1. Hôpital Paul Brousse
Université Paris-Saclay
René Adam
Place de la Transplantation Hépatique dans les
Métastases de Cancer Colorectal
et les tumeurs hépato-biliaires

2. Liver Transplantation for Cancer
Non HCC: 2.4% of all LT

4. Indications reconnues Contre-Indications
• CHC
• CCK Péri-hilaire
• Hémangio Endothéliome
• Métas Neuro-endocrines
• CCK intrahépatique
• Angiosarcome
• Métas CR
TH pour Cancer

5. CHC

6. Too extensive tumor…
Higher risk of extrahepatic disease…
Indications in the 80-90 ies

7. Patient Survival vs the Indication of LT
01/1988 - 12/2004
83
76
72
66
62
78
62
54
46
42
67
63 61
58
56
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10
Cirrhosis : 31090
Cancers : 6547
Acute hepatic failure : 4822
(%)
Yrs
Total Log Rank test p = 0.0001
Acute Hepatic Failure vs Cirrhosis : 0.0001
Cancers vs Cirrhosis : 0.0001
Acute Hepatic Failure vs Cancers : 0.0001 (Wilcoxon test)
p Log Rank :
ELTR
12/2004

8. Resection Transplantation
n = 60 n = 60
OS DFS OS DFS
Total series 52% 27% 49% 46%
Size
< 3 cm 39% 18% 60% 56%
≥ 3 cm 56% 32% 43% 39%
Number of nodules
Single 53% 28% 46% 20%
Multiple 46% 20% 51% 49%
Size + Number
< 3 cm < 3 nodules 41% 18% 83% 83% p < 0,01
≥ 3 cm ≥ 3 nodules p < 0,05 46% 44%
H Bismuth… R Adam et al. Ann Surg 1993
p< 0.001
Resection vs Transplantation for HCC with cirrhosis

9. Liver Resection vs Transplantation for HCC
The Paul Brousse « rule of 3 » policy since 1993:
≤ 3 cm ≤ 3 nodules
- To transplant « resectable » patients
- To resect those « untransplantable »
Impact of this better selection:
- No LT for HCC > 3 nodules > 3 cm
- Improvement of 5-year survival from 49% (1984-
91) to 77% (1992- 1996)
H Bismuth… R Adam et al. Ann Surg 1993

10. Liver Resection vs Transplantation for HCC
LT for HCC could achieve as better results
as LT for benign disease… for patients with
HCC ≤ 3 nod ≤ 3 cm
or unique ≤ 5 cm
( Mazzaferro V et al, N Engl J Med 1996)

11. 70 %
23 %
47 %
+ 59%
Evolution of Patient Survival after LT for HCC in Europe
88 %
48 %
11 %

13. Hémangioendothéliome
epithelioide
Angiosarcome
TH pour Cancer

14. Overall Survival after LT
Dg LT
UNOS HEHE DATA BASE
1987-2005
130 Pts 64% Survie à 5 ans
78 adults
Canadian Experience
83%
74%
83%
72%
70%
A good indication : Epithelioid Hemangioendothelioma

15. 1986-2004 ELTR

16. Cholangiocarcinome péri-hilaire
TH pour Cancer
Peri-Hilaire

17. Graft Survival
ELTR Overall vs Klatskin
May 1968 – March 2016
0
,2
,4
,6
,8
1
Survie
Cum.
0 1 2 3 4 5 6 7 8 9 10
Years
71%
37%
30%
84%
73%
62%
Biliary Tract K (n=358)
ELTR Overall (n=111,996)
Overall vs Biliary tract p<0.0001

18. Revisiting LT for Klatskin tumors…
The Mayo Clinic Protocol

19. Mayo Clinic Treatment Protocol
External beam radiation therapy
Brachytherapy
Protracted venous infusion of 5-FU
Abdominal exploration for staging
Liver transplantation
from Charles B. Rosen

20. Liver transplantation for Hilar Cholangiocarcinoma
Heimbach JK et al, Liver transplantation, 2004
Enrollment
56 pts
Staging
43 pts
OLT
28 pts
Survival
22 pts
Disease spread / Death
During radiation: 8 pts
Metastatic Disease
Precluding OLT: 14 pts
Death post-LT
6 pts
Awaiting OLT
6 pts

22. Up-date Mayo Clinic 2012
10-yr DFS: 66% 10-yr OS: 61%
Prognostic factors:
- Elevated CA 19-9
- Portal vein encasement
- Residual tumor on explant
Murad et al , Hepatology 2012;56:972-981
10-yr OS : 61% 10-yr RFS : 66%

23. CCK intrahépatique et HCA :
encore une contre-Indication ?
TH pour Cancer
Intrahepatic

24. 0
,2
,4
,6
,8
1
Survie
Cum.
0 1 2 3 4 5 6 7 8 9 10
Years
Graft Survival
Primary Cancers vs Non Cancer
May 1968 – March 2016
Biliary tract (n=358)
HCC (n=22075)
IHCK (n=637)
84%
65%
52%
71%
37%
30%
66%
30%
21%
CCC vs Klatskin p=0.02 CCC vs Non Cancer p<0.001
CCC vs CHC p<0.001 Klatskin vs Non Cancer p<0.001
Klatskin vs CHC p<0.00 HCC vs Non Cancer p<0.001
Non Cancer (n=87243)
75%
66%

25. 2016
48 pts with iCCA on
the liver explant

26. 1984 – 2015 : 12 pts transplanted for HCC-CCA discover on
the explant matched 1:3 with HCC on Pathological Data
Good Results in Well
Differenciated HCC-
CCA 2018

27. 2002-2014 : 75 cirrhotic patients with iCCA or HCA on the specimen
L
N=49
N=26
Liver Transplantation versus Resection
for Small Intrahepatic Cholangiocarcinoma
or Hepatocholangiocarcinoma on Cirrhosis
E De Martin et al
Liver Tranplantation 2020
Resection
Transplant

28. 74%
34%
P=0.03
LT
RS
Median follow-up 59 (30-88) Mo
79%
59%
Overall Survival
p = 0.001
66%
21%
LT
Surg
58%
16%
Cumulative Recurrence Rate
E De Martin et al, Liver Tranplantation 2020

29. Résection vs Transplantation
Diameter < 2 cm Diameter 2 to 5 cm

30. Overall and Recurrence-Free Survival in Liver
Transplantation according to diameter

31. Conclusions
La transplantation améliore considérablement la survie
des CCK IH ou des Hépato-CCK < 5 cm sur cirrhose
comparativement à la résection
Reconsidération de la TH pour CCK IH / Hépato-CCK < 5 cm

32. Métastases Hépatiques de
Tumeur Neuro-endocrine
TH pour Cancer

33. 0
,2
,4
,6
,8
1
Survie
Cum.
0 1 2 3 4 5 6 7 8 9 10
Years
79%
51%
33%
Patient Survival after LT for NET
in Europe (n= 455)
ELTR: 09/1982 – 12/2011
Median Survival: 67 Mo

34. LT for liver metastases of NET
Metastatic disease confined to the liver
 extensive work-up before LT
 CT-scan, octreosan, PetCT
 Laparotomy, laparoscopy

35. LT for liver metastases of NET
 Well-differenciated NET only
G1: OK
G3: NO
G2 : ?
Ki67<10%*
Ki67<15%**
Ki67<20%*** *ENETS and AJCC grading system
Grade* Mitotic count (10
HPF)
Ki67 index
(%)
G1 <2 ≤2
G2 2-20 3-20
G3 >20 >20
*Rosenau et al. Transplantation 2002
**Olausson et al. Liver Transpl 2007
***Mazzaferro et al. Tumori 2010

36. LT for Liver Metastases of NET
 Unresectable Metastatic disease
 50% involvement
 Often after failure of all the
other treatment options

37. LT for liver metastases of NET
What have we learnt ?

38. Two lists of Prognostic Factors
Le Treut et al., Am J Transpl 2008
Retrospective
Multicentric
N=85
Mazaferro et al., J Hepatol 2007
Prospective
Monocentric
N=24
1. Hepatomegaly ≥ 120%
2. Bad Differenciated
3. Duodeno pancreatic
1. Age ≥ 55 yrs
2. High grade
3. No Portal Drainage
4. Residual EHD
5. Extension ≥ 50%
6. No Stable disease ≥ 6
months
Hépatomégalie: +1
Duodénopancréatique: +1

39. The paradox of LT for NET…
The less symptomatic the patients, the best the results!...
Volume
tumor
Symptoms Survival
Le Treut, Ann Surg 2013

40. Mazzaferro, Am J Transpl 2016

41. Mazzaferro, Am J Transpl 2016
Benefit in survival in months
Univariate Multivariate (PS)
D-MST p D-MST p
5 yrs 12,8 < 0,001 6,8 0,02
10 yrs 48,6 < 0,001 38,4 < 0,001

42. Evolution of Patient Survival after LT for NET
in Europe
09/1982 – 06/2021
78%
88%
52%
71%
37%
45%
Since 2010 (n=237)
Before 2010 (n=400)
Logrank test, p=0.0001
0 1 2 3 4 5 6 7 8 9 10
Years

43. TH pour MCR :
encore une contre-Indication ?
TH pour Cancer

44. ELTR
12/04
0
.2
.4
.6
.8
1
0 1 2 3 4 5 Years
73%
50%
36%
22% 18%
Patient Survival after LT for
Colorectal Metastases
N=50, Feb. 1977 – Dec. 2004
80% before 1995
44% of deaths unrelated to tumor recurrence

45. ELTR
12/04
Liver Transplantation for
Colorectal Liver Metastases
- Improved expertise in the management of LT
- Better knowledge of biology of metastatic disease
- Better imaging: PET/ CT
- More effective chemotherapy
- More adapted immunosuppression
What has changed ?

46. ELTR
12/04
Liver Transplantation for
Colorectal Liver Metastases
In 2004... a proposed reasonable hypothesis:
LT for very selected patients with
• Liver-only disease assessed by modern imaging
• Confirmed unresectability by partial hepatectomy
• Preop.control of the tumor by active chemotherapy
and routine adjuvant treatment post-transplant
• Adapted immunosuppression
May significantly improve the results and offer long-
term survival…
R Adam, Personal Communication Eurotranplant 2004

48. ELTR
12/04
Ann Surg 2013
60%

50. Oslo University Hospital

51. 12 Pts from 4 european centers (1995 -2015)
• For 9 /12 Pts Liver metastases were
diagnosed within 12 months
• Median No : 9 LM, 2 lines Chemo
• DFS possible … but only in deliberate
procedures (6pts) with oncoSurge approach:
(chemo + liver resection in 10 pts before LT)
• None with progressive disease
83%
62%
50%
C Toso, H Pinto Marques, A Andres, F Castro Sousa, R Adam, A Kalil, PA Clavien,
E Furtado, E Barroso, H Bismuth

52. Liver Transplantation for
Colorectal Liver Metastases
Is there still a room for improvement ?

53. Randomized Trial: TransMet
• Chemotherapy and LT vs Chemotherapy alone
in the treatment of definitively non resectable
colorectal liver metastases :
On going Prospective randomised multicentric Trial
• Better patient selection

54. PHRC : Multicentric Randomised Trial
Towards a better Patient Selection …
- ≤ 65 years
- Confirmed non resectable liver metastases of colorectal cancer,
- High standard carcinological resection of the primary
- No extrahepatic tumor localisation
- Treatment by ≥ 3 months of optimal chemotherapy
- Stable or Partial Response while on ≤ 3 lines of chemotherapy
- No BRAF mutation
- Serum CEA levels < 100 ng/ml or 50% decrease from baseline
Independant Validation of the indication…
by the steering committee of the study including oncologists,
radiologists and hepatologists / Transplant surgeons
OncoSurgical Approach…
Tailored Immunosuppression…

55. • 1ry End Point: 5-yr OS
• Objective : ≥ 50% with LT
• 80 Pts (40 in each group)
to demonstrate a 40% diff
(50 vs 10%)
• 16 French centers
• 10 European centers
(2 Italy, 6 Belgium…)
TransMet : Multicentric Randomised Trial

56. TransMet : Evolution of the inclusion rate up to July 2021
Submitted to the independent committee
Randomized
En 2017:13 patients En 2018: 28 Patients En 2019:19 patients
En 2016: 7 Patients En 2020:20 patients
1st Results: 2022-23

57. 3-Year Survival of Excluded Patients 3-Year Survival of All Randomized Patients
TransMet : Overall data of excluded and included Pts
10 %
57 %

58. TRANSMET : Case-matched comparison with the Oslo criteria (Hagness 2013)
Hagness, 2013 : 21 Pts
OS at 5 years: 60%
TransMet : 9 Pts (same criteria)
OS at 5 years : 100%
Hagness M et al, Ann Surg 2013

59. TRANSMET : Case-matched comparison with the Oslo criteria (Dueland 2020)
TransMet : 20 Pts
OS at 3 years : 78 % (3 deaths)
Dueland, 2020 : 15 Pts
OS at 3 years : 80 %
Dueland S et al, Ann Surg 2020

60. • At least 10% response (Recist criteria) to chemotherapy
• Time from diagnosis to LT > 1 year
SECA- II
15 Pts
DFS

61. Homme, 57 ans, Metastases bilobaires synchrones multiples,
ACE 40 ng/ml, Tres bonne réponse à 2 lignes de chimio…
Randomisation TH, Suites: Tako Tsubo évolution favorable…
Spécimen : 37 Nodules 70% Nécrose…
Vivant sans récidive à 4.5 ans

62. Homme, 41 ans, > 30 Métastases bilobaires synchrones multiples,
ACE 500 ng/ml, Tres bonne réponse à 2 lignes de chimio…
Randomisation TH, Chimio adjuvante…
Vivant sans récidive à 2.5 ans

63. Conclusions
• TH pour MCR : contre-indiquée sur des données anciennes est
aujourd’hui réexplorée du fait de l’efficacité de la chimiothérapie et de
la plus grande expertise des équipes en transplantation …
• Des survies à 5 ans de 70-80% sont obtenues chez des patients très
sélectionnés, non résécables mais fortement répondeurs à la chimio…
• Ces résultats très prometteurs laissent augurer d’une supériorité par
rapport à la chimiothérapie seule, qui reste néanmois à confirmer par
les résultats de l’essai randomisé TransMet
• Reste que la récidive est assez fréquente, indolente pour les
métastases pulmonaires mais plus grave pour les autres localisations
Résultats à plus long terme à considérer…

64. Tumor Biology vs Transplant Oncology
• All the models of hepatic tumors either primary or secondary demonstrate that
the key factor of good results is the selection of patients and the control
/downstaging of the tumoral disease
• As for any oncologic surgery, the tumor should be at the best, controlled by
chemotherapy, radiotherapy or any other means before LT…
• While LT was initially considered for extensive liver disease …
The more limited the tumoral disease either initially or after chemotherapy, the
more curative the LT…
• Molecular biology will become in a near future a major selection tool
All these principles are justified in the context of organ shortage, with
the objective to obtain with LT of malignant tumors equivalent outcomes
as those of LT for benign disease

66. LT for Liver Malignancy
Good indications
• HCC
• Hemangioendothelioma
• IntraHepatic CCK < 5 cm
• Hilar CCK Mayo protocol
• Neuroendocrine (TNE) G1-G2
Contraindications
• Hemangiosarcoma
• IntraHepatic CCK > 5 cm
• Hilar CCK > 3cm
• G3 TNE, Non colorectal LM
Pending indications
• Colorectal LM