Liver transplantation for HCC - pushing the limits

Gian Luca Grazi
Hepato-Biliary-Pancreatic Surgery
National Cancer Institute Regina Elena
Rome
Liver transplantation for hepatocellular carcinoma:
pushing the limits

Liver transplantation for hepatocellular carcinoma: pushing the limits
Pushing the limits !!!

Patient survival by era.
Abscissa-percentage recipient survival of total
recipients.
Ordinate-years post liver transplant.
P value <0.001 for each group compared with
reference 1987–1990.
Long-term survival outcomes after surviving past
first year.
Abscissa-percentage recipient survival of total
recipients.
Ordinate-years post liver transplant.
No group is significantly different from the other.
Rana A, Ann Surg 2019; 269:20-27.

Nasralla D. Nature 2018, 557: 50–56

EASL, J Hepatol. 2018; 69: 182-236

Chapman WC, J Am Coll Surg 2017; 224:610-621.

Number of publications appearing in PubMed while searching for
«Liver Transplantation» [AND] «Hepatocellular Carcinoma»
Year of publication

Hwang JW, J Int Med Res 2019; 47:1467-1482.

Indications
Allocation of organs to HCC patients
Bridging therapy
Downstaging therapy
Tumor recurrence
Prevention of tumor recurrence

Indications Primary
Savage transplantation
De principle transplantation
Allocation of organs to HCC patients Selection criteria Milan
UCSF
Up-to-seven
Toronto
Kyoto
Allocation MELD
Modified MELD
Bridging therapy Locoregional therapy Hepatectomy
PEI
RFA
microwave
TACE
SIRTEX
Stereotactic radiotherapy
Downstaging therapy TACE
Radioembolization
Tumor recurrence Immunosuppressive treatment Calcineurine inhibitors
Prevention of tumor recurrence Inhibitors of mTOR
Sorafenib

Principle Application HCC
Utility It refers to maximization of
post-transplant outcome.
Mainly used for HCC and therefore focused on
post-transplant prognostication with the aim
to reduce post-transplant cancer recurrence
and prolong survival
Urgency It refers to minimization of the
pre-transplant risk of dying.
Typically devoted to non-HCC/cirrhotic
patients, with worse short term outcomes
while on the waiting list because of a rapid
deterioration of liver function.
Usually based on of the MELD score, it
promotes the sickest as the first patient to
receive a donated graft.
When considered for HCC e often
showing intermediate or low MELD
scores e this principle requires
adjustments of priority rules including
the risk of tumor progression and
response to therapy, instead of the risk
of dying on the waiting list
Benefit It refers to the difference in the
number of years offered by
transplantation minus the
number of years offered by
alternative non-transplant
treatments.
Ranks patients according to the net survival
benefit and maximizes the lifetime gained
through transplantation.
When considered for HCC e this principle
requires adjustments in order to avoid
futile transplantation and prioritization of
cases at a higher risk of recurrence
Allocation policies in transplantation for HCC
Bhoori S, Practice & Research Clinical Gastroenterology 2014; 28: 867-879

Bhoori S, Practice & Research Clinical Gastroenterology 2014; 28: 867-879

Mazzaferro V, Hepatol 2016; 5:1707-1717

Who should not
be transplanted
Who should
be transplanted
How to increase the number of
patients that could benefit for
transplantation.
How to decrease the possibility to
have recurrence of the tumor after
transplantation

Center Morphologic Criteria Biomarker Criteria Survival
Milan 1 lesion ≤ 6.5 cm
2-3 lesions ≤ 4.5 cm each
None 4 yr OS: 85%
UCSF 1 lesion ≤ 6.5 cm
2-3 lesions ≤ 4.5 cm each
Total tumor diameter ≤ 8 cm
None 5 yr OS: 72.4%
Pamplona 1 lesion ≤ 6 cm
2-3 lesions ≤ 5 cm each
None 5 yr OS: 79%
Edmonton 1 lesion ≤ 7.5 cm
Multiple lesions < 5 cm each
None 4 yr OS: 82.9%
4 yr RFS: 76.8%
Dallas 1 lesion ≤ 6cm
2-4 lesions ≤ 5 cm each
None 5 yr RFS: 1 lesion ≤ 6 cm:
63.9%/or 2-4 lesion 3.1 cm- 5
cm each: 64.6%
Valencia 1-3 lesions ≤ 5 cm each
Total tumor diameter ≤ 10 cm
None 5 yr OS: 67%
Up to 7 The sum of the size and number of tumors not exceeding 7 in
the absence of microvascular invasion
None 5 yr OS: 71.2%
Center Morphologic Criteria Biomarker Criteria Survival
Hangzhou Total tumor diameter ≤ 8 cm
Total tumor diameter > 8 cm with histopathologic grade I or II
If total tumor diameter
> 8 cm AFP ≤ 400 ng/ml
5 yr OS: 70,7%
5 yr DFS: 62.4%
Rome Total tumor diameter ≤ 8 cm AFP ≤ 400 ng/ml 5 yr DFS: 74.4%
Warsaw UCSF or Up-to-7 criteria AFP ≤ 100 ng/ml 5 yr OS: 100%
Geneve (TTV) Total tumor volume ≤ 115 cm3 AFP ≤ 400 ng/ml 4 yr OS: 74,6%
Metroticket
2.0
Up-to-Seven
Up-to-Five
Up-to-Four
AFP ≤ 200 ng/ml
AFP ≤ 400 ng/ml
AFP ≤ 1000 ng/ml
5 yr Cancer Specific
Survival: 75%
Selection Criteria for LT in HCC
cadaveric donor liver transplantation (CDLT)

1. Tumor confined to the liver—i.e., no pulmonary or nodal metastases
2. No radiologic evidence of venous or biliary tumor thrombus
3. No cancer-related symptoms. These symptoms were defined as a weight loss over 10 kg and/or an
increase in the Eastern Cooperative Oncology Group score of 1 point over a period of 3 months.
Also, patients had to have a performance status of 0.
4. A mandatory percutaneous tumor biopsy of the largest lesion (per protocol) that determined the
lesion to be not poorly differentiated. Biopsy was only required for those patients who exceeded
the Milan criteria but were within the ETC and was done percutaneously in all cases.
5. Those patients with tumors that exceeded the Milan criteria who had massive ascites and/or
coagulopathy that precluded a biopsy of the tumor were not included on the waiting list.
Sapisochin G, Hepatology 2016; 64:2077-2088.

M+ group: tumors exceeded Milan criteria
M group: within Milan criteria

Long-term actuarial patient survival
from the time of transplant. (All
patients)
Long-term actuarial patient
survival from the time of listing –
ITT analysis

ITT analysis according to AFP at
the time of listing.
Actuarial patient survival according to AFP at the time of
transplant within the M and M1 groups.

It is possible to achieve excellent long-term survival after LT for HCC using
a selection algorithm (the ETC) that does not rely only on measurement
of tumor size or number.
• Poor tumor differentiation,
• cancer-related symptoms, and
• elevated AFP
levels should be considered in future selection algorithms of LT for HCC.

Maximal enrollment of candidates,
Securing a 5-year recurrence rate (95% upper confidence limit) below 10%, and
Not to search for factors associated with recurrence or establish a prediction model for recurrence.
• Maximal diameter of the tumors set at 5 cm
• Both AFP and DCP proved to be significant predictors for HCC recurrence after LDLT in previous
nationwide survey.
• The upper limit of the tumor number and serum AFP/DCP value satisfying a 5-year recurrence rate
(95% upper confidence limit) below 10% with the maximal enrollment of candidates was computed
and investigated as follows;
the upper (and the lower limit) of confidence interval was computed as “actual recurrence rate +
1.96*standard error” (and “actual recurrence rate - 1.96*standard error”).
Shimamura T, Transpl Int 2019; 32:356-368.

the 5-5-500 rule

The Kaplan–Meier curve for
recurrence-free survival,
stratified by the indication
criteria.
The Kaplan–Meier curves for
overall patient survival,
stratified by the indication
criteria.

The 5-5-500 rule
5 HCC nodules
no greater than 5 cm in size
with an AFP value below 500 ng/ml
The new criteria could secure the 95% upper confidence limit of a
recurrence rate below 10%, and coupled with the Milan criteria,
could increase the number of eligible LDLT candidates by 19%.

Lai Q, Hepatology 2017;66:1910-1919
Radiological
Biological

The ITT survival benefit of LT enables better discrimination
among HCC patients waiting for LT in relation to their real
need for transplantation.
Such a stratification may lead to an improved and more
equitable liver allocation.
New aspects such as radiological response post-LRT should
be implemented in clinical practice as a selection parameter
to be used in HCC patients.
The combination of radiological and biological tumor
characteristics should be considered to be the gold standard
for HCC selection instead of the conventionally used “only
morphological” criteria.

Halazun KJ, Ann Surg 2018; 268:690-699.
AFP levels at diagnosis
Maximum AFP at any time point Max-AFP
Final immediate pre-OLT AFP Final-AFP
AFP levels > 200 Cut-off for marked elevation
AFP levels > 1000 Cut-off for extreme elevation
(French AFP and UNOS regulations)
Alpha-Fetoprotein (AFP) Cut-off and AFP-Response

New York/California Score (NYCA)

Kaplan-Meier curve and Log Rank testing
according to NYCA score categories
Competing risk regression analysis (with
death as a competing risk to recurrence)
by NYCA score category

 NYCA provides an accurate objective measure of HCC
outcome through incorporation of an AFP response,
predicting both 5-year RFS, overall survival, as well as
correlating with explant pathology.
 As UNOS moves to abandon the strictly dichotomous
Milan criteria, adding static AFP levels, incorporation of an
AFP response using NYCA into the current UNOS model
would further advance our goal of offering transplantation
to patients that would benefit most through a better
understanding of biological HCC behavior.

Mehta N, Clin Liver Dis 2019; 13:20-25.

Mehta N, Clin Liver Dis 2019; 13:20-25.
To maximize survival benefit, the LT community should consider reducing (or eliminating) priority for
the 10% to 20% of patients with HCC with very long wait-list life expectancy (e.g., Child-Pugh A, low
MELD and AFP, and single tumor up to 3 cm with complete response to LRT).
On the other end of the tumor burden spectrum, some determination of tumor biology should be
obtained in patients presenting beyond Milan criteria (in addition to AFP).
Reasonable approaches include LRT for tumor down-staging, measuring novel biomarkers such as AFP-
L3 and DCP, and PET scan.
Results from the various proposed pre-LT models that include such criteria have suggested that
acceptable post-LT outcome can be achieved in selected patients with HCC beyond Milan criteria.

UCSF
Pamplona
Edmonton
Dallas
Valencia
Up to 7
Hangzhou
Rome
Warsaw Geneve Tokyo
Asian
Medical
Center
Chang Gung
Hong Kong
Kyushu
Kyoto
Toronto
Japanese Expanded
NYCA
French AFP
TTV-AFP
Pre-MoRAL
HALT-HCC
Nat Cancer
Center Korea
Who is still really
following Milan Criteria
?
TAKE HOME MESSAGES (1)

 Milan criteria were the firsts giving an homogeneous
view to indication-criteria for liver transplantation for
hepatocellular carcinoma during several years.
 New criteria were already proposed by several
institutions, introducing intriguing considerations, but
increasing dispersion
 The inclusion of dynamic and biological variables will
give the systems added value.

 A consensus on the grade of expansion has not yet been reached
and considering that complex regional/local conditions play a
major role in prioritizing cancer patients (according to, e.g.,
• the wait list distribution and
• dynamics,
• organ availability and
• quality),
 new criteria should be determined a priori after a thorough
analysis of survival and benefit endpoints.

 In the era of “precision” medicine and “precision” surgery, further
efforts should be placed to better understand the genomic profiles
of hepatocellular carcinoma.
 New, future classification of different tumor behaviors will gave us
new perspective on indication criteria for liver transplantation for
HCC.

Gian Luca Grazi
Hepato Biliary Pancreatic Surgery
National Cancer Institute “Regina Elena”, Rome, Italy
gianluca.grazi@ifo.gov.it
www.chirurgiadelfegato.it

Liver transplantation for HCC - pushing the limits

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