Grazi oporto 2017

Gian Luca Grazi
Hepato-Biliary-Pancreatic Surgery
National Cancer Institute Regina Elena
Rome
Advances in the treatment of
hepatocellular carcinoma

Advances in the treatment of hepatocellular carcinoma

• Cancers are far more complex than realised, more genetically heterogeneous
than appreciated and genetic information quite difficult to analyse from a
systems biology perspective, especially pathway mapping.
• The nature of the genetic information is also protean (genetic analysis involves
transcriptional profiling often referred to as expression signatures, miRNA
profiling, assessment of long non-coding RNAs, determination of copy number
aberrations, deep exome sequencing, quantification of hemizygous and
homozygous deletions, and promoter methylation).
• To further confound interpretation of the genetic analysis, there are driver
mutations important in the biology of the cancer and passenger mutations
which are unimportant, distinguishing between the two is not easy.
• The cancer genetics must also be compared with non-tumour tissue to identify
cancer specific alterations.
• The cancer programme also varies over time, and hence genetic features
critical for carcinogenesis may vary from the metastasis genetic programme;
such a process likely evolves via clonal evolution.

Given this byzantine complexity of tumour genetics, it is
not surprising that meaningful progress has been
difficult, and none of the existing guidelines in HCC
incorporate genetic tools.

Schulze K, Nat Genet 2015, 47(5): 505-511

• This study identified relationships between environmental
exposures and mutational patterns in HCC as well as the
landscape of driver genes and pathways altered in different
clinical stages and etiological backgrounds.
• For patient care, genomic alterations identified in targetable
genes will be useful to identify patients with HCC who could
potentially benefit from targeted treatment in future clinical
trials.
Schulze K, Nat Genet 2015, 47(5): 505-511

Bruix J, Lancet 2017;389:56-66

J Hepatol 2012;56:908-943

Single nodule > 5 cm?

Kudo M, Dig Dis 2011, 29: 339-364

Schmidt S et al. J Gastroenterol Hepatol 2011, 26: 1779-1786

 Four guidelines can be strongly recommended,
the majority of the domains scoring above 60%
showing a good overall quality of the guidelines.
 Eighteen can be recommended with provisos
and alterations, the majority of the domains
scoring between 30% and 60%.
 The remaining 10 CPG cannot be recommended
due to their poor scoring in the majority of the
domains.
Schmidt S et al. J Gastroenterol Hepatol 2011, 26: 1779-1786

Nathan H et al. J Clin Oncol 2011; 29: 619-625

16 academic-drafted guidelines from different geographical areas are now
available, the most important and popular of them being the North American
and European guidelines, which were first released in 2001 and updated in
2005 and 2011 and endorsed by the American Association for the Study of
Liver Diseases (AASLD) and the European Association for the Study of the
Liver–European Organisation for Research and Treatment of Cancer (EASL–
EORTC) scientific societies; the Asian guidelines endorsed by the Asian–Pacific
Association for Study of the Liver; and the Japanese guidelines endorsed by the
Japan Society of Hepatology.

 The reliability of BCLC staging as an allocative therapeutic
system in clinical practice might be questioned.
 The BCLC staging system has been endorsed by AASLD
and EASL guidelines for almost 15 years.
 However, it has only been validated internally and
externally as a prognostic stage system; in this setting, its
reliability is widely accepted.
 The most noticeable weakness concerns therapeutic
decisions on patients belonging to the intermediate-
stage HCC.

Santi V, J Hepatol 2012, 56: 397-405

HCC
131
Intrahepatic
Cholangiocarcinoma
45
Metastases
259
Perihilar
Cholangiocarcinoma
26
Others
70
551 Liver Resections
(June 2010 – April 2017)
Gallbladder
20

5,6%
40,7%
45,4%
8,3%

• BRIDGE is a multiregional cohort study including HCC patients
diagnosed between January 1, 2005 and June 30, 2011.
• A total of 8,656 patients from 20 sites were classified into four
groups:
a) 718 ideal resection candidates who were resected;
b) 144 ideal resection candidates who were not resected;
c) 1,624 nonideal resection candidates who were resected; and
d) 6,170 nonideal resection candidates who were not resected.
• Median follow-up was 27 months.
Roayaie S, Hepatology 2015; 62: 440-451

Survival curves of patients stratified by whether they met
AASLD/EASL criteria for resection and type of treatment used.
All patients

≈ 20% of candidates who meet current EASL/AASLD criteria for LR are
denied surgery, and this is associated with a 2-fold increase in mortality.
A common practice is to offer surgery to patients beyond the
recommended criteria (majority of patients undergoing resection did not
meet criteria)
The current criteria might be expanded to include pts with either
moderate PH or slightly elevated total bilirubin >1 mg/dL, but not both,
without increase in mortality.
Expansion of criteria along other lines, such as tumor characteristics,
liver function, and performance status, is associated with significantly
lower survival.
For patients who do not meet criteria for surgery, LR may still associated
with longer survival, when compared to TACE and “other” treatments,
and shorter survival, in comparison to RFA and LT, when controlling for
other relevant factors.

Torzilli G, et al. Arch Surg. 2008;143:1082-90.

Retrospective evaluation of 455 consecutive patients who
had undergone an initial curative liver resection for HCC
without extrahepatic metastasis at Tokyo University Hospital
between November 1994 and December 2004
Ishizawa T, et al. Gastroenterology. 2008;134:1908-

• Liver resection can provide a survival benefit
for patients with multiple HCCs associated
with Child–Pugh class A cirrhosis
• Resection for HCC also may be indicated for
patients with PHT

• Esophageal varices detectable at endoscopy
• Splenomegaly (major diameter > 12 cm) with
a platelet count < 100,000 /mm3
Capussotti L, et al. World J Surg. 2006;30:992-9;
Llovet JM, et al. Semin Liver Dis.1999;9:329-338.
Definition of portal hypertension

• A first logistic regression model was applied in order to identify predictors of
postoperative irreversible liver failure
• To overcome biases owing to the different distribution of covariates among
patients with and without portal hypertension, a one-to-one match was created
using propensity score analysis
• The propensity score represents the probability of each individual patient being
assigned to a particular condition in a study given a set of known covariates.
• Propensity scores are used to reduce selection bias by equating groups based on
these covariates and are used to adjust for selection bias in observational studies
through matching
• A second multivariate logistic regression model, based on preoperative covariates
that significantly affect postoperative liver failure, was built to predict the
probability of each individual patient of having or not having portal hypertension
(predictive values)
• The model was then used to obtain a one-to-one match by using the nearest
neighbor matching method
• Once the matched groups had been obtained, differences in intraoperative and
postoperative course were further analyzed in order to assess the real impact of
presence of portal hypertension on clinical outcome
Cucchetti A, et al. Ann Surg. 2009;250:922-8.
Statistical method

• Univariate analysis of predictive factors of postoperative (PO) liver failure after
hepatectomy after match for portal hypertension
• Categories with the lowest prevalence represent the reference group for odds
ratio calculation

Overall survival curves of the
whole study population of 241
cirrhotic patients undergoing
liver resection for hepatocellular
carcinoma with and without
portal hypertension (p = 0.008)
Overall survival curves of the
matched study population of
156 cirrhotic patients
undergoing liver resection for
hepatocellular carcinoma with
and without portal hypertension
(p = 0.453)

Citterio D, JAMA Surg., 2016; 151(9):846-853

Citterio D, JAMA Surg., 2016; 151(9):846-853
• The risk for LD after liver resection can be stratified
accurately before surgery according to a hierarchic
order of factors represented by
• the presence of portal hypertension,
• extension of the hepatectomy,
• and the MELD score.
• The potential influence of the proposed model on the
decision-making process regarding surgery in HCC
could turn out to be significant not just for physicians
but for patients too.

Cescon M, et al. Arch Surg. 2009;144:57-63.

Stremitzer S et al. Br J Surg 2011, 98: 1752-1758

• Complication rates differed significantly at a cut-off
HVPG value of 5 mmHg
• HVPG exceeding 5 mmHg was associated with
• worse liver fibrosis (P = 0·004),
• higher rates of postoperative liver dysfunction (5 of
13 versus 1 of 18; P = 0·022) and
• ascites (7 of 14 versus 3 of 21; P = 0·022), and
• a longer hospital stay (median (range) 11 (7–26)
versus 8 (4–20) days; P = 0·034).
• Overall postoperative morbidity did not differ between
patients who had preoperative HVPG assessment and
those who did not (P = 0·142).

 Liver resection for HCC can be performed safely in
patients with HVPG between 1 and 5 mmHg.
 In contrast, patients with portal hypertension
(HVPG 6–10 mmHg) are at risk of postoperative
complications, but mortality is still low.

Can we summarize ?

Current guidelines recommend resection only for single nodules of any
size in patients without tumor related symptoms and clinically significant
portal hypertension (CSPH) and with normal bilirubin (<1 mg/dL).
If this profile is not fulfilled, postoperative morbidity increases and long-
term survival is significantly reduced.
An extension of the recommendation has been repeatedly suggested
because in patients with CSPH multiple nodules or intrahepatic vascular
invasion resection can be attempted with high rates of technical success
in experienced centers, even though tumor elimination by surgery
translates into improved survival only in properly selected candidates.
Actually, while tumor removal would be technically feasible in patients
with a large tumor burden or impaired liver function, resection may not
be worth attempting as survival could even be decreased.
In real life the decision to resect HCC is based on individual patient
components and local conditions that are not captured by guidelines.
Romagnoli R, Bruix J, Mazzaferro V, Hepatology 2015, 62: 340-342

Shindoh J, J Hepatol 2016; 64:594-600

Cucchetti A, Ann Surg Oncol 2012, 19: 3697-3705

Forest plot displaying the result of the meta-analysis comparing a
5-year overall survival of the AR group versus the NAR group

Forest plot displaying the result of the meta-analysis comparing a
5-year disease free survival of the AR group versus the NAR group

Can we further improve results of
resective surgery ?

Bruix J, Lancet Oncol 2015;16:1344-1354

Liver Resection – Liver Transplantation
Authors Journal Year publication
Jacques Belghiti –
Oliveir Scatton –
Olivier Soubrane
J Gastrointest Surg 2016
Daniel Cherqui –
Henri Bismuth –
Didier Samuel –
Denis Castaing –
René Adam
Annals of Surgery 2016
Juan Carlos Garcia-Valdecassis –
Jordi Bruix -
Josep Fuster
Hepatology 2016

Bhangui P. Ann Surg. 2016;264:155-163

Bhangui P. Ann Surg. 2016;264:155-163
The feasibility of SLT after initial resection in transplantable HCC-
cirr patients was 34%,which seems to be the Achilles heel of this
strategy.
PLT was associated with better OS and DFS on an ITT basis
compared to initial resection with or without later salvageLT.
The fact that patients who did ‘‘succeed’’ the resection first and
later SLT strategy had good perioperative outcomes, and almost
comparable OS and DFS as compared with PLT patients, suggests
that a better selection of HCC-cirr patients for the ‘‘resection
first’’ approach and close follow-up for recurrence may help in
achieving better outcomes with the SLT strategy.

Tribillon E, J Gastrointest Surg 2016; 20:66-76

Tribillon E, J Gastrointest Surg 2016; 20:66-76
de principe enlistment for LT following primary LR for
HCC offers greater overall and disease-free survivals
compared to salvage LT when patients fulfilled the
Milan criteria at the time of primary resection and
when intermediate or bad prognostic factors are
found on the specimen.

Ferrer-Fàbrega J, Hepatol 2016; 63:839-849

• For those patients with solitary lesions and an absence of portal
hypertension, LR constitutes an effective, potential curative treatment
approach.
• In these patients, transplant may not offer survival benefit.
• On the contrary, LT should be offered to those patients with
microvascular invasion and/or satellites in the resected specimen, there
being no benefit in waiting for recurrence recognition by imaging.
• In order to avoid aggressive disease recurrence with dismal prognosis, a
waiting time of at least 6 months between resection and enlistment for
transplant should be in place.
• Beyond this time point, priority strategies based on preoperative
imaging should allow patients to be effectively transplanted.
• Such a policy offers optimal outcomes and optimizes the use of the
currently limited pool of donors.
Ferrer-Fàbrega J, Hepatol 2016; 63:839-849

Mazzaferro V, Hepatol 2016; 5:1707-1717

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

We propose a novel measure to weight liver resection
over the natural history of the disease for any HCC BCLC
stage, and we show that this therapeutic approach has a
higher net survival benefit compared with non-surgical
treatments, regardless of the BCLC stage in well selected
HCC patients (MELD ≤ 9, Child A, and PST 0-1).
Resection could result in survival benefit over LRT for HCC
patients regardless of their BCLC stage, provided that liver
dysfunction (Child B or MELD >9) and PST >1 are absent.

Bruix J, Gastroenterology 2016: 150: 835-853

Vivarelli M et al. Ann Surg 2004; 240: 102-107

Nanashima A et al. J Surg Oncol 2010, 101: 481-485

Nanashima A et al. J Surg Oncol 2010, 101: 481-485
• Tumor recurrence rates after treatment did not differ
significantly between modalities.
• In HCC with 2–3 lesions ≤ 3 cm, overall survival was
significantly longer with hepatectomy than with ablation,
although survivals did not differ significantly between
modalities for solitary HCC.
• Poor liver function might also influence overall survival in
patients with 2–3 HCC lesions 3 cm.
• In cases of multiple small HCCs, hepatic resection should be
selected as the first-line treatment over local ablation therapy
in cases where liver function has been preserved.

Hasegawa K et al. J Hepatol 2008, 49: 589 - 594

Resection
Ablation

 This large prospective study based on data derived from a
nationwide survey in Japan suggested that surgical
resection may offer some advantage over percutaneous
ablation in terms of the time-to recurrence rate of
patients with HCC.
 The results should be regarded as preliminary, because of
the short follow-up.

Kudo M, Dig Dis 2011, 29: 339-364

Huang GT, Lee PH, Tsang YM, Lai MY, Yang PM, Hu RH, et al.
Percutaneous ethanol injection versus surgical resection for the treatment of
small hepatocellular carcinoma: a prospective study.
Ann Surg 2005;242:36-42
Chen MS, Li JQ, Zheng Y, Guo RP, Liang HH, Zhang YQ, et al.
A prospective randomized trial comparing percutaneous local ablative therapy
and partial hepatectomy for hepatocellular carcinoma.
Ann Surg 2006;243:321-328
Two randomized controlled trials showed results
in favor of percutaneous ablation

 There are no papers showing superiority of
local ablation on surgical resection
 Local ablation gives similar results to surgical
resection if performed by experienced
physicians

Huang GT, Lee PH, Tsang YM, Lai MY, Yang PM, Hu RH, et al. Percutaneous
ethanol injection versus surgical resection for the treatment of small
hepatocellular carcinoma: a prospective study. Ann Surg 2005;242:36-42
Chen MS, Li JQ, Zheng Y, Guo RP, Liang HH, Zhang YQ, et al. A prospective
randomized trial comparing percutaneous local ablative therapy and partial
hepatectomy for hepatocellular carcinoma. Ann Surg 2006;243:321-328
Because of these problems, the results of the two RCTs do not allow firm
conclusions to be drawn concerning the important clinical question: is surgery
or percutaneous ablation the treatment of choice for early or moderately
advanced HCC?
The study designs of these 2 trials were critically flawed by factors such as
•insufficient sample size,
•excessively optimistic hypotheses, and
•high conversion ratios.
Hasegawa K, J Hepatol 2013, 58: 724-729

12,968 patients who met the following criteria:
1)Liver function classified as liver damage A or B defined by the
Liver cancer Study Group of Japan;
2)Number of tumors 3 or less;
3)Maximum tumor diameter ≤3cm.
The 12,968 patients were divided into 3 groups according to the
treatment received:
•SR group (n=5,361, 41.3%),
•RFA group (n=5,548, 42.8%), and
•PEI group (n=2,059, 15.9%).

Resection
Ablation

 Surgical resection was associated with significantly lower risk
of both death and recurrence as compared to RFA and PEI in
patients with early or moderately advanced HCC.
 The study reconfirms that surgery is associated with a
reduced recurrence rate and newly shows that surgery yields
a longer overall survival than percutaneous ablation
therapies.
 The results of the subgroup analyses indicated that surgical
resection would effectively prevent recurrence in patients
with relatively advanced HCC (2 to 3 cm in diameter) among
the study populations, irrespective of liver damage class or
number of tumors.
CONCLUSIONS

 Presence of single or multiple (up to three
nodules) HCC smaller or equal to 6 cm which
underwent LR or LAT during the study period
from 1995 to 2009.
 In order to reduce potential bias in effect
estimation, a propensity score was used to
assess the conditional probability of treatment
according to the individual's covariates and to
balance treatment choice-related variables such
that the analysis simulates random assignment.
Ruzzunente A et al. J Gastrointest Surg 2011, Nov 18. [Epub ahead of print]

Baseline variables in LR and LAT subject groups
for the matched sample

Resection
Ablation Resection
Ablation

 Surgery and LAT have comparable survival and disease-
free survival for patients with a single HCC smaller than 5
cm or with two to three HCCs smaller than 3 cm.
 Local recurrence rate: the two treatments were
comparable only for HCCs smaller than 2 cm whereas the
local recurrence rate is significantly higher in the LAT
group for HCC >2 cm.
 Surgical resection in all patients with HCC larger than 2
cm proved its superiority in terms of local tumor control
and long-term results.

Huang J et al. Ann Surg 2010; 252: 903-912

Santi V, J Hepatol 2012, 56: 397-405

Giuliante F, J Am Coll Surg 2012, 215: 244-254

Kaplan-Meier curves showing overall survival (OS) after liver
resection (LR) in the entire cohort of patients (n = 588).

Kaplan-Meier curves showing disease free survival (DFS) after
liver resection (LR) in the entire cohort of patients (n = 588).

• The number needed to transplant (NTT) was defined as the reciprocal of the
absolute risk difference between post-LT and post-HR 5-year survival
estimations.
• We calculated a NTT value for each enrolled patient using the predicted 5-
year survival after HR (using the Cox model) and the hypothetical 5-year
survival after LT (using the Metroticket model).
• As a final step, we explored how this distribution was influenced by the main
variables considered in this study: diameter of the largest nodule, number of
nodules (one or two), and presence of MVI.

Vitale A, J Hepatol 2014; 60:1165-1171

This study represents an attempt to measure the transplant
benefit in resectable HCC for patients either within or beyond
the Milan criteria and using NTT as benefit measure.
The strong impact of MVI on LT benefit and the high
prevalence of this aggressive feature also in small tumors
undergoing HR, suggest that resectable HCC is a
contraindication to LT when a 5-year time horizon is adopted.
The 10-year scenario, conversely, increased the transplant
benefit in all subgroups of resectable patients, and LT became
an effective therapy (NTT <5) for all patients without MVI
whenever tumor extension and for oligonodular HCC with MVI
within conventional LT criteria.
Vitale A, J Hepatol 2014; 60:1165-1171

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