Hepatocellular Carcinoma Extended Indications

8/14/2019 Hepatocellular Carcinoma Extended Indications

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Department of General, Visceral and Transplantation Surgery

University Hospital Essen

Hepatocellular Carcinoma

Extended Indications

Massimo Malag


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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


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God sent

plagues

to humans...


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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


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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


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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


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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


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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


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Are we denying therapy to patients

who deserve it ??


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LTX ESSENApril 1998 May 2007

n = 931

Split (123)

LDLT (195)

Standard-Tx (605)

Reduced Liver (8)


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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.


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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


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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


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Living donor LT for HCC - EssenLiving donor LT for HCC - Essen

Extended criteria, but not open endPoor results in Decompensated cirrhosis

Age > 60


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Are we denying therapy to patients

who deserve it ??

Or

Are we overtreating patients?

Intention to treat


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Intention to treatDiagnostic accuracy pre - LT


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Intention to treatDiagnostic accuracy pre - LT


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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.


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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


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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


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Overall patient and recurrence-free-survival rates afterLT

Essen Experience 04/98-04/07n = 124

O f f


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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


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LTx for HCC - ResultsUniklinikum Essen n= 96

Prognosis: AFP

Uniklinikum Essen

Uniklinikum Essen according to

Todo et al Ann Surg 2004


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Meta-analysis of tumor

recurrence after livertransplantation for

hepatocellular carcinoma

Sotiropulos et al. JACS 2007 in press


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Meta-analysis of tumor recurrence after LT for HCC:

Vascular invasion

Common OR: 8.727


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Nr of tumors

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


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Tumor grading

Common OR: 2.89


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Milan criteria

Common OR: 4.205


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Tumor size

Common OR: 13.32


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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


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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)


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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


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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


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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 Extended Indications