Hepatocellular Carcinoma Extended Indications

Hepatocellular Carcinoma
Extended Indications
Massimo Malagó
Department of General, Visceral and Transplantation Surgery
University Hospital Essen
HCC Extended Indications
The patients who most need a LT are the

sickest ones
Thomas Starzl
The worst complication of Liver

transplantation is to die before receiving
the transplant
Henri Bismuth
Department of General, Visceral and Transplantation Surgery, University Hospital Essen

God sent
plagues
to humans...

HCC - LDLT
HCV epidemic worldwide

Increasing incidence of HCC
372.000 new cases / year in USA
4,6% all malignancies
2002: HCC Ca. 1 million new cases / year

Solomon, Am J Epidemiology 2002: 156, 761
Liver resections
Essen Apr. 1998 - 2007
Hemihepatectomies 659
Extended Hemihepatectomies 193
Anatomical Liver resections 237
Atypical Liver resections 692
Resection of the hilar bifurcation 43
Live Donor Hepatectomies 174
___________
Liver resections
overall 1998
156 liver resection for HCC

LTx in patients with HCC
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 <0,05

LT in patients with HCC and cirrhosis
- 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

LTx for HCC
Strategy in Essen
CLTx LDLTx
Conservative policy
Opening to selected
(Milan criteria - 5cm)
advanced tumors
“organ rescue”
Immunosuppression
Low dose Csa-Fk Monotherapy + (Sirolimus late postop.*)
Csa150-200ng/ml FK 3-7ng/ml
*since 2003
Are we denying therapy to patients
who deserve it ??

LTX ESSEN April 1998 – May 2007
n = 931
Reduced Liver (8)
LDLT (195)
Split (123)
Standard-Tx (605)

LTx for HCC - Adults
N = 124
Essen 04/1998 -05/2007
ALDLT n=160 Cadaver LTx n=728
HCC 35% HCC 9,3%
68 4
56
hcc
hcc other tumors
other tumors other disease
other disease Segment 4
93
9 656
Mean F-up 39 mo.

LTx for HCC - Adults N = 124 Essen 04/1998 -05/2007
DDLT LDLT p-value

No. of patients 68 56
Age (mean±SD, years) 53.4±9.1 55.0±10.1 0.239
Gender 0.908
Male 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 12
HBV/HCV 0 2
HCV 27 18
MELD Score 0.085
<10 24 19
>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 = 124 Essen 04/1998 -05/2007
DDLT LDLT p-value

No. of patients 68 56
Lobar distribution 0.441
Unilobar 37 26
Bilobar 18 19
AFP 0.708
≤20 31 22
>20, ≤200 12 14
>200, ≤1000 8 5
>1000 4 4
Milan criteria 0.717
Within 25 23
Beyond 30 22
UCSF criteria 0.658
Within 27 25
Beyond 28 20
Perioperative mortality 5 9 0.203

Living donor LT for HCC - Essen
Extended criteria, but not “open end”

Poor results in Decompensated cirrhosis
Age > 60
Intention to treat
Are we denying therapy to patients

who deserve it ??
Or
Are we overtreating patients?

Intention to treat
Diagnostic accuracy pre - LT

Intention to treat
Diagnostic accuracy pre - LT

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.

Univariable Analysis of tumor recurrence after 124 LT for HCC
• 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 <0.0001
• pTNM I / II / IIIA / IIIB n.s.
• Milan Criteria meeting / exceeding 0.0148
• UCSF Criteria meeting / exceeding 0.0092

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

Overall patient and recurrence-free-survival rates after
LT
n = 124

Overall patient and recurrence-free-survival rates after
LT
n = 124
1,0 1,0
0,9 0,9 p=0.8658
0,8 0,8
Recurrence rate
DDLT
0,7 0,7
% (x100)
0,6 0,6
LDLT
0,5 0,5
0,4 0,4
0,3 0,3
DDLT
0,2 0,2
0,1 p=0.1688 0,1 LDLT
0,0 0,0
0 12 24 36 48 60 0 12 24 36 48 60
Survival (months) Survival (months)

LTx for HCC - Results
Uniklinikum Essen n= 96
Prognosis: AFP
Uniklinikum Essen
Uniklinikum Essen according to

Todo et al Ann Surg 2004
Meta-analysis of tumor
recurrence after liver
transplantation for
hepatocellular carcinoma
Sotiropulos et al. JACS 2007 in press

Meta-analysis of tumor recurrence after LT for HCC:
Vascular invasion
Common OR: 8.727

Nr of tumors
Due to inhomogeneity of the studies, no common OR could be calculated

Tumor grading
Common OR: 2.89

Milan criteria
Common OR: 4.205

Tumor size
Common OR: 13.32

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

Meta Analysis and Survival 1610 cases
Author PubYear Study- N AFP Tumor Tumor Lobar Vascular Differentiation Milan UCSF
period number size distribution invasion criteria criteria
06.87-
Otto 1998 50 - >0.05 0.038 - 0.017 - - -
06.96
Klintmalm 1998 09.97 152 - - >0.05 - >0.05 0.0009 - -
01.90-
Figueras 2001 307 0.04 0.8 0.52 0.65 0.01 - - -
12.00
Molmenti 2002 374 - - 0.0019 - - 0.0163 - -
12.85-
De Carlis 2003 154 0.02 >0.05 >0.05 - >0.05 0.03 - -
12.99
09.92-
Leung 2004 144 0.04 - >0.05 - >0.05 >0.05 >0.05 0.09
03.03
09.88-
Roayaie 2004
09.02
57 - >0.05 0.017 - - 0.012 - -
01.89-
Zavaglia 2005 155 >0.05 >0.05 >0.05 >0.05 0.02 0.0009 >0.05 >0.05
12.02
06.85-
Löhe 2005
12.03
93 - - >0.05 - <0.001 >0.05 >0.05 -
04.98-
Actual series 2007
03.06
124 0.13 0.30 0.25 0.24 0.38 0.0154 0.21 0.10
Significant
according to no no yes no yes yes no no
Tippet
Meta analysis of the multivariable results in Cox regression analysis (Tippet’s Method)
Sotiropoulos et al: JACS 2007 (In press)
Meta Analysis and Recurrence
Author PubYear Study- N AFP Tumor Tumor Lobar Vascular Differentiation Milan UCSF
period number size distribution invasion criteria criteria
Klintmalm 1998 09.97 151 - - 0.0133 - - 0.0134 - -
06.87-
Otto 1998
06.96
46 - >0.05 0.023 - >0.05 - - -
1985-
Hemming 2001
2000
112 >0.05 >0.05 >0.05 - 0.03 >0.05 - -
Molmenti 2002 370 <0.0001 0.0002 0.0003 - - -
12.85-
De Carlis 2003
12.99
154 0.0001 >0.05 >0.05 - 0.0005 0.0002 - -
09.92-
Leung 2004
03.03
144 0.03 - >0.05 - >0.05 >0.05 >0.05 0.03
08.92-
Hwang 2005
12.02
274 0.95 >0.05 <0.001 0.22 0.049 0.012 >0.05 -
02.99-
Takada 2006
09.04
93 >0.05 0.002 >0.05 >0.05 >0.05 0.003 >0.05 -
04.98-
Actual series 2007
03.06
124 0.09 - - - 0.27 0.006 0.90 0.035
Significant
according to yes yes yes yes yes yes no no
Tippet
Meta analysis of the multivariable results in Cox regression analysis (Tippet’s Method)
Sotiropoulos et al: JACS 2007 (In press)

Liver 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 for

patients 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 protocol
studies
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


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Hepatocellular Carcinoma

The patients who most need a LT are the

The worst complication of Liver

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

HCV epidemic worldwide

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

156 liver resection for HCC

• “Intention to treat” (RADIOLOGY) vs “Reality” (PATHOLOGY) Analysis

• End-points: short and median term survival,

• Median follow-up: 39 months (3-89 months), follow-up rate 100%

• Statistic: t-Test, Chi-square, Wilcoxon (non-parametric), significance <0,05

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

• „Extended“ indications (LD LTx,“rescue“ ):

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

Mean F-up 39 mo.

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

DDLT LDLT p-value

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

DDLT LDLT p-value

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

Extended criteria, but not “open end”

Are we denying therapy to patients

Are we overtreating patients?

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

• Risk Factor p-value

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

Uniklinikum Essen according to

Sotiropulos et al. JACS 2007 in press

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

Common OR: 8.727

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

Due to inhomogeneity of the studies, no common OR could be calculated

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

Common OR: 2.89

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

Common OR: 4.205

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

Common OR: 13.32

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

In the cases of bigger sample size meta-analysis (for “vascular

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

Klintmalm 1998 09.97 151 - - 0.0133 - - 0.0134 - -

Molmenti 2002 370 <0.0001 0.0002 0.0003 - - -

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

•Patient selection: Age and liver disease severity

•LD as important “investigational tool” and essential hope for

•Current staging criteria are not sufficient for proper stratification

•Skip staging “surrogates” aiming to true biological markers

Department of General, Visceral and Transplantation Surgery, University Hospital Essen

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