation
Mrs A. G. 19 year-old Biopsy: compatible with FNH. But ASAT and ALAT were Elevated (> 100 UI/L) Second biopsy! CT scan: no evidence of tumor in the lower right part of the liver
Second biopsy HCC, fibrolamellar HCC on normal liver Per-cutanenous cholangiography : segment II biliary duct stenosis, Transcutaneous portal veinography : left portal stenosis tumoral arterial embolization Before resection of the tumor Which type of hepatectomy?
Fibrolamellar HCC: what we have removed
Left hepatectomy enlarged to segments I, V et VIII under 53 of TVE
Tumor with some fields of necrosis and «a nodule in the nodule», left intrahepatic biliary tract dilation, normal non-tumoral liver
Trabecular pattern with fibrous Connective tissue 3 criteria: Collagen with lamellae formation 1. well differenciated 2. Oncocytic aspect 3. collagen with lamellae formation Oncocytic aspect cells with nucleols nucleus
Final diagnosis Fibrolamellar HCC developped on normal liver Tumor of 14 X 11 X 7.5 cm diameter Follow-up: NED at > 92 months
Liver resection for HCC in 101 patients with normal, non-normal-non cirrhotic and cirrhotic liver 101 patients Normal N= 7, NNNC = 38, Cirrhotic N = 56 Disease Free survival were: for normal liver for NNNC liver for cirrhotic liver 63 months 48 months 30 months Zanella MC et al. Center of Geneva (Manuscript in preparation)
100% Mean overall survival (N=101) = 51.8 months 63% 38% Zanella MC et al.
HCC on cirrhosis
Treatments of HCC? Center Living donor? Tumor Liver Underlying disease Percutaneous ethanol (PEI) Chemoembolization (TACE) Radiofrequency (RFTA) Resection Transplantation Patient
100 cirrhotic patients with HCC indication to resection 20 with one nodule, 20 with one nodule, poor liver function good liver function 60 with multiple tumors Ct scan, angiography, RMI 5 with only one nodule 15 with multiple tumors Standard indications to resection + hepatic venous pressure gradient < 10 mmhg 35 / 1265 patients = 2.8% Llovet JM et al. Hepatology 1999; 30: 1434-1440
Survival following resection: Child A patients stratified according to portal hypertension et bilirubin Llovet Hepatology 1999 74% HTP < 10mmHg, Bili <17mMol/l 50% PHT > 10mmHg, Bili <17mMol/l 25% PHT > 10mmHg, Bili>17mMol/l
Continuous improvement of survival outcomes of resection of hepatocellular carcinoma 55% 35% 42% 24% Fan ST. et al. Ann Surg 2011; 253: 745-758
100 cirrhotic patients with HCC indication to transplantation 20 with one nodule, 20 with one nodule, poor liver function good liver function 60 with multiple tumors Age, general condition, Ct scan, angiography 8 OLT criteria 12 OLT criteria 10 OLT criteria 30 patients on the OLT waiting list Drop-out 30% 18 months 21 will effectively be transplanted
Liver transplantation for HCC Early diagnosis and liver transplantation are clearly the best approach at the moment Why? OLT adresses the multifocal potential of HCC OLT treats the underlying liver disease OLT can be applied regardless of liver function
HCC curative treatment Cirrhotic patients with HCC Criteria for OLT 1 tumor < 5cm 3 tumors < 3 cm Criteria for resection
Geneva: 81 patients had an OLT for a known HCC (481 TH) 2008 KM transplanted patients 1,00,90,80 OS: 86% 8 recurrences (10%),70,60,50 Cum Survival,40,30,20 Survival Function,10 0,00 Censored 0 6 12 18 survival 40 OLT 24 30 36 42 48 54 60
Long-term survival Resection Transplantation 100% 71% 60% 50% Jonas S. et al Hepatology 2001 1 year 5 years 10 years
Transplantation vs. ( no) alternatives: the traditional metrics Resection vs. Transplantation disease-free survival Transplantation : 14 p Log Rank = 0,003 100 Resection : 14 (%) 86 80 86 86 76 76 86 60 40 49 20 29 0 0 1 2 3 20 10 4 5 (Years) Resection is always palliative! Bismuth, Majno, Adam. Sem Liver dis 1997
Conclusion Liver transplantation is the safest and most effective long-term treatment for early HCC in cirrhosis
Reviews for balanced and referenced discussion
Liver transplant single HCC 5 cm 3 HCC 3 cm Mazzaferro et al. NEJM 1996
Selection Criteria 1 nodule < 5 cm, or 3 nodules< 3cm No macroscopic vascular invasion (T1 and T2 patients) Within: good in predicting that patients will not recur (90%)
Criteria are effective to provide good results 100 82% Recurrences: 11% 76% 80 74% 75% 60 1985-1991 43% N=60 53% 40 Recurrences 33% 20 0 1992-1995 N=45 0 1 2 Years 3 4 5 Bismuth 34
Selection Criteria 1 nodule < 5 cm, or 3 nodules< 3cm No macroscopic vascular invasion (T1 and T2 patients) Within: good in predicting that patients will not recur (90%) Outside: poor at predicting which patients will recur (?%)
Liver transplant Expanded criteria for HCC
Correlation between size and number of nodules (vascular invasion) and occult metastases Extrahepatc disease 90% biological invasiveness (vascular invasion) 50% Size Number 10%
1.0 CHC-transplantation 0.9 Tumour number % tumor-free survival 0.8 P=0.5 0.7 0.6 0.5 <=3 >3 0.4 0.3 0.2 0.1 0.0 0 12 24 36 48 60 72 84 96 108 120 96 108 120 Months since transplantation 1.0 0.9 Tumour diameter P<0.05 % tumor-free survival 0.8 0.7 0.6 0.5 0.4 <=5 cm >5 cm 0.3 0.2 0.1 0.0 0 12 24 36 48 60 72 84 Months since transplantation
Outside criteria: a mess! Number of Nodules 6 the longer the trip the higher the price Metroticket 5 4 3 2 1 0 0 1 2 3 75-80 % 4 5 6 50-75 % 5-year survival 7 8 9 35-50 % Tumor Size 10 (cm)
CHC-transplantation UCSF criteria single HCC 6.5 cm 3 HCCs 4.5 cm with maximum total diameter of 8cm Yao et al. Hepatology 2001 Yao et al. AJT 2008
www.hcc-olt-metroticket.org Predicting survival after liver transplantation in patients with HCC beyond the Milan Criteria: a retrospective, exploratory analysis 282 Patients 5 Centers America 1274 Patients 31 Centers Europe BELGIUM NEDERLANDS SPAIN Web-based, survey No sponsorship 10 months recruitment period 36 Liver Transplant Centers 1556 Patients FRANCE ITALY SWITZERLAND PORTUGAL POLAND GERMANY UK SWEDEN AUSTRIA 1112 confirmed as Milan OUT Mazzaferro et al. Lancet Oncology 2009
Patients distribution (N=1556) Number Size (mm) Mazzaferro et al. Lancet Oncology 2009
Size is what matters 0.0 0.5 Hazard Ratio for death increases in an EXPONENTIAL fashion with SIZE -0.5 log Relative Hazard 1.0 1.5 Deaths and recurrences: 0 50 100 150 Diameter (mm) Adjusted to: noduli.t=3 Adjusted to number of nodules = 3 Mazzaferro et al. Lancet Oncology 2009
0.5 0.0 steep rise up to 3 nodules then plateau -0.5 log Relative Hazard 1.0 Number matters less (...after 3) 0 3 5 10 15 N. of nodules Adjusted to: dim.t=35 Adjusted to Diameter = 35 mm Mazzaferro et al. Lancet Oncology 2009
Identify a combination of size, number and vascular invasion that predicts survival equal to Milan + A good outcome group exists up-to-7 (6+1; 5+2...) without vascular invasion Median follow-up: 53 months Mazzaferro et al. Lancet Oncology 2009
5-year survival as a function of size and number (HCC forecast chart) (N=1556) Probabilities Size (mm) www.metroticket-olt-hcc-org
HCC transplantation Total Tumor Volume calculated by adding the maximum volume of each HCC ((4/3)πr3)
CHC-transplantation Volume (nb of cells) Tumour growth is not linear Nb of cell cycles
CHC-transplantation 115 cm3= 1 HCC of 6 cm (diameter) 3 HCCs of 4.2 cm
CHC-transplantation - No tumour number restriction - More power to larger HCCs Diameter (cm) Volume (cm3) 1 0.5 2 4 3 14 4 33 5 65 6 113 Toso et al. Liver Transplant 2008
CHC-transplantation Radiological accuracy Alberta, n: 52 Toronto, n: 154 Colorado, n: 82 Milan (%) UCSF (%) TTV* (%) p TTV vs Milan p TTV vs UCSF 32 (62) 37 (71) 45 (87) 0.005 NS 110 (71) 123 (80) 146 (95) 0.0001 0.0001 57 (70) 57 (70) 70 (85) 0.01 0.01 Combined results, n: 288 199 (69) 217 (75) 261 (91) 0.0001 0.0001 Toso et al. Liver Transplant 2008
CHC-transplantation Survival p 0.001 Toso et al. Liver Transplant 2008
CHC-transplantation Up-to-seven criteria: comparison with TTV 1 HCC 6 cm 2 HCCs 5 cm 3 HCCs 4 cm 4 HCCs 3 cm 5 HCCs 2 cm 6 HCCs 1 cm 113 cm3 131 cm3 101 cm3 57 cm3 21 cm3 3 cm3 Similar to TTV (115 cm3) Mazzaferro et al. Lancet Oncology 2009
HCC after OLT: toward a zero recurrence How to improve accuracy? Adding a biological marker to the morphology
CHC-transplantation TTV 115 AFP 400 ng/ml 3 cm Toso et al. Hepatology 2009
CHC-transplantation HR= 2 (95%CI:1.7-2.4) p 0.001 Toso et al. Hepatology 2009
Liver transplant P=0.3
CHC-transplantation Which AFP should be used?
AFP changes on waiting list Post-transplant survival p 0.01 Merani et al. J Hepatol 2011
CHC-transplantation Can we consider any patient (even with high AFP) for downstaging and transplantation? Merani et al. J Hepatol 2011
CHC-transplantation AFP over 1000ng/ml (n=34) AFP 700-1000 ng/ml (n=20) AFP 400-700 ng/ml (n=32) AFP below 400 ng/ml Merani et al. J Hepatol 2011
CHC-transplantation Intent-to-treat survival p=0.008 Merani et al. J Hepatol 2011
Proportion of patient successfully downstaged <400 ng/ml CHC-transplantation 25 p=0.015 20 15 10 5 0 400 to 700 ng/ml 700 to 1000 ng/ml over 1000 ng/ml Original AFP level Merani et al. J Hepatol 2011
CHC-transplantation Bad prognosis: high AFP (>400 ng/ml) or increasing AFP Good prognosis: low AFP ( 400 ng/ml) or decreasing AFP Last AFP should be used (surveillance and treatment on the list) Merani et al. J Hepatol 2011
CHC-transplantation What is the impact of expended scores on the waiting list?
In your center, HCC patients are being listed Additional polls to: for DDLT according N=85 * Nodules < 1 cm disregarded and/or number of tumors > 3 For those centers that enlist patients outside Milan criteria, you are using: Up-to-seven TTV/AFP UCSF Other* *Asan Medical Center in Korea or Hangzhou, China criteria or Clinica Universitaria de Navarra or Kyoto, Japan 0 10 20 30 Proportion of votes (%) 40 50
CHC-transplantation Based on Alberta Cancer Registry, n= 270 Mazzaferro (1996), Milan Kwon (2007), Seoul Silva (2008), Valencia Toso (2009), TTV/AFP Yao (2001), UCSF Herrero (2001), CUN Sugawara (2007), Tokyo Lee (2008), Asan Takada (2007), Ito (2007), Kyoto Onaca (2007), Dallas Toso (2008), TTV Zheng (2008), Hangzhou 0 10 20 30 40 50 60 70 Increase in number of HCC transplant candidates compared to Milan (%) decrease liver graft availability for non-hcc candidates no impact on post-transplant survival of non-hcc recipients decrease intent-to-treat survival from listing of non-hcc patients Toso et al. Transplant Int, 2009
CHC-transplantation Summary OLT is the only curative treatment Milan criteria can be safely expended Size more important that number Up-to-seven Best outcomes can be achieved with TTV (115 cm3) and last AFP (400 ng/ml)
Toward a zero recurrence rate after OLT for HCC
LDLT: the easiest way for priority
LDLT similar to DDLT? Multicentric from Japan (Todo Ann Surg 2004) 137 Milan +ve vs. 172 Milan -ve
Theoretical? Come to my clinic Child A, solitary nodule
Scenarios depend on quantifiable individual variables young HBV Groupe AB Living-donor Has had its chance Cirrhosis x Groupe O Incompatible friends
AFP changes on waiting list Intent-to-treat survival p 0.001 Merani et al. J Hepatol 2011
CHC-transplantation Last AFP should be used: Intent-to-treat survival from listing* Last alpha feto-protein level (Log, ng/ml) HR 95% CI p 1.56 1.34-1.82 0.001 Survival since transplant* Last alpha feto-protein level (Log, ng/ml) 1.53 1.32-1.78 0.001 * results were corrected for date of listing, MELD at listing, age at listing primary liver disease (non HCC), use of sirolimus at discharge (yes vs. no), use of anti-cd25 antibody induction (yes vs. no) and donor risk index. AFP at listing and AFP velocity were not significant. Listing AFP and AFP changes: NS Merani et al. J Hepatol 2011
Liver transplant Expanded criteria for HCC Total tumor volume (TTV) TTV/alpha fetoprotein (AFP) Downstaging HCC Feasibility Adjuvant post-transplant management Sirolimus
10 mm 50 mm
Survival of 135 Child A patients Poon RT et al. Ann Surg 2002; 240: 698-710 DFS OS 70% 36%
Toso C, Transpl International 2009 Selection criteria for transplantation Author, yr, journal Selection criteria Survival
Chemoembolization: utility has become evidence based A Comparison of Lipiodol Chemoembolization and Conservative Treatment for Unresectable Hepatocellular Carcinoma Volume 332:12561261 May 11, 1995 Number 19 Groupe d'etude et de Traitement du Carcinome Hépatocellulaire
NEJM Groupe d étude et de traitement du Carcinome hépatocellulaire. N Engl J Med 1995; 332: 1256-61 Lancet Llovet JM Bruix J. Barcelona Clinic Liver Cancer group The Lancet 2002; 359: 1734-39