-
8/14/2019 Hepatocellular Carcinoma Extended Indications
1/46
Department of General, Visceral and Transplantation Surgery
University Hospital Essen
Hepatocellular Carcinoma
Extended Indications
Massimo Malag
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
2/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
The patients who most need a LT are theThe patients who most need a LT are the
sickest onessickest ones
Thomas StarzlThomas Starzl
The worst complication of LiverThe worst complication of Liver
transplantation is to die before receivingtransplantation is to die before receivingthe transplantthe transplant
Henri BismuthHenri Bismuth
HCC Extended IndicationsHCC Extended Indications
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
3/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
God sent
plagues
to humans...
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
4/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
HCV epidemic worldwide
Increasing incidence of HCC
372.000 new cases / year in USA
4,6% all malignancies
HCC - LDLT
Solomon, Am J Epidemiology 2002: 156, 761
2002: HCC Ca. 1 million new cases / year2002: HCC Ca. 1 million new cases / year
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
5/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
Liver resections
Essen Apr. 1998 - 2007
___________
Liver resectionsoverall 1998
156 liver resection for HCC
659
193
237
69243
174
Hemihepatectomies
Extended Hemihepatectomies
Anatomical Liver resections
Atypical Liver resectionsResection of the hilar bifurcation
Live Donor Hepatectomies
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
6/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
LTx in patients with HCCLTx in patients with HCC
Essen - Methods -Essen - Methods -
Retrospective review of a consecutive series of 124 transplanted patients with HCC
between 04/98 and 03/07
Intention to treat (RADIOLOGY) vs Reality (PATHOLOGY) Analysis
Standard pre-, intra- and post-LTx data including DDLT vs LDLT, Child-Pugh
Classification, staging (UICC, Okuda, Milano, UCSF)
End-points: short and median term survival,
disease free survival
Median follow-up: 39 months (3-89 months), follow-up rate 100%
Statistic: t-Test, Chi-square, Wilcoxon (non-parametric), significance
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
7/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
LT in patients with HCC and cirrhosisLT in patients with HCC and cirrhosis
- Definitions -- Definitions -
Standard indications (DD LTx): Solitary tumor 5 cm
2 or 3 tumors, none >3 cm
Extended indications (LD LTx,rescue ): No extrahepatic disease
No vascular invasion/portal vein thrombosis
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
8/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
LTx for HCC
Strategy in EssenCLTx LDLTx
Conservative policy
(Milan criteria - 5cm)
organ rescue
Opening to selected
advanced tumors
ImmunosuppressionLow dose Csa-Fk Monotherapy + (Sirolimus late postop.*)
Csa150-200ng/ml FK 3-7ng/ml
*since 2003
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
9/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
Are we denying therapy to patients
who deserve it ??
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
10/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
LTX ESSENApril 1998 May 2007
n = 931
Split (123)
LDLT (195)
Standard-Tx (605)
Reduced Liver (8)
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
11/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
56
9
93
hcc
other tumors
other disease
ALDLT n=160ALDLT n=160
HCC 35%HCC 35%
684
656
hcc
other tumors
other disease
Segment 4
Cadaver LTx n=728Cadaver LTx n=728
HCC 9,3%HCC 9,3%
LTx for HCC - AdultsLTx for HCC - Adults
N = 124N = 124Essen 04/1998 -05/2007Essen 04/1998 -05/2007
Mean F-up 39 mo.Mean F-up 39 mo.
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
12/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
DDLT LDLT p-value
No. of patients 68 56Age (meanSD, years) 53.49.1 55.010.1 0.239
Gender 0.908Male 54 39
Female 14 17
Child-Turcotte-Pugh classification 0.368
A 19 10
B 23 24
C 11 13
Serology 0.367
Negative 13 13
HBV 15 12HBV/HCV 0 2
HCV 27 18
MELD Score 0.085
10, 20 29 20
>20, 30 0 5
>30 2 1
Tumor size 0.294
2 cm 11 4>2, 5 cm 14 14
>5 cm 30 27
No tumors 0.961
1 26 20
2 9 8
3 2 1
4 18 16
LTx for HCC - Adults N = 124LTx for HCC - Adults N = 124 Essen 04/1998 -05/2007Essen 04/1998 -05/2007
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
13/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
DDLT LDLT p-value
No. of patients 68 56Lobar distribution 0.441
Unilobar 37 26Bilobar 18 19
AFP 0.70820 31 22>20, 200 12 14>200, 1000 8 5>1000 4 4
Milan criteria 0.717Within 25 23Beyond 30 22
UCSF criteria 0.658Within 27 25Beyond 28 20
Perioperative mortality 5 9 0.203
LTx for HCC - Adults N = 124LTx for HCC - Adults N = 124 Essen 04/1998 -05/2007Essen 04/1998 -05/2007
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
14/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
15/46
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
16/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
17/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
Living donor LT for HCC - EssenLiving donor LT for HCC - Essen
Extended criteria, but not open endPoor results in Decompensated cirrhosis
Age > 60
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
18/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
Are we denying therapy to patients
who deserve it ??
Or
Are we overtreating patients?
Intention to treat
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
19/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
Intention to treatDiagnostic accuracy pre - LT
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
20/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
Intention to treatDiagnostic accuracy pre - LT
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
21/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
Univariable Analysis of patient survival after 124 LT for HCC
Essen Experience 04/98-04/07
Gender m/ w n.s. Virus HCV / HBV / None n.s. AFP 20 / >20,200 / >200,1000 / >1000 n.s. MELD-Score 10 / >10,20 / >20,30 / >30 n.s. CHILD A / B / C n.s.
Bridging yes / no n.s. LT-Procedure DDLT / LDLT n.s. Lobar distribution unilobar / bilobar n.s. Nr. tumors 1 / 2 / 3 / 4 n.s. Tumor size 2 cm / >2,5 cm / >5 cm n.s. Portal invasion Vp0 / Vp1 / Vp2 / Vp3 n.s. Differentiation well / moderate / poor 0.0154
pTNM I / II / IIIA / IIIB n.s. Milan Criteria meeting / exceeding n.s. UCSF Criteria meeting / exceeding n.s.
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
22/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
Gender m/ w n.s. Virus HCV / HBV / None n.s. AFP 20 / >20,200 / >200,1000 / >1000 0.0003 MELD-Score 10 / >10,20 / >20,30 / >30 n.s. CHILD A / B / C n.s.
Bridging yes / no n.s. LT-Procedure DDLT / LDLT n.s. Lobar distribution unilobar / bilobar n.s. Nr. tumors 1 / 2 / 3 / 4 n.s. Tumor size 2 cm / >2,5 cm / >5 cm n.s. Portal invasion Vp0 / Vp1 / Vp2 / Vp3 0.0001 Differentiation well / moderate / poor
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
23/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
Multivariate cox regression analysis Risk Factor p-value
Survival
Differentiation 0.028
Recurrence
AFP n.s.
Portal invasion n.s.
Differentiation 0.006
Milan criteria n.s.
UCSF criteria 0.035
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
24/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
Overall patient and recurrence-free-survival rates afterLT
Essen Experience 04/98-04/07n = 124
O f f
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
25/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
0,0
0,1
0,2
0,3
0,40,5
0,6
0,7
0,8
0,9
1,0
Recurrencerate
0 12 24 36 48 60
Survival (months)
DDLT
LDLT
p=0.8658
0,0
0,1
0,2
0,3
0,40,5
0,6
0,7
0,8
0,9
1,0
%(
x100)
0 12 24 36 48 60
Survival (months)
DDLT
LDLT
p=0.1688
Overall patient and recurrence-free-survival rates afterLT
Essen Experience 04/98-04/07n = 124
LT f HCC R lt
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
26/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
LTx for HCC - ResultsUniklinikum Essen n= 96
Prognosis: AFP
Uniklinikum Essen
Uniklinikum Essen according to
Todo et al Ann Surg 2004
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
27/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
28/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
Meta-analysis of tumor
recurrence after livertransplantation for
hepatocellular carcinoma
Sotiropulos et al. JACS 2007 in press
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
29/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
Meta-analysis of tumor recurrence after LT for HCC:
Vascular invasion
Common OR: 8.727
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
30/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
Meta-analysis of tumor recurrence after LT for HCC:
Nr of tumors
Due to inhomogeneity of the studies, no common OR could be calculated
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
31/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
Meta-analysis of tumor recurrence after LT for HCC:
Tumor grading
Common OR: 2.89
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
32/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
Meta-analysis of tumor recurrence after LT for HCC:
Milan criteria
Common OR: 4.205
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
33/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
Meta-analysis of tumor recurrence after LT for HCC:
Tumor size
Common OR: 13.32
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
34/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
Meta-analysis of tumor recurrence after LT for HCC
in studies showing homogeneity of the data
In the cases of bigger sample size meta-analysis (for vascular
invasion n=411, tumor differentiation n=630), the statistical effect was
more significant
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
35/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
36/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
37/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
Meta Analysis and Survival 1610 cases
nonoyesyesnoyesnonoSignificant
according toTippet
0.100.210.01540.380.240.250.300.1312404.98-03.06
2007Actual series
->0.05>0.050.05--9306.85-12.03
2005Lhe
>0.05>0.050.00090.02>0.05>0.05>0.05>0.0515501.89-12.02
2005Zavaglia
--0.012--0.017>0.05-5709.88-09.02
2004Roayaie
0.09>0.05>0.05>0.05->0.05-0.0414409.92-03.03
2004Leung
--0.03>0.05->0.05>0.050.0215412.85-12.99
2003De Carlis
--0.0163--0.0019--3742002Molmenti
---0.010.650.520.80.0430701.90-12.00
2001Figueras
--0.0009>0.05->0.05--15209.971998Klintmalm
---0.017-0.038>0.05-5006.87-06.96
1998Otto
UCSFcriteria
Milancriteria
DifferentiationVascularinvasion
Lobardistribution
Tumorsize
Tumornumber
AFPNStudy-period
PubYearAuthor
Meta analysis of the multivariable results in Cox regression analysis (Tippets Method)Sotiropoulos et al: JACS 2007 (In press)
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
38/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
Meta Analysis and Recurrence
nonoyesyesyesyesyesyes
Significant
according to
Tippet
0.0350.900.0060.27---0.0912404.98-
03.062007Actual series
->0.050.003>0.05>0.05>0.050.002>0.059302.99-09.04
2006Takada
->0.050.0120.0490.220.050.9527408.92-12.02
2005Hwang
0.03>0.05>0.05>0.05->0.05-0.0314409.92-03.03
2004Leung
--0.00020.0005->0.05>0.050.000115412.85-
12.992003De Carlis
---0.00030.00020.050.03->0.05>0.05>0.051121985-2000
2001Hemming
--->0.05-0.023>0.05-4606.87-06.96
1998Otto
--0.0134--0.0133--15109.971998Klintmalm
UCSFcriteria
Milancriteria
DifferentiationVascularinvasion
Lobardistribution
Tumorsize
Tumornumber
AFPNStudy-period
PubYearAuthor
Meta analysis of the multivariable results in Cox regression analysis (Tippets Method)Sotiropoulos et al: JACS 2007 (In press)
Liver Transplantation for HCC "Liberal ApproachLiver Transplantation for HCC "Liberal Approach
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
39/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
Liver Transplantation for HCC Liberal ApproachLiver Transplantation for HCC Liberal Approach
Conclusion
Improve diagnostic tools for a correct Intention-to-treat decision making
Patient selection: Age and liver disease severity
LD as important investigational tool and essential hope forpatients with HCC
Current staging criteria are not sufficient for proper stratification
Skip staging surrogates aiming to true biological markers
Extended Indications for HCC justified in protocolstudies
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
40/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
Metastatic Potential of HCC:
Assessment of Biologic Properties Higher grade histology correlates,
albeit imperfectly, with larger tumor size
Rate of tumor cell proliferation Proliferating cell nuclear antigen (PCNA)
Cytogenetic abnormalities DNA aneuploidy
p53 expression
Fas / Fas ligand
Gene chip array techques
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
41/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
42/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
43/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
44/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
45/46
Department of General, Visceral and Transplantation Surgery, University Hospital Essen
-
8/14/2019 Hepatocellular Carcinoma Extended Indications
46/46