Carcinome Hépatocellulaire : Résection ou Transplantation pour un CHC de petite taille

Hôpital Paul Brousse
Université Paris-Sud
René Adam
Resection or Transplant as 1st line treatment ?

What are the Keys of Decision ?

LRLT vs Resection. Lee et al L Surg Oncol 2009

OS DFS
When comparing the results DFS : a major item…

1- DFS more than OS…

Surgical Resection vs. Transplantation
Yamamoto J et al. Cancer 1999;86:1151
When comparing the results 10-Yr Survival mandatory…
OS DFS
Hepatectomy
Transplantation

2- Survival at 10 years more than at 5 years…

3- Cirrhosis or not Cirrhosis ?

Study Flow
• Local Ablation n = 1,550
• Segmental Resection n = 703
• Lobectomy (incl. extended resection) n = 619
• Transplant n = 1,117
16,209 Patients with HCC in SEER Database (2004-2007)
3,989 Patients
Include only patients who underwent surgical treatment.
Exclude patients with metastatic disease, no staging data.

Overall Survival with Cirrhosis

Overall Survival with Minimal Fibrosis

4- Within Milan or Beyond ?

Within Milan
Beyond Milan
A large difference in DFS !…
No difference at all !…

5- Comparative results

Study N 5-year survival Mortality (%)
Iwatsuki (2000) 344 49 % –
Tamura (2001) 53 61 % –
Hemming (2001) 112 57 % 13
Jonas (2001) 120 59 % 1.7
Figueras (2001) 307 63 % –
Yao (2001) 60 75 % 1.4
Todo (2004) 316 69 % (3-y ) –
Gondolesi (2004) 36 45 % 22
Zavaglia (2005) 155 72 % 11
Takada (2006) 93 64 % –
Cherqui (2009) 18a 70 %b 0
Lee (2010) 78 68 % 5.1
Coelho (2009) 45 4 recurrences 0
a Salvage transplantation after resection
b From time of transplantation
Selected series of Liver Transplantation for
Hepatocellular Carcinoma since 2000

Study N 5-year survival (%) Mortality (%)
____________________3540___________________________________________
Zhou (2001) 1000 63 1.5
Grazi (2001) 264 42 4.9
Yamamoto (2001) 58 62 –
Poon (2002) 135 70 3.7
Wayne (2002) 249 41 –
Grazi (2003) 308 42 4.9
Ercolani (2003) 224 42 –
Hu (2005) 154 – –
Pawlik (2005) 300 27 5
Wu (2005) 161 (1991-96) 28 3.7
265 (1997–02) 34 0.4
Taura (2007) 166 46 4
Yamashita (2007) 59 71 –
Cherqui (2009) 67 72 4.5
Lee (2010) 130 52 0.8
Selected series of Hepatic Resection for
Hepatocellular Carcinoma since 2000

49,43%
62,09%
Mean 5-year survival (Resection vs Liver transplantation)
Selected series published since 2000 with 5-y survival available
1376 patients (11 series)
3386 patients ( 14 series)
P = 0.02

6,7%
3,3%
Postoperative Mortality (Resection vs Liver transplantation)
Selected series published since 2000 with PO mortality available
p=0.28

1. What are the respective results of Resection and LT
for Small Single HCC (up to 5cm) ?
2. Is there a cut-off size for which Resection could be
preferred to LT ?
Adam et al, Ann Surg 2012

Consecutive series of 97 Resections and 101 LT for:
- Single HCC up to 5 cm
- in cirrhotic patients
- Operated by the same surgical team
Potential bias : more Child B/C expected in the LT group:
- Would penalize Transplantation compared to Resection
- No influence on the tumor outcome « per se »
(recurrence not influenced by liver function status…)
Resection vs LT in Small HCC
Paul Brousse Hospital 1990-2010

VARIABLES
GROUP R
n = 97
GROUP T
n = 101 p value
Post Operative death
(up to 2 months)
Yes 4 (4.1%) 3 (3%) 0.72
Post Op
Complications
≥ Grade 3 Clavien 18 (19.1%) 24 (24.7%) 0.35
Tumour recurrence Yes 60 (61.9%) 10 (10.9%) < 0.0001
Site of tumour
recurrence
Hepatic
Extrahepatic
Hepatic and
Extrahepatic
49 (50.5%)
2 (2.1%)
9 (9.3%)
3 (3%)
5 (5%)
2 (2%)
0.33
Present Status
Alive
Alive without Disease
54 (55.7%)
26 (26.8%)
59 (58.4%)
55 (54.5%)
0.7
< 0.0001
Post operative Outcome Resection vs Transplantation
for Single HCC ≤ 5 cm on Cirrhosis

Survival for Single HCC ≤ 5 cm on Cirrhosis
Overall Survival Disease-Free Survival

FACTOR AND GROUPS OVERALL PATIENT COHORT
p value RR CI 95%
ALL PATIENTS (n = 198)
Overall Survival
Resection group
Maximum Diameter of nodule at diagnosis ≥ 3 cm
Microvascular Invasion
Disease free survival
Resection group
Maximum Diameter of nodule at diagnosis ≥ 3 cm
Microvascular Invasion
0.002
0.0003
0.005
< 0.0001
0.0004
0.02
2.15
2.41
1.95
4.88
2.02
1.56
[1.32 ; 3.48]
[1.5 ; 3.87]
[1.23 ; 3.09]
[3.11 ; 7.66]
[1.37 ; 2.99]
[1.06 ; 2.31]
Multivariate analysis in patients who underwent resection (n = 97) or
transplantation (n = 101) for single HCC on cirrhotic liver up to 5 cm diameter

Is there a cut-off size for which Resection is
at least equivalent to Transplantation ?

Survival for Solitary HCC 3-5 cm on Cirrhosis

p value RR CI 95%
Overall Survival
Resection group
Microvascular invasion
Resection group
Microvascular invasion
0.0006
0.0042
< 0.0001
0.0196
3.59
2.34
6.96
1.83
[1.73 ; 7.44]
[1.31 ; 4.19]
[3.22 ; 15.04]
[1.1 ; 3.03]
Multivariate analysis in patients who underwent resection (n= 51)or
transplantation (n = 35) for single HCC on cirrhotic liver 3-5 cm diameter

Survival for Solitary HCC ≤ 3 cm on Cirrhosis

p value RR CI 95%
Overall Survival
Resection group
Age > 60
Period before 2000
Resection group
-
0.0049
0.0086
< 0.0001
-
2.78
2.72
4.35
-
[1.36 ; 5.67]
[1.29 ; 5.74]
[2.39 ; 7.92]
Multivariate analysis in patients who underwent resection (n= 47)or
transplantation (n = 68) for single HCC on cirrhotic liver < 3 cm diameter

Carcinome Hépatocellulaire : Résection ou Transplantation pour un CHC de petite taille

6- Equity of access to cure with Salvage ?

Salvage transplantation : the solution ?

Resection as a bridge to LT
2 different situations…
Decision LT
Resection
LT
« Bridge » LT
« Salvage » LT
Resection 1st
Recurrence
LT

Resection and Salvage LT ?
Adam and coll, Ann Surg 2003
Overall Survival Disease-free Survival

Belghiti et al, Ann Surg 2003
Resection as a Bridge / Salvage to LT ?
Cherqui et al, Ann Surg 2009
Bridge Salvage

Log rank p= 0.17
73%
70%
68%
53%
84%
88%
Primary LT : 349
Secondary LT : 33
Secondary vs Primary Transplantation for HCC
Overall Survival

Secondary vs Primary Transplantation for HCC
Disease-free Survival
Log rank p= 0.015
70%
51%
65%
43%
81%
75%
Primary LT : 349
Secondary LT : 33

Yes because:
More technical challenging
Increased risk of recurrence
Decreased disease-free survival
Liver Resection: a risk for secondary LT ?

Is recurrence after Resection always
suitable for Transplant ?

Resection
2nd LT 1st LT
Decision LT Decision LT
Drop out
Recurrence Out of Milan
criteria
Life-threatening
GI Bleeding
Infected Ascites
Liver Failure
Drop out
CANDIDATES
ELECTED

Author
Adam
Margarit
DelGaudio
Cherqui
Fucks
Present S
Country
France
Spain
Italy
France
France
France
Year
2003
-
2008
2009
2010
2011
Res / Rec
98 /75
37
80 / 39
67 / 36
118 / 90
117/ 91
% LT
23%
27%
26%
61%
43%
36%
LT after Liver resection :
A low transplantability rate overall…

From 1996 to 2005, we treated 227 cirrhotic patients with HCC
transplantable: 80 LRs and 147 LTs of 293 listed for
transplantation. Among 80 patients eligible for transplantation
who underwent LR, 39 (49%) developed HCC recurrence and
12/39 (31%) of these patients presented HCC recurrence
outside Milan criteria. Only 10 of the 39 patients underwent LT,
a transplantation rate of 26% of patients with HCC recurrence.
26% Transplantability rate of recurrence !
12.5% Transplantability rate of all LR !

Transplantability rate is much lower
in practice than it is theoretically
expected :
Up to 50% of patients could loose
the chance to be transplanted…
Transplantability after Resection
The reality…

« This low salvage rate may represent a lost opportunity for a
number of patients who, had they received a primary transplant may
have had better long term survival. For these patients the potential
for cure has been lost »
« Therefore, if we are going to propose resection to the patient with
HCC and cirrhosis we are potentially treating the patient with an
option that gives this patient a greater chance of recurrence and a
questionable overall survival when compared to primary liver
transplantation »

Resection with possible LT vs Primary LT
Overall Survival
68%
59%
56%
32%
88%
84%
Log rank test, p<0.0001
Primary LT : 352
Primary resection ± LT : 115
From the time of LR
From the time of LT

Resection with possible LT vs Primary LT
Disease-free Survival at last follow up
65%
31%
54%
20%
82%
70%
Log rank test, p<0.0001
Primary LT : 352
Primary resection ± LT : 115

Multivariate Analysis on Patients Eligible for Transplant
Resected or Transplanted (n=466)
RRP IC 95%
Overall survival
Disease-free survival
No nodules > 3 2.030.0008
Max size > 30 mm 1.710.002
[1.34 ; 3.08]
[1.22 ; 2.40]
Resection + LT 1.910.02 [1.11 ; 3.28]
No nodules > 3 1.710.02
Max size > 30 mm 1.770.002
[1.09 ; 2.67]
[1.24 ; 2.52]
Resection + LT 1.910.02 [1.11 ; 3.28]

6- Equity of access to cure with Salvage ?
7- Could organ shortage justify all strategies ?

Shortage of Organs…
1- A living donor could sometimes be available…
2- Even not available, results of LT for HCC within
Milan criteria are as good as that of Benign disease
So….
Why to penalize patients with transplantatble HCC
precluding 80% of them from a possibility of long term
survival if not cure ?…
Yes but…

CONCLUSIONS
1- Although liver resection may provide good survival benefit to
hyperselected patients, LT is overall the best option at long
term and on a disease-free basis
2- Resection provides similar survival only for single HCC< 3 cm
with however a lower disease-free survival compared to LT
3- Salvage transplantation is not the solution since a significant
proportion of pts loose the chance to be transplanted…
4- Provided that the survival benefit of HCC patients is similar to
that of ESLD, there is no ethical reason to discriminate HCC…

Carcinome Hépatocellulaire : Résection ou Transplantation pour un CHC de petite taille

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Carcinome Hépatocellulaire : Résection ou Transplantation pour un CHC de petite taille