Hepatocarcinoma today between guidelines and medical therapy. The role of surgery.pptx

Gian Luca Grazi
Hepatocarcinoma today: between
guidelines and medical therapy.
The role of surgery?

2
Hepatocarcinoma today | Prof. Gian Luca Grazi – HBP Surgery, University of Florence
Qin S, Lancet. 2023;402(10415):1835-1847. doi: 10.1016/S0140-6736(23)01796-8.
Treatment was 1200 mg intravenous atezolizumab plus intravenous bevacizumab 15 mg/kg every 3 weeks
for up to 12 months or 17 cycles, whichever occurred first.

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Qin S, Lancet. 2023;402(10415):1835-1847. doi: 10.1016/S0140-6736(23)01796-8.
Treatment was 1200 mg intravenous atezolizumab plus intravenous bevacizumab 15 mg/kg every 3 weeks
for up to 12 months or 17 cycles, whichever occurred first.

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Qin S, Lancet. 2023;402(10415):1835-1847. doi: 10.1016/S0140-6736(23)01796-8.

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Qin S, Lancet. 2023;402(10415):1835-1847. doi: 10.1016/S0140-6736(23)01796-8.
Four or more tumors the largest < 5 cm
Up to three tumors the largest ≤ 5 cm
with vascular invasion
Up to three tumors the largest > 5 cm

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Qin S, Lancet. 2023;402(10415):1835-1847. doi: 10.1016/S0140-6736(23)01796-8.
Four or more tumors the largest ≤ 5 cm
Up to threetumors the largest < 5 cm

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Qin S, Lancet. 2023;402(10415):1835-1847. doi: 10.1016/S0140-6736(23)01796-8.
Four or more tumors the largest < 5 cm
Up to threetumors the largest < 5 cm

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Kaplan-Meier analysis of recurrence-free survival based on independent assessment
Qin S, Lancet. 2023;402(10415):1835-1847. doi: 10.1016/S0140-6736(23)01796-8.

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Patients were randomly assigned (1:1) to receive 400 mg twice a day of oral sorafenib or placebo for a
maximum treatment period of 4 years (204 weeks ± 1) or until disease recurrence.
Bruix J, Lancet Oncol. 2015;16(13):1344-54. doi: 10.1016/S1470-2045(15)00198-9

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Patients were randomly assigned (1:1) to receive 400 mg twice a day of oral sorafenib or placebo for a
maximum treatment period of 4 years (204 weeks ± 1) or until disease recurrence.

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Reig M. et al., J Hepatol. 2022 Mar;76(3):681-693

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

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

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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.

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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.

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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.

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Evidence-based approach
Comprehensive vision
Treatment guidance
Prognostic accuracy
Simplicity
International consensus
Comparison of results
Trevisani F, J Hepatol. 2024 ;80(4):661-669. doi: 10.1016/j.jhep.2024.01.010

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Evidence-based
Treatment guidance
Prognostic accuracy
Simplicity
This staging system was devised based on
evidence supported by the literature rather
than based solely on expert opinions

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Treatment guidance
Prognostic accuracy
Simplicity
In allocating patients to a given stage,
the BCLC algorithm simultaneously
considered tumour burden, liver
function, general conditions, and
recommended treatment with an
expected overall survival

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Treatment guidance
Prognostic accuracy
Simplicity
This algorithm provided clear treatment
recommendations for each stage,
emphasising the use of curative therapies
(surgical resection, liver transplantation, or
local ablation) for early-stage HCC and
palliative or experimental treatments
(transarterial chemoembolization [TACE],
novel systemic therapies) as opposed to
best supportive care for intermediate and
advanced stages.

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Treatment guidance
Prognostic accuracy
Simplicity
The BCLC staging system demonstrated
the ability to predict patient outcomes
based on their respective stage, evidenced
by declining overall survival probability with
advancement in stage from 0 to D.
Moreover, it was able to predict the natural
history of untreated HCC, lending further
credence to the independence of its
prognostic power regardless of the impact
of treatment.

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Treatment guidance
Prognostic accuracy
Simplicity
The BCLC algorithm is easy to use in
clinical practice, providing a clear
framework for staging and
treatment decision- making based
on well-recognised parameters. Its
simplicity also makes it possible to
succinctly communicate with
patients regarding their overall
prognosis

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Treatment guidance
Prognostic accuracy
Simplicity
The BCLC algorithm was
widely accepted among
hepatologists and liver cancer
experts

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Treatment guidance
Prognostic accuracy
Simplicity
Its widespread use has facilitated the
comparability of results in research and
clinical practice across different centres.
The BCLC system allowed for more
accurate stratiﬁcation of patients with
HCC in clinical trials.

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But, beyond these "merits", can we outline
other considerations on the method with
which to classify patients with HCC for a
possible treatment?

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In the stage hierarchy definition,
treatment is considered an outcome variable similar to survival.
Original BCLC definition
Vitale A, Lancet Oncol. 2023;24(7):e312-e322. doi: 10.1016/S1470-2045(23)00186-9

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In the treatment hierarchy definition, staging or prognostic systems and treatment allocation or
algorithm are independent; staging can help to inform, but not dictate, treatment allocation
The Asia-Pacific and Japanese guidelines

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Studies supporting therapeutic hierarchy as independence of ordinal treatment
variable from tumour staging (multivariable models)

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In the ordinal therapeutic hierarchy, treatment is used as an independent predictor variable
and an ordinal variable (ie, in a hierarchical order of therapeutic options)

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Studies supporting therapeutic hierarchy as an ordinal therapeutic variable within tumour stages

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BCLC UNDER SIEGE

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Multiparametric therapeutic hierarchy
The concept of converse therapeutic hierarchy is represented with a dashed arrow, since the evidence supporting this concept is
still weak.
Ordinal
therapeutic
hierarchy
Conversion
or
adjuvant
approach
Multiparametric multidisciplinary expert decision

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still weak.
Ordinal
therapeutic
hierarchy
Conversion
or
adjuvant
approach

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still weak.
Ordinal
therapeutic
hierarchy
Conversion
or
adjuvant
approach

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still weak.
Ordinal
therapeutic
hierarchy
Conversion
or
adjuvant
approach

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Learning from the past to improve the future: Proposal for the
management of patients with HCC in the context of personalised
medicine

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Therapeutic hierarchy battleship
In the therapeutic hierarchy battleship, different first-choice and second-choice treatment options are established based on different tumor
characteristics (vertical axis) or functional parameters (horizontal axis) Vitale A, Lancet Oncol. 2023;24(7):e312-e322. doi: 10.1016/S1470-2045(23)00186-9

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Bo Z, Comput Biol Med. 2024;173:108337. doi: 10.1016/j.compbiomed.2024.108337.

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• Published studies on AI radiomics for the individualized treatment of HCC are mainly exploratory and
preliminary.
• It is difficult to validate the reliability and applicability of the reported results due to the
heterogeneity and lack of a rigorous evaluation system in clinical practice.
• In the future, prospective large-scale studies are needed to provide more compelling evidence
regarding the application value of AI radiomics in the field of precision medicine for HCC.

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But then, how can we manage
patients with HCC hoping for a
transformation of the indications??

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Kawaguchi Y, Am J Gastroenterol. 2021;116(8):1698-1708. doi: 10.14309/ajg.0000000000001256

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• To derive a prognostic model for OS on the basis of the largest HCC diameter and the number of HCCs, a Cox
proportional hazard model analysis was performed through a 10-fold cross validation approach.
• The largest diameter and number were included in Cox proportional hazards models as continuous variables by using
3-knot restricted cubic splines together with the diameter 3 number linear and nonlinear interaction terms. This choice
was made to provide a better fit between predictors and outcomes compared with the use of linear terms.
• To balance covariates other than the largest HCC diameter and the number of HCCs between the 3 treatments, inverse
probability of treatment-weighted (IPTW) analyses were performed using stabilized weights.
• For performing IPTW analyses, the propensity score (the probability of treatment assignment conditional on baseline
characteristics) for each patient was calculated as the predicted probability of liver resection, TACE, and ablation from a
multinomial logistic regression model.
• The data were plotted on a Cartesian plane (a plane including 2 perpendicular number lines: the x axis and the y axis)
and graphed using a surface plot (a display of a 3-dimensional surface showing a functional relationship between
designated dependent variables and 2 independent variables) and a contour plot (a display of a 2-dimensional
format representing a 3-dimensional surface).
Statistical analyses

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Cartesian plot of the 5-year overall probability after IPTW adjustment in
relation to the largest HCC diameter in patients undergoing liver resection,
TACE, and ablation by the number of HCCs.

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Surface plots of the 5-year overall survival probability after IPTW
adjustment on the basis of the largest HCC diameter and the number of
HCCs in patients undergoing liver resection, TACE, and ablation.
HCC, hepatocellular carcinoma; IPTW, inverse probability of treatment weighing; OS, overall survival; TACE,
transarterial chemoembolization.

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Contour plot of the 5-year
overall survival
probability after IPTW
adjustment according to
the largest HCC diameter
and the number of HCCs

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https://plaza.umin.ac.jp/htokyotransplant/hbp/calculation.htm
l

Hepatocarcinoma today: between guidelines and medical therapy. The role of
surgery?
Prof. Gian Luca Grazi
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Hepatocarcinoma today between guidelines and medical therapy. The role of surgery.pptx

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