Journal Pre-proof

BCLC strategy for prognosis prediction and treatment recommendations: The 2025
update

Maria Reig, Marco Sanduzzi-Zamparelli, Alejandro Forner, Jordi Rimola, Joana

Ferrer-Fàbrega, Marta Burrel, Ángeles Garcia-Criado, Alba Díaz, Neus Llarch,
Gemma Iserte, Meritxell Mollà, Robin K. Kelley, Peter R. Galle, Vincenzo Mazzaferro,
Riad Salem, Bruno Sangro, Amit Singal, Arndt Vogel, Ted K. Yanagihara, Carmen
Ayuso, Ferran Torres, Jordi Bruix

PII: S0168-8278(25)02571-1
DOI: https://doi.org/10.1016/j.jhep.2025.10.020
Reference: JHEPAT 10323

To appear in: Journal of Hepatology

Received Date: 12 September 2025

Revised Date: 23 October 2025
Accepted Date: 23 October 2025

Please cite this article as: Reig M, Sanduzzi-Zamparelli M, Forner A, Rimola J, Ferrer-Fàbrega J,
Burrel M, Garcia-Criado Á, Díaz A, Llarch N, Iserte G, Mollà M, Kelley RK, Galle PR, Mazzaferro V,
Salem R, Sangro B, Singal A, Vogel A, Yanagihara TK, Ayuso C, Torres F, Bruix J, BCLC strategy for
prognosis prediction and treatment recommendations: The 2025 update, Journal of Hepatology, https://
doi.org/10.1016/j.jhep.2025.10.020.

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© 2025 European Association for the Study of the Liver. Published by Elsevier B.V. All rights are
reserved, including those for text and data mining, AI training, and similar technologies.
Title: BCLC strategy for prognosis prediction and treatment recommendations:
The 2025 update

Short title: BCLC staging system 2025

Maria Reig1,2,3,4*, Marco Sanduzzi-Zamparelli1,2,4, Alejandro Forner1,2,3,4, Jordi

Rimola1,4,5, Joana Ferrer-Fàbrega1,3,4,6, Marta Burrel 1,3,5, Ángeles Garcia-Criado1,3,5,
Alba Díaz1,3,4,7, Neus Llarch1,3,4,8, Gemma Iserte1,3,4,8, Meritxell Mollà 1,3,9,, Robin K.
Kelley10, Peter R. Galle11, Vincenzo Mazzaferro12, Riad Salem13, Bruno Sangro4,14,

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Amit Singal15, Arndt Vogel16,17, Ted K. Yanagihara18,19, Carmen Ayuso1,3,5, Ferran

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Torres20, Jordi Bruix1,3,4

1BCLC
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group. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS),
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Barcelona, Spain; 2Liver Oncology Unit, Liver Unit, ICMDM, Hospital Clínic Barcelona,
Barcelona, Spain; 3University of Barcelona, Barcelona, Spain; 4Centro de
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Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas

(CIBEREHD), Madrid, Spain; 5 Radiology Department, Liver Oncology Unit, CDI,
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Hospital Clínic Barcelona, Barcelona, Spain; 6Surgery Department, Liver Oncology

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Unit, ICMDM, Hospital Clínic Barcelona, Barcelona, Spain; 7Pathology Department,

CDB, Liver Oncology Unit, Hospital Clínic Barcelona, Barcelona, Spain; 8Liver
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Oncology Unit, ICMDM, Hospital Clínic, Barcelona, Spain; 9Department of Radiation

Oncology, ICAMS, Hospital Clínic Barcelona, Barcelona, Spain; 10Helen Diller Family
Comprehensive Cancer Center, University of California, San Francisco, California.
USA; 11Department of Internal Medicine, Mainz University Medical Center, Mainz,
Germany; 12Department of Oncology, University of Milan and HPB Surgery and Liver
Transplantation, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy;
13Department of Radiology, Section of Interventional Radiology, Northwestern
University, Chicago, IL. USA; 14Liver Unit, Clínica Universidad de Navarra, Pamplona,
Spain; 15Department of Internal Medicine, University of Texas Southwestern Medical
Center, Dallas, Texas, USA; 16Toronto General Hospital, Princess Margaret Centre,
University of Toronto, Toronto, ON, Canada; 17 Department of Gastroenterology,
Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School,
Hannover, Germany; 18University of North Carolina Lineberger Comprehensive
1
Cancer Center, Chapel Hill, NC, USA; 19Department of Radiation Oncology, University
of North Carolina, Chapel Hill, NC, USA. 20Biostatistics Unit, Medical School,
Universitat Autònoma de Barcelona, Barcelona, Spain.

*Corresponding author. Address: BCLC group, Liver Unit, ICMDM, CIBERehd,

IDIBAPS, Hospital Clínic, c/ Villarroel, 170, Escala 11, 4a planta, 08036 Barcelona.

Spain. Tel.: +34 932279803, fax: +34 932275792. E-mail address: [email protected]

(M. Reig)

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Keywords: HCC, survival, BCLC, ablation, surgery, liver transplantation TACE,
TARE, EBRT, systemic treatment, immunotherapy, ALBI score, AFP, CUSE.

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Electronic word count: 9418
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Number of figures and tables 5

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Conflict of interest statement:

MR: received consultancy fees and/or travel support from AstraZeneca, Bayer, BMS,
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Eli Lilly, Gilead, Roche, Biotoscana Farma; lecture fees from Bayer, BMS, Gilead,
Jo

AstraZeneca Roche, Guerbet and Lilly and research grants (to the Institution) from
Bayer, ROCHE and Ipsen. Educational Support (to the institution): Bayer,
Astrazeneca, Eisai- Merck MSD, Roche, Ipsen, Lilly, Terumo, BMS, Next, Boston
Scientific, Ciscar Medical, Eventy C3 LLC (Egypt), Servier, Guerbet; MSZ: received
consultancy/advisory fee from Captor Therapeutics, speaker fees from Bayer,
AstraZeneca and Roche and travel grants from Bayer, BTG, Eisai and Roche; AF:
received advisory fee from AstraZeneca, Incyte, Boston Scientific and Taiho and
speaker fees from AstraZeneca, Roche and Boston Scientific; JR: has consulted for
Roche and received speaker fees from Bayer and Roche and travel grants from Bayer
JFF; received Lecture fees from AstraZeneca; MB: received honoraria from: Terumo,
Boston Scientific, Guerbet, Bayer, Astrazeneca and Travel support: Terumo, Boston
Scientific; AGC: received lectures fee from Roche; AD: ; none NLL: received
consultancy fees from Bayer, Universal DX and AstraZeneca, speaker fees from

2
Roche and AstraZeneca, travel funding from Bayer and congress registration from
Eisai; GI: received travel grants from Bayer and received speaker fees from ROCHE
MM; I have received honoraria as a speaker and moderator in educational sessions
from the Clinic Foundation for Biomedical Research (Clinic Barcelona); RK; received
consulting fee from: Compass Therapeutics, CVS Caremark, Elevar, GSK, Jazz, J
Pharma, Moderna, Regeneron, Tyra Biosciences; travel grants from: Astra Zeneca,
Merck; Data Safety Monitoring Board from: Genentech/Roche; PG; received
honoraria from Bayer, Boston Scientific, AstraZeneca, Adaptimmune, BMS, Eisai,
MSD, Sirtex, Lilly, Roche, Guerbet and grants from ; VM; none; RS: received
honoraria from: Boston Scientific, Cook, Bard, Genentech, Astrazeneca, Eisai, Autem,

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Terumo, Astellas, Siemens, Sirtex, Trisalus, Terumo; BS; reports grants from Bristol

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Myers Squibb and Roche; consulting fees from AstraZeneca, Bayer, Boston Scientific,

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Bristol Myers Squibb, Eisai, Incyte, Roche/Genentech, Sanofi Pasteur, and Sirtex
Medical; honoraria from AstraZeneca, Eisai, Incyte, and Roche; and travel support
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from AstraZeneca, Bristol Myers Squibb, Eisai, Roche, and Sirtex Medical; AS: has
served as a consultant or on advisory boards for Genentech, AstraZeneca, Eisai,
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Bayer, Exelixis, Merck, Elevar, Boston Scientific, Sirtex, FujiFilm Medical Sciences,
Exact Sciences, Helio Genomics, Curve Biosciences, Glycotest, Abbott, DELFI,
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Mursla Bio, ImCare, and Universal Dx; AV; Roche, AstraZenca, Böhringer-Ingelheim,
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Ipsen, Incyte, Cogent, EISAI, Zymeworks, Biologix, BMS, Terumo, Elevar, Servier,
MSD, Tahio, Jazzpharma, Medivir, Abbvie, Tyra, Falk, Janssen, Lilly; Roche,
Jo

AstraZenca, Böhringer-Ingelheim, Ipsen, Incyte, Cogent, EISAI, Zymeworks, Biologix,

BMS, Terumo, Elevar, Servier, MSD, Tahio, Jazzpharma, Medivir, Abbvie, Tyra, Falk,
Janssen, Lilly; Travel grants froma: Roche, MSD, Astellas, Data Safety Monitoring
Board: Roche, AstraZenca, Böhringer-Ingelheim, Ipsen, Incyte, Cogent, EISAI,
Zymeworks, Biologix, BMS, Terumo, Elevar, Servier, MSD, Tahio, Jazzpharma,
Medivir, Abbvie, Tyra, Falk, Janssen, Lilly; TKY: Honoraria: Carolina Confab invited
speaker and panelist; Payment expert: North Carolina Medical Board Expert
Independent Reviewer; Travel support: HistoSonics Inc.; CA: received lecture fees
from Bayer and Roche (educational material); FT: DSMB fees from Argenx BV,
Archivel and Connecta; Consultancy fees from Archivel, UniversalDX (diagnostics),
LEO Pharma, FAES and Boehringer Ingelheim; JB: Consultancy: AbbVie,
Adaptimmune, Arquile, Astra-Medimmune, Basilea, Bayer-Shering Pharma, Bio-
Alliance, BMS, BTG- Biocompatibles, Eisai, Gilead, IKF, Incyte, Ipsen, Kowa, Lilly,
3
MSD, Nerviano, Novartis, Polaris, Quirem, Roche, Sirtex, Sanofi, Terumo. Paid
conferences: Bayer, BTG, Ipsen, Astra-Zeneca. Paid talks: Bayer, BTG-
Biocompatibles, Eisai, Terumo, Sirtex, Ipsen

Financial support statement:

MR: received grant support from Instituto de Salud Carlos III (PI15/00145, PI18/0358
and PI22/01427), from the Spanish Health Ministry (National Strategic Plan against
Hepatitis C), from Centro de Investigación Biomédica en Red - CIBER (Immune4Al,
S2300092_3) and from the Spanish Association Against Cancer (AECC,

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PRYCO234831); MSZ: received grant support from Instituto de Salud Carlos III

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(FI19/00222) and Centro de Investigación Biomédica en Red en Enfermedades

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Hepáticas y Digestivas - CIBEREHD (EHD25PI02); AF: Grant from Instituto de Salud
Carlos III (PI15/01229 and PI18/00542) and from Centro de Investigación Biomédica
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en Red - CIBER (Immune4Al, S2300092_3); JR: registry grant from European
Association for the Study of the Liver (EASL); JFF; none; MB; none; AGC: none; AD:
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none; NLL: received grant support from PERIS_IPIF19-SLT008/18/00182; GI; Grant

support from Asociación Española del Hígado (Beca de Enfermería); “Ajuts per la
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iniciació a la recerca 2022” from Societat Catalana de Digestologia (SCD); MM; none;
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RK; Agios, Astra Zeneca, Bayer, BMS, Compass Therapeutics, Eli Lilly, EMD Serono,
Exelixis, Genentech/Roche, Merck, Partner Therapeutics, QED, Relay Therapeutics,
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Servier, Surface Oncology, Taiho, Tyra Biosciences; PG: none; VM: none; RS: none;
BS; received grant support from Centro de Investigación Biomédica en Red - CIBER
(Immune4Al, S2300092_3); AS: none; AV; none; TKY: Radiation Oncology Institute
Research Support; Lineberger Comprehensive Cancer Center Research Support;
Medtronic Inc.; CA: none; FT: JB: received grant support from Instituto de Salud
Carlos III (PI18/00768), the Spanish Health Ministry (National Strategic Plan against
Hepatitis C), AECC (PI044031) and WCR (AICR) 16-0026. CIBERehd is funded by
the Instituto de Salud Carlos III.

4
Authors contributions: a list of the authors' contributions to the study; concept and
design MSZ, AF, JB, MR, experiments and procedures MSZ, AF, JB, MR, JR, JF,
MB, AGC, AD, NLL, GI, MM, CA; all the authors contributed to writing the article

Data availability statement: The 2025 BCLC treatment strategy (cut-off August 5,
2025) builds on prior iterations to guide individualized decision-making. To generate
the evidence synthesis, we conducted a PubMed search restricted to humans, adults
(≥19 years), and English-language records. We performed (1) an individual-
participant-data (IPD) meta-analysis of external beam radiotherapy (EBRT) that
included approximately 5,000 patients (Moon et al.), and (2) an aggregate-data meta-

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analysis comprising 73 studies of patients with macrovascular invasion (MVI) (Fortuny

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et al., submitted). We also reviewed all additional relevant information according to

of nurses according to BCLC approach.[1]

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prespecified criteria that is described in Supplementary material A including the role
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Key points
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 The 2025 BCLC strategy refines clinical decision-making and treatment

recommendations in line with recent scientific advances.
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 Prognosis in HCC depends on the dominant drivers—tumor burden and/or liver

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function—while management adapts to evolving evidence.

 The 2025 update preserves the 2022 staging system but clarifies BCLC-B,
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replacing “multifocal” with explicit criteria: >3 nodules, or ≤3 nodules with at

least one >3 cm.
 First recommended treatment options for each stage are listed preferentially
according to level of scientific evidence for overall survival benefit.
 Personalized treatment recommendations are guided by the CUSE framework,
which integrates Complexity, Uncertainty, Subjectivity, and Emotion with the
patient’s full clinical, biological, and psychosocial profile
 CUSE is a flexible, human-centered decision-support framework—not a rigid
protocol—that helps make uncertainty explicit and fosters shared,
multidisciplinary, and evidence-based decision-making across diverse clinical
settings.

5
Impact and Implications

The 2025 BCLC update provides the scientific justification for integrating recent
advances into a cohesive, evidence-based framework that remains the global
reference for prognostication and treatment allocation in HCC. By incorporating the
CUSE framework, it provides multidisciplinary teams with a structured approach to
navigate evidence gaps, explicitly address uncertainty, and tailor therapy to patient
goals and context. These updates are particularly important for clinicians, tumor
boards, and guideline developers, as well as for patients and caregivers who face
complex choices in real-world practice. In practical terms, the prognostic capacity of

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BCLC is embedded within person-centered decision-making, fostering iterative

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treatment planning and laying the foundation for future studies assessing the clinical
impact of CUSE, while acknowledging the need for validation and variability in
implementation across healthcare settings.
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Summary
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The 2025 BCLC update incorporates recent advances in the field of treatment
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recommendations for hepatocellular carcinoma while preserving its simplicity. Each

stage remains directly linked to its evidence-based first-option treatment. The BCLC
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algorithm provides guidance to evaluate patient prognosis and propose a therapeutic

strategy according to the current scientific evidence.
Tumor boards require structured methodologies to address clinical complexity.
Beyond published evidence, decision-making should incorporate biological,
psychosocial, and contextual factors that may affect morbidity, feasibility, and patient
vulnerability. Such a multidimensional approach ensures treatments remain evidence-
based and patient-centered. The updated clinical-decision-making chapter embeds
the CUSE framework (Complexity, Uncertainty, Subjectivity, Emotion). CUSE turns
unavoidable doubt into a shared, iterative process to: (i) define the therapeutic goal
(survival, tumor control, quality of life, etc.); (ii) grade each option, noting evidence
strength and gaps; (iii) align choices with comorbidities, feasibility, oncologic risk, and

6
patient values and goals; and (iv) select a plan with regular check-ins as new
information or needs arise.

Lay Summary
The 2025 BCLC update maintains its clear, stage-based framework and ties each
stage to the strongest evidence-based first treatment (see Figure 4). It also introduces
the concept of CUSE—Complexity, Uncertainty, Subjectivity, Emotion—to guide care
teams when direct comparisons are not possible, data are lacking, or clinical scenarios
are complex (see Figure 1a-b). Health care teams start the clinical decision by defining

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each person’s treatment goals (e.g., longer survival, tumor control), identifying patient

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priorities (e.g., safety, quality of life, symptom relief), and recognizing real-world

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practice constraints outside clinical trials (e.g., appointments burden, travel distance,
and costs). Thereafter, the health care team, in collaboration with the patient,
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assesses strengths and gaps in the data, tailor options to that person’s health and
values, and finally select a plan with regular check-ins as new information or needs
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arise.
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7
Introduction
Across successive updates [2–9], Barcelona Clínic Liver Cancer (BCLC) prognosis
and staging system has refined hepatocellular carcinoma (HCC) staging and
treatment allocation. We underscore those developments that justify a strategic shift
and explain why other promising—but still nascent—approaches remain premature for
inclusion. All findings are graded by study design—recognizing both the insights and
limitations of observational data—and, as before, we engage external experts to
broaden the BCLC group’s perspective. Here, we have incorporated new datasets
analyzable by BCLC stage, and we have omitted data without clear, stage-specific

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results. The 2025 update also preserves all previous prognosis refinements—such as

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albumin–bilirubin (ALBI) and alpha-fetoprotein (AFP) stratification; a detailed

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assessment of decompensating events (such as prior variceal bleeding and ascites
grade or response); performance status (PS); and frailty, which is defined as a
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multidimensional syndrome of reduced reserve and increased vulnerability. It further
provides a clearer definition of multifocal disease in intermediate stage B. Finally, we
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have introduced the CUSE framework (Complexity, Uncertainty, Subjectivity, Emotion)

to structure person-centered decision making when evidence about separate
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alternatives is non-comparable or lacking (Figure 1a-b).

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The Supplementary material is structured in three parts: SUP-A—literature

interpretation and tailored approaches for BCLC-0/A and BCLC-B; SUP-B—tailored
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approaches for BCLC-C and BCLC-D; SUP-C—non-proven options/sequences and

patient experience/quality of life.

Prognosis prediction and patient characterization

Life expectancy in HCC is modelled by three interacting forces: tumor burden, liver
function, and cancer-related symptoms. Hence, a single multivariable model to predict
outcomes across all evolutionary stages of the disease would bear excessive
complexity.[10] In addition, some parameters that would be key for some stages
would be of no value in others, as happens at the time of treatment recommendation.
Therefore, from its inception, the BCLC strategy has followed a two-step approach: (i)
delineate broad evolutionary stages with the major prognostic variables, and (ii)
develop more granular prognostic and therapeutic models within each stage. This
8
architecture was first advanced in 2000[2] and has been validated repeatedly and
adopted by most guidelines worldwide as the starting point for describing individuals
with HCC. It has also served to characterize the study population in most HCC-related
investigations, including phase III clinical trials.
Tumor burden should be assessed with contrast-enhanced multi-phase computed
tomography (CT) or magnetic resonance imaging (MRI) by liver cancer–dedicated
radiologists to avoid under- or over-staging, as even one additional nodule or a more
accurate diameter may shift stage. Chest CT is advised to complete staging when
appropriate[11,12]. Contrast-enhanced ultrasound (CEUS) is accepted as a
complementary tool for diagnosis when CT/MRI are inconclusive[11], while positron

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emission tomography (PET) is not recommended.[13]

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Liver function is no longer stratified solely by the Child–Pugh (CP) score since 2018

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[6] because CP class A may still include patients with decompensation such as
ascites, variceal bleeding or prior hepatic encephalopathy—clear signs of severe
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portal hypertension that reflect advanced liver disease. The incorporation of the ALBI
score refines mortality risk prediction across all BCLC stages.[14,15] For
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decompensated disease, sequential refinements of the MELD score improve short-

term prognostication.[16–18]
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Cirrhosis status represents the first branching point in the framework (Figure 2). If
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cirrhosis is present, prognosis depends on whether it is compensated or

decompensated, independent of the number of CP classification. In compensated
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cirrhosis, outcomes are mainly driven by the biology and extent of HCC. In
decompensated cirrhosis, residual liver function—alongside HCC extent and tumor
biology —takes precedence. Grading ascites refines the prognosis prediction as
subclinical ascites detected at imaging is not equivalent to have tense ascites.[19]
Some individuals develop HCC without cirrhosis, or after sustained virologic response
to hepatitis C virus (HCV) regardless of fibrosis regression. In these cases, prognosis
depends almost entirely on HCC biology.
Importantly, decompensation does not represent an absolute and irreversible
contraindication to specific therapies. Patients who achieve recompensation[20] after
treating the etiologic factor of the underlying liver disease or an adequate controlled
state through best supportive measures for cirrhosis complications (e.g., diuretics,
dietary interventions, or treatment of encephalopathy, variceal bleeding, or renal

9
dysfunction) may re-enter specific therapeutic pathways, as reflected in the CUSE
framework (Figure 2).
Cancer-related symptoms—captured objectively by the Eastern Cooperative
Oncology Group (ECOG-PS)—remain a robust, stage-independent predictor of overall
survival (OS) and are a common stratification factor in phase III trials of systemic
therapy.[21] By design, cancer-related symptoms (ECOG-PS) reflect cancer-
attributable symptoms rather than those due to comorbidities or underlying liver
disease. However, attribution can be challenging in decompensated cirrhosis and
even in compensated cirrhosis with marked fatigue. ECOG-PS is a useful tool to
estimate functional status, but in advanced cirrhosis or elderly patients its

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interpretation is complex. Reduced activity or fatigue may not always be due to HCC,

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but rather cirrhosis-related complications (ascites, encephalopathy, sarcopenia) or

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frailty associated with aging and comorbidities. In this context, complementing ECOG-
PS with dedicated frailty assessment tools may better disentangle tumor-driven
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symptoms from other contributors, while clinical judgment remains essential to
interpret patient-reported limitations.
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An elevated AFP concentration signals worse prognosis and may exclude

transplantation [22,23], but it does not preclude other therapies. Many additional
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biomarkers—lectin-bound AFP, Prothrombin Induced by Vitamin K Absence II

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(PIVKA-II), inflammatory cytokines, C-reactive protein—have been proposed, yet

none has gained sufficient validation to replace the established predictors.[24,25]
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SUP-A&B
In practice, HCC staging starts with clinical assessment and imaging; prognosis is
refined by liver-function tests, ECOG-PS, and biomarkers. Decisions rest with a
multidisciplinary tumor board (MTB)— diagnostic and interventional radiology,
hepatology, medical and radiation oncology, surgery, pathology, nuclear medicine,
molecular biology, specialized nursing, palliative care, dietitian and social work——
with immune-related adverse-event (irAEs) experts added since immunotherapy has
been introduced.[26] This team maps stage to predict survival and selects therapy by
integrating clinical, imaging, pathology, laboratory, and psychosocial data. Leadership
within the MTB should be assumed by the professional best positioned to integrate
scientific knowledge with organizational skills, ensuring coordinated and efficient
decision-making. This approach reflects the BCLC’s emphasis on humanistic

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management, prioritizing shared responsibility, transparent communication, and
patient-centered care.

Treatment
In the following paragraphs we outline the proposed treatment options for each BCLC
stage. After stage characterization, the 2025 BCLC again lists preferred options for
each stage. Treatment-stage migration (TSM) tempers the linear algorithm (Figure
3), permitting access to alternative treatments for earlier stages or even to liver
transplantation (LT) once listing criteria are met with recognition of the increased risk
of morbidity and/or the potential negative impact on expected survival. Untreatable

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progression (UTP)—first defined for transarterial chemoembolization (TACE) [27] but

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now applied across all stages—signals failure of the current strategy and triggers

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transition to the treatment recommended for the next BCLC stage, even in the absence
of radiological progression. Major response after treatment——still lacking a
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consensus definition—remains a major source of uncertainty in HCC decision-making,
as the necessity and efficacy of subsequent therapies in this setting are unknown.
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Although prognosis in BCLC is mainly determined by liver function and tumor burden,
additional individual factors may also influence outcomes. The BCLC 2025 model
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makes these determinants explicit so that they can be systematically weighed together
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with stage and therapy. Importantly, the BCLC system was originally conceived as a
starting point at diagnosis or initiation of therapy. Over time, concepts such as TSM
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and BCLC upon progression[28] were incorporated to capture patient trajectories. The
advent of immunotherapy now raises a new challenge: defining BCLC upon response.
This notion—commonly referred to as therapeutic conversion—recognises that
profound tumor regression marks not a return to a prior disease stage, but the
emergence of a distinct clinical state: a form of “treatable tumor regression” requiring
its own staging framework.

Clinical decision-making

The 2022 BCLC strategy[9] introduced a clinical decision framework, which the 2025
revision refines by integrating the CUSE approach. CUSE is a structured framework
applied when there is a gap between available evidence and its application to an
individual patient. It integrates clinical data, patient and treatment goals, and

11
contextual factors to organize complexity, align dilemmas with therapeutic priorities,
and apply the best available evidence. This process supports multidisciplinary teams
in reaching explicit, reproducible, and patient-centered decisions.

BCLC.CUSE.AI, is under development and it will become accessible online. It will

offer a tailored, case-specific appraisal of the evidence to reduce tumor board
workload and standardize CUSE implementation across diverse settings (SUP-A).
This framework clarifies the concepts and parameters that the MTB must combine into
a personalized treatment plan for HCC. When interpreting evidence (SUP-A), greater
weight is given to prospective studies—particularly randomized controlled trials

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(RCT)—while retrospective studies remain more prone to bias, even with adjustments

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such as propensity score matching or inverse-probability of treatment weighting
(IPTW).[29–31] Treatment allocation in such studies often reflects center-specific
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strategies, with surgery prioritized as first-line and ablation or locoregional therapy
reserved for patients unsuitable for resection. This structural selection bias cannot be
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fully eliminated and is explicitly acknowledged within the CUSE frame work.[29–31]
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Person-oriented CUSE decision framework (Figure 1)

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CUSE addresses two recurrent evidence gaps: (i) no demonstrated OS benefit and
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(ii) robust OS data that are not comparable across options. It draws on Mishel’s
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taxonomy of illness uncertainty,[32] McCormick’s concept of temporality,[33] and

Griffiths’ emphasis on exposing doubt,[34] to explicitly incorporate CUSE into
decision-making. CUSE advocates defining choices as ‘optimal’ rather than ‘best’
when evidence is lacking—avoiding false certainty—and promotes explicit acceptance
of uncertainty through time-bound, reviewable decisions with clear objectives. This
ensures that each person’s unique profile guides therapy beyond trial data alone.

Process (co-designed; Figure 1b) : The process involves (1) establishing the goals
of care; (2) assessing the clinical and social context, including hepatic reserve,
performance status, frailty, comorbidities, deliverability, affordability, and caregiver
capacity; (3) evaluating the evidence by level of certainty and applicability, translating
population data into person-level choices, and communicating options in plain
language with absolute numbers; (4) deliberating within the multidisciplinary team; (5)

12
making a shared decision documented with rationale and consent; and (6) iterating
the plan to reflect changing goals, clinical status, and evolving evidence, with interim
decisions in ambiguous scenarios (e.g., time-limited therapy, as used in downstaging)
and predefined review points.

Purpose & scope: align treatment with the patient’s goals, values, and life context
[35–38] while staying evidence-anchored and safety-first. This includes clarifying
goals of care (cure, survival, symptom relief, function), acceptance of risk/toxicity, day-
to-day realities (work, caregiving, travel, costs), and preferred involvement in
decisions.

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Dimensions include: Complexity (multifactorial comorbidities and competing

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treatments with equal or absent evidence); Uncertainty (individual prognostic
ambiguity, evidence gaps, rapidly evolving standards); Subjectivity (variability in how
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individuals and clinicians interpret information and express preferences); and
Emotion (the psychological impact of stress, prior experiences, hopes, beliefs, or
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values on patients, caregivers, and clinicians).

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Decision thresholds (with patient agreement): GO— clear goal, robust safety
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evidence, favorable benefit–risk, adequate hepatic reserve and performance status,

and assured deliverability; CONSIDER—marginal eligibility or modifiable risks
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needing optimization (including prehabilitation strategies to enhance physical

reserve),[39] information gaps to address, or suitability for an approved clinical trial;
NO-GO—high decompensation risk, absolute contraindications, uncontrolled
comorbidity, non-deliverable care (logistics, access, or affordability constraints), or
absence of robust safety evidence; such options are not offered outside approved
trials, and care pivots to best supportive care or stage-appropriate alternatives.

When to invoke CUSE: CUSE is typically invoked when therapeutic ambiguity arises
as result of the following scenarios:

Multiple RCTs reporting improved OS — When more than one RCT demonstrates a
survival benefit, but no head-to-head comparisons are available. Important
considerations regarding the interpretation of median survival times are provided in
13
SUP-A. Exploratory methods such as restricted mean survival time (RMST), milestone
survival rates, progression-free survival (PFS), landmarks, time to treatment failure
(TTF) or duration of response (DoR), quality-adjusted survival (QALY/QALD), post-
progression survival (PPS), or the cumulative incidence of clinically relevant events
(e.g., liver failure, transplantation, variceal bleeding) may provide complementary
insights. While network meta-analyses (NMA) may provide additional insights in the
absence of head-to-head comparisons, their interpretation requires caution.
Differences in trial populations, study design, and the temporal context in which trials
were conducted may introduce heterogeneity and bias, potentially limiting the validity
of indirect comparisons. Therefore, although such analyses can support clinicians

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when carefully performed, they should not be taken as evidence of clear superiority of

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one systemic option over another. In line with this principle, the BCLC update has

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refrained from presenting cross-trial hazard ratios or survival curve metrics, so as not
to imply a hierarchy unsupported by direct evidence.
-
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The BCLC 2025 framework considers these approaches potentially useful for
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providing descriptive information and generating hypotheses, particularly to anticipate

expected outcomes under a given treatment. Their main value lies in informing shared
na

decision-making between healthcare providers and patients by clarifying potential

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trajectories of benefit, toxicity, or quality of life, thereby guiding treatment choices in

contexts of uncertainty.
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RCT but with immature OS — data due to short follow-up and few events, especially
late deaths— yet curative intent (e.g., neoadjuvant or combination therapy in early to
intermediate HCC) may be at stake. Teams must balance the statistical power of an
interim readout from a phase III RCT against the smaller yet fully mature, signal from
a phase II study. Consistent with this principle, BCLC 2025 recommends waiting for
the final phase III results and, in the meantime—while no OS benefit is proven—
basing treatment recommendation on mature phase II data (safety, response, and
survival), prospective projects, and individual-patient meta-analyses that provide
granular OS estimates in well-characterized cohorts. When event numbers are low,
stating that a therapy shows “no detrimental effect on OS” is clinically meaningless:
the absence of observed harm does not imply benefit—or even neutrality.

14
Favorable PFS in the absence of valid OS data— PFS is informative if the trigger for
it is fully defined—tumor growth, liver decompensation, death, or a composite—and
the outcome for each event is clearly described, with competing risks in people with
cirrhosis reported separately (Figure 5). Development of liver decompensation that
prevents treatment maintenance is a clinically relevant event that may result in the
‘failure of treatment strategy’ endpoint as introduced in the ABC-HCC trial comparing
systemic therapy vs chemoembolization (NCT04803994). In clinical trials, its
underlying cause should be described in detail. The clinical team should accept that a
PFS gain may never translate into an OS advantage, but it can justify a temporary
decision to attempt a potential delay of tumor progression, during which the person

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may reach the next-line therapy —ideally one with proven curative potential or stronger

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survival data. The benefit, however, remains provisional and should be framed within

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the inherent uncertainty. PFS remains a vulnerable endpoint and is not considered a
robust surrogate for OS in major guidelines for intermediate to advanced
-
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stages.[11,40]
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Absence of RCT — When RCT are lacking, interpretive flexibility depends on the type
of available evidence (e.g., phase I–II non-randomized studies, individual patient data
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meta-analyses (IPDM), real-world evidence, aggregated-data meta-analyses, case

reports) and on the intended goal (safety or efficacy). Their main primary role is to
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support clinical judgment and shared decision-making by contextualizing expected

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benefits and risks in situations of evidence scarcity. In this context, prospective and
retrospective evidence must be clearly distinguished when informing treatment
strategies. Prospective single-arm phase I/II trials may justify clinical adoption when
they represent the highest or most applicable evidence available, as seen with highly
selective molecular therapies in other cancers. By contrast, single retrospective
studies or aggregate meta-analyses of retrospective data are more prone to bias and
should be regarded as hypothesis-generating unless externally validated. In addition,
the growing role of real-world evidence requires careful appraisal, and its quality
should be assessed using established frameworks such as the ESMO-GROW
guidelines before informing therapeutic recommendations.[41]

Expected survival after first treatment option based on evidence-based OS

15
Under the BCLC framework, the expected median OS after the first therapy is >5 years
for individuals at very-early and early stages (BCLC 0/A), more than 2.5 years for those
at the intermediate stage (BCLC B), roughly 2 years for the advanced stage (BCLC
C), and <1 year for end-stage disease (BCLC D). These estimates represent best-
case outcomes with effective first-line therapy, but individual prognosis varies widely.
When sequential treatment is deployed—moving promptly to the next, stage-
appropriate option once treatable progression emerges—survival can extend far
beyond these medians. However, candidacy for sequential treatments itself is a
prognostic marker and does not confirm survival improvement from any particular
sequencing strategy.

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First treatment option and CUSE framework per stage

Very early stage (BCLC 0)

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This is defined as a single intrahepatic HCC ≤2 cm without neoplastic vascular
invasion (macrovascular invasion) or extrahepatic spread in a patient with preserved
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liver function and no cancer-related symptoms.[42,43] BCLC-0 management varies

according to the potential access to LT and specific profiles as described in CUSE
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BCLC0/A section.
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In patients without clinically significant portal hypertension (CSPH; hepatic venous

pressure gradient [HVPG] >10 mmHg or surrogate markers[44]),liver resection (LR)
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remains the recommended first step. [45–50] Because of the risk of recurrence, the
potential for Ab initio LT should always be considered within local policy[51,52] in
selected cases or reserve LT as rescue therapy if recurrence occurs. Regulations and
prioritization rules, however, differ worldwide and may prevent Ab initio LT and delay
timely LT. Indeed, for very early HCC an alternative approach is to “ablate and wait”
until recurrence takes place and at that time consider LT if still within criteria.[37,53,54]
AFP levels > 1,000 ng/mL signals an unacceptably high risk of post-transplant
recurrence.[22,23] If LT is not an option, ablation with percutaneous thermal
techniques (radiofrequency [RFA] or microwave [MW]) has historically been the
standard. Increasing evidence indicates that TACE, transarterial radioembolization
(TARE) and external-beam radiotherapy (EBRT) may achieve comparable outcomes.
Thus, so current practice considers these modalities as valid alternatives, with the final
choice largely driven by tumor features, expertise, and local resources.
16
In selected patients, minimally invasive resection (laparoscopic/robotic) may also be
considered, particularly for peripherally located tumors where ablation carries higher
risks such as tract seeding or damage to adjacent organs.[9]

Percutaneous ablation offers survival comparable to LR with less invasiveness. [55–

60]. The prospective SURF-RCT did not demonstrate a survival advantage for LR over
RFA in early, small, predominantly single HCC—supporting ablation as a valid first-
line option [55]. Minimally invasive LR (laparoscopic/robotic) reduces perioperative
morbidity versus open surgery, but its survival impact remains uncertain [61].
Observational signals in very small cohorts conflict with meta-analytic findings, so no

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definitive superiority can be claimed.[60,62] MW provides more reliable local control

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than RFA for tumors up to 3-4 cm and is therefore the preferred percutaneous
technique when feasible.[63,64]
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For radiation-based approaches, TARE achieves high objective responses, including
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frequent complete responses in small lesions.[63,65] In the recurrent setting post
resection/RFA, EBRT shows survival and toxicity comparable to repeat RFA. [66]
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Early stage (BCLC-A)

na
ur

This is defined as a single intrahepatic HCC >2 cm, or up to three HCCs none larger
than 3 cm, without macrovascular invasion, extrahepatic spread, and ECOG PS 0 in
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a patient with preserved liver function. In patients with liver decompensation, the
management principles are commented in CUSE 0/A section.
In BCLC-A, treatment selection is guided by HCC-related factors such as tumor
burden and location as well as presence of CSPH, and should also consider available
expertise and technology.

Single intrahepatic HCC

As in BCLC-0, treatment selection requires a multiparametric approach. Liver function

should be stratified by CSPH which predicts higher postoperative risk and worse
survival.[67–69] Non-invasive methods may help to rule out or confirm CSPH but
HVPG is still the gold standard.[44,70] However, HVPG reliability may be suboptimal

17
in steatotic liver disease.[71,72] HVPG may decrease after eradication of HCV
infection, but this has to be carefully assessed.[73]
In the absence of CSPH, resection (preferably minimally invasive) is the first option.
In patients with mildly increased CSPH, minimally invasive surgery remains an option
for single peripheral HCC with adequate remnant liver volume.
Surgery is preferred in potential LT candidates, as pathology provides key prognostic
data. The presence of microvascular invasion and satellites, predictors of
recurrence,[45–50] may support Ab initio LT.[51,52]
The macrotrabecular-massive (MTM) pattern is a morphologically distinct and
aggressive subtype of HCC but only microvascular invasion and satellite nodules are

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validated predictors of aggressive recurrence and mortality [47] The vessels-

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encapsulating tumor clusters (VETC) pattern—endothelial vessels encasing tumor

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clusters, typically highlighted by CD34 immunostaining—is another poor-prognosis
phenotype [74] that often overlaps with MTM. Other parameters have been proposed
-
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such as liquid biopsy[75,76] to stratify recurrence risk, but only conventional
pathological predictors are validated, and no molecular profile is yet reliable for
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recurrence risk assessment.

In patients with CSPH, resection poses significant risk,[68,77] and LT offers better
na

survival. However, when LT is not an option and ablation is suboptimal (e.g., large
ur

tumors), alternative treatments may be considered, including intra-arterial locoregional

therapies or external beam radiation, or laparoscopic resection in selected cases with
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favorable tumor location and mild CSPH—before moving to systemic therapy in

BCLC-A, consistent with the CUSE framework. [61,78]

Multifocal up to 3 HCC nodules, each ≤3 cm

Within Milan Criteria defined by up to 3 HCC nodules, each ≤3 cm[79], multifocal

disease is best managed by LT, given the high risk of recurrence after resection or
ablation [79–81]. When LT is not feasible, ablation is the option because the relative
merits of resection or intra-arterial locoregional treatment or EBRT versus RFA/MW
remain unsettled.

CUSE tailored approach – BCLC-0/A patients

18
Treatment decisions for people with very-early or early HCC (BCLC-0/A) often shift
when person-specific factors rule out the default option shown in Fig. 4. The literature
supporting this proposal is detailed in SUP-A.
If LT (BCLC-0) or surgical resection for single lesions (and LT for multifocal BCLC-A)
are not feasible, but liver function is preserved ablation remains the pillar of care.
For patients listed for LT, oncologic treatment is recommended to prevent HCC
progression that could rule out LT, particularly when there is an increased risk of HCC
progression or prolonged waiting-list time. Ablation and intra-arterial locoregional
treatment are the most widely used options for this purpose.

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Patients with single HCC and severe liver dysfunction or decompensation should

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proceed directly to LT if they meet listing criteria (age, comorbidities, and other
relevant factors). When LT is contraindicated for non-HCC reasons, these individuals
-
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are classified as BCLC stage D because survival is limited chiefly by liver failure.
However, some contraindications may be transient and thus, the multidisciplinary
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team must assess whether the exclusion factor can be corrected, allowing LT
candidacy to be reconsidered if the condition improves and the HCC has not
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progressed beyond local transplant criteria.

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When ablation is selected for a BCLC 0/A patient, choosing the specific modality
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exemplifies CUSE decision-making: the multidisciplinary team must tailor the

technique to the individual’s circumstances and to the available evidence for single
intrahepatic lesions. The 2025 BCLC update supports a CUSE-guided choice of
ablation procedure (RFA/MW)[82,83] as the preferred percutaneous approach.
Laparoscopic ablation is reserved for selected cases, and PEI is considered only in
rare situations with technical or safety constraints. TARE offers comparable efficacy,
while EBRT has demonstrated antitumor activity with median survival exceeding five
years.[63,65,84–87]

TARE was endorsed in BCLC 2022 as an ablative alternative, supported by the

LEGACY (median tumor size 2.6 cm; range 0.9–8.1 cm) which reported a 36-months
survival rate of 86.6%,[65] and more recently validated by the RASER (mean tumor
size 2.1 cm, standard deviation 0.4),[63] with an actuarial 1- and 2-year OS of 96%.
19
Therapy planning has since been refined, based on dosimetric recommendations for
radiation segmentectomy.[88]
Super-selective delivery (“radiation segmentectomy or lobectomy”) has achieved
durable responses in retrospective studies, comparable to ablation in patients
unsuitable for surgery or percutaneous techniques.[63,65,89,90] Radiation lobectomy
can also increase future remnant liver volume and facilitate resection in borderline
cases.[91]
EBRT has advanced with improved technology and better understanding of liver and
tumor response. Techniques such as SBRT, proton beam, and carbon ion therapy can
deliver ablative doses with a broad therapeutic window. Consensus guidelines now

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define parameters for ablative EBRT[92], with <5% risk of severe toxicity.[93] A phase

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II trial of SBRT for single HCC ≤4 cm unsuitable for resection or RFA reported a 3-

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year OS of 65.4% (95% CI, 54.5–75).[86] Pooled analyses including 484 BCLC-0 and
1,123 BCLC-A patients (134 and 468 treatment-naïve, respectively) showed favorable
-
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long-term outcomes: in naïve BCLC-0, overall median OS was not reached and by it
was 6.4 years with photons and 8.6 years with photons and protons, respectively. In
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treatment-naïve BCLC-A, median OS was 5.4 years and 4.3 and 4.9 years with
protons, respectively. The TRENDY trial,[85] a multicenter phase II study of patients
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with single naive HCC ≤6 cm (median 3.4 cm), reported a median OS of 36.8 months
ur

with Drug-eluting beads (DEB)-TACE and 44.1 months with SBRT (HR 0.58; 95% CI
0.18–1.85; P = 0.36). However, most RCTs enrolled patients with recurrent HCC after
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prior therapy, and several failed to meet accrual targets,[94,95] limiting the strength of
the evidence for first-line use.
These results suggest encouraging outcomes in early disease, particularly BCLC-0/A
with well-preserved liver function, although heterogeneity and selection bias remain
important limitations.[84] For these reasons, BCLC 2025 incorporates EBRT as an
ablative option in BCLC-0 patients.
Complete pathological response (CPR) is frequently observed in small solitary tumors
after selective or super-selective TACE,[96–100] but radiologic complete response
does not consistently predict histologic necrosis. [101]
A retrospective analysis of UNOS liver transplant candidates with an HCC exception
(2019–2024) reported that first-line TARE was associated with a higher rate of
complete pathologic necrosis on explant compared to TACE (~34% vs ~20%,

20
respectively) and a lower risk of waitlist dropout (IPTW-adjusted HR 0.78 [95% CI
0.68–0.89]).[102]
While higher CPR rates have been reported with certain locoregional therapies—
including TARE - SBRT achieved a 25% overall rate in a series of 88 patients used for
bridging or downstaging (30% vs. 12%, respectively).[103] Thus, CPR may serve as
a useful tool for assessing treatment efficacy, but it is not yet a definitive surrogate for
OS. Although TACE is not strictly ablative, outcomes from TRENDY and retrospective
cohorts suggest OS comparable to SBRT and TARE, and cohort data indicate
favorable long-term results in early stages, with apparent advantages in BCLC-0 over
BCLC-A as expected. [104,105]

f
While some LRTs are associated with higher rates of CPR, long-term survival

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differences across modalities remain modest, highlighting the importance of

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individualized patient selection and multidisciplinary evaluation.[106–108]
Retrospective cohort comparisons between bland embolization (TAE) and DEB-TACE
-
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are confounded by selection and center-strategy biases. These results should be
interpreted descriptively, not as definitive head-to-head evidence.
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BCLC-A multifocal (Up to three lesions, each ≤3 cm)

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The BCLC 2025 supports the same recommendation of BCLC 2022 on the role of
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ablation but also consider the following data for the tumor board discussion : (a) Vitale
et al. and Yu et al. report favorable outcomes after resection in selected multifocal
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BCLC-A cohorts[109,110]; (b) A recent RCT in small, late-recurrence HCC found no

survival difference between resection and RFA combined with conventional
TACE;[111] (c) In BCLC 0/A, emerging data have reported promising long-term
outcomes with EBRT in an IPDM setting.[84]
In hepatitis B virus (HBV)-related HCC with CSPH within Milan Criteria (MC), an open-
label RCT[112] found no clear survival advantage of partial hepatectomy over
locoregional therapy—even within the portal-hypertension subgroup— underscoring
that CSPH is the main driver of surgical risk rather than modality-specific benefit.
Among trials with uniform early-stage populations, Fang et al. (BCLC-A) showed that
adding TACE to resection improved outcomes vs resection alone in selected
candidates,[113] whereas Méndez-Romero et al. (BCLC-A) reported similar survival
between DEB-TACE and SBRT despite early termination of the trial.[85] For patients

21
with BCLC-A multifocal disease, no single treatment pathway can be established, as
therapeutic choice must be tailored to disease characteristics and patient profile.

While resection may appear favorable for early multifocal HCC in terms of absolute
survival, comparisons with locoregional therapies remain limited by strong selection
bias—including age, number of lesions, liver function, and portal hypertension —
despite propensity-score analyses. Moreover, Wang et al.[114] also reported that MW
ablation was associated with fewer complications and shorter hospital stay than
resection, underscoring that minimally invasive resection should not be the default
first-line option in multifocal BCLC-A but rather weighed through a CUSE evaluation

f
that balances feasibility, safety, oncologic risk, and patient priorities.

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Minimally invasive resection/ablation for Milan-IN disease is practiced in well-

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compensated patients, as reflected in the EASL Guidelines.[11] However, the
supporting evidence is limited—RCTs included very few multifocal cases (e.g., 15 per
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arm in SURF,[115] 24 vs 31 in IMbrave050,[116] and <10% in Yuan et al.[112]), while
retrospective series involved highly selected Child–Pugh A patients with low tumor
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burden (mostly two nodules, platelet count >134 × 10³/µL, and <7% requiring major
resection).
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Phase II data for EBRT and TARE remain small and heterogeneous. Hence, the BCLC
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2025 figure includes a CUSE note indicating that resection, TARE and EBRT may be
considered in selected cases, ensuring alignment with the EASL Guidelines while
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avoiding unjustified generalization.

Irreversible electroporation[117] and high-intensity focused ultrasound [118–120]
appear to be effective and safe ablation modalities, but robust evidence in HCC is still
awaited before formal recommendations can be made. TACE remains the standard
first-line option, supported by the largest body of evidence, whereas resection, EBRT,
and TARE are considered only in selected, well-compensated patients under a CUSE
framework.

Role of laparoscopic approaches, age and HCC location

Recent studies have compared laparoscopic approaches and ablation techniques in

early-stage HCC. In a multicenter analysis, laparoscopic microwave ablation
(LAMWA) showed lower morbidity than laparoscopic hepatectomy (14.7% vs. 34.7%;
22
p = 0.006), while OS at 1, 3, and 5 years was similar between both groups (LAMWA:
88.2%, 69.9%, 45.6% vs. hepatectomy: 86.1%, 72.9%, 51.4%; p = 0.693).[121,122]
In patients with portal hypertension, the complication rate of MW was significantly
lower than that of liver resection (p < 0.001), supporting ablation as a safer option in
this setting.[123]
Tumor location is also a key determinant factor in treatment selection. Indeed, HCC
location and patient age are key factors often considered by multidisciplinary boards
when deciding treatment. However, data on their impact after ablation remain limited.
In a recent cohort[124], neither tumor location nor age (elderly vs. non-elderly) at the
time of first ablation were associated with OS or with the need to change treatment

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strategy.[125–130]

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By contrast, in a cohort of 225 patients treated with RFA/MW at the BCLC group,

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suboptimal locations (subcapsular, dome, proximity to heart, hilum, gastrointestinal
tract, or major vessels) were linked to shorter time to recurrence (13.1 vs. 20.7 months)
-
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and earlier need for treatment change (17.6 vs. 25.1 months) compared with optimal
sites.[124] Taken together, these findings suggest that while tumor location may not
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independently impact on survival, ablation in technically challenging sites carries a

higher risk of earlier recurrence and strategy modification.
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Functional decline and frailty significantly influence perioperative outcomes in elderly

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HCC patients, regardless of surgical approach. While minimally invasive hepatectomy

reduces hospital stay and morbidity, these factors remain key predictors of
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complications. The Barthel Index has been shown to independently predict

postoperative risk, underscoring its value in preoperative assessment.[131]

Intermediate stage (BCLC-B)

In the intermediate stage, tumor burden is defined as more than 3 HCC nodules, or
up to 3 nodules with at least one larger than 3 cm and ECOG PS 0. Preserved liver
function is required to be considered for locoregional therapies or downstaging
strategies. Patients with liver decompensation enter the pathway of decompensated
cirrhosis (Figure 2). They may be evaluated for LT if they meet local listing criteria.
The 2025 update leaves the BCLC-B stratification unchanged from 2022 [9] as no new
high-quality evidence warrants modification.

23
The first subgroup includes patients with well-defined HCC nodules who may be
candidates for LT if they meet the institution’s Extended LT criteria. AFP level >1,000
ng/mL signals an unacceptably high risk of post-transplant recurrence.[22,23] Where
access to LT is limited by donor shortage, living-donor grafts may mitigate this
constraint.[132,133] Such an alternative must balance donor risk against community
benefit, underscoring the need for expert, CUSE-guided judgment.
The second subgroup comprises patient’s ineligible for LT but with preserved portal
flow and defined tumor burden, allowing selective access to feeding tumor arteries;
these individuals are candidates for intra-arterial therapies. TACE remains the
standard locoregional therapy, as no head-to-head trials have proved any alternative

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superior in terms of OS. If tumor distribution or hepatic function precludes effective

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TACE, the pathway moves directly to systemic therapy with extensive considerations

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about potential alternatives as exposed in the CUSE section.
AFP levels, subtle gradients of liver dysfunction within CP-A, and tumor heterogeneity
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all modulate prognosis, yet robust universal thresholds remain elusive. Several scores
have been proposed to predict prognosis after TACE (SUP-B). However, they do not
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alter TACE candidacy under conventional selection criteria.

The third subgroup includes patients with diffuse, infiltrative, or extensive HCC liver
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involvement, where TACE cannot be performed selectively, systemic therapy is

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recommended, although no strict cutoff defines this transition.

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Treatment for BCLC-B

Conventional TACE (cTACE) involves injection of a chemotherapy–lipiodol emulsion

followed by vessel occlusion with gelatin sponge.[134] DEB-TACE allows slow drug
release, reducing systemic peaks while maintaining efficacy and improving tolerability.
[135,136] A higher incidence of biliary changes has been reported with DEB-
TACE,[137,138] though these are mostly image-detected dilatations without clinical
impact.
Two randomized trials have evaluated the impact of DEB-TACE compared with TAE
in HCC. Malagari et al. demonstrated DEB‑TACE achieved higher complete response
rates (26.8% vs 14%) and reduced early recurrence at 12 months (45.7% vs 78.3%)
in patients with intermediate-stage HCC, suggesting a benefit in local tumor

24
control.[139] In contrast, Brown et al. found no significant differences in objective
response rate (ORR), PFS, or OS between DEB-TACE and bland embolization in an
HCC population beyond BCLC-B.[140] This broader selection may help explain the
suboptimal survival. Thus, the trial does not establish equivalence between the two
options. In a cohort of 1,461 HCC patients (730 TACE, 731 TAE), the TAE group had
poorer liver function and higher HBV prevalence,[141] propensity-matched analyses
favored TACE over TAE for OS and response. In contrast, Roth et al.[142] found that
an apparent survival advantage of TACE attenuated after propensity weighting in the
overall cohort. However, among CP-A, TACE retained a survival advantage,
suggesting that benefit is concentrated in compensated patients.

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The STOPPER trial[143] showed high short-term survival with epirubicin-loaded

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TACE, and TACTICS showed that outcomes with TACE alone were more favorable

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within the up-to-7 criteria or six to twelve[144] than outside. Collectively, these findings
indicate that the efficacy of TACE alone depends heavily on tumor burden and BCLC
-
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stage distribution. In summary, when liver function is preserved, TACE is generally
preferred over TAE (see SUP-A). In unselected or less compensated populations,
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difference is less certain, and residual confounding limits causal inference.

In practice, patients with extensive bilobar disease are unlikely to benefit from TACE,
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making systemic therapy the preferred option. The transition between these
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subgroups is best guided by the CUSE framework, balancing feasibility, risk, and
patient priorities. However, available evidence lacks granular data on systemic therapy
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outcomes in this subgroup, as trial baseline characteristics have not reported such
detail; further clarification is awaited. The CUSE section offers further insight into
treatment selection for BCLC B patients.

CUSE tailored approach – BCLC-B patients

Treatment decisions for people with intermediate HCC often shift when person-
specific factors rule out the default option shown in Fig. 4. The literature supporting
this proposal is also detailed in SUP-A.
While the MC[79] are the standard benchmark, growing evidence supports the
inclusion of certain BCLC-B patients beyond MC —particularly those successfully
downstaged and with AFP levels below a specific cutoff that varies across
jurisdictions— can achieve post-LT outcomes equivalent to those within MC.[145–147]
25
This has led to the development of extended and biomarker-integrated selection
models. In contrast, AFP levels exceeding 1,000 ng/mL consistently predict poor
survival and higher recurrence risk, and are widely considered a contraindication to
LT, regardless of tumor burden.[22,23]
Although AFP reduction following downstaging is common, the optimal magnitude and
duration of decline required for transplantation eligibility remain undefined. In this
setting, though it must be weighed carefully against donor risk and overall societal
benefit.[133,148]
In this context, what is often termed “neoadjuvant” therapy largely corresponds to
downstaging or bridging therapy, widely applied in patients beyond MC but within

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extended criteria to prevent drop-out and refine selection. LT after major response to

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systemic treatment —particularly immunotherapy— is also emerging, though still

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investigational and supported only by limited prospective evidence. To avoid
ambiguity, we refer to these strategies as “bridging therapy” and “systemic treatment
-
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prior to LT.” Both remain within the realm of clinical decision-making and, in the 2025
BCLC, systemic treatment prior to LT is categorized as alternative sequences that
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may be considered but have not been proven, underscoring persistent uncertainty
when LT indication is discussed.
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Resource allocation requires balancing individual benefit with societal utility.[149] LT

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should be prioritized for candidates achieving the largest net survival gain over
alternatives, without excluding those with substantial—though not maximal—benefit.
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Modern utility frameworks incorporate dynamic parameters, including tumor control

duration, AFP kinetics, and overall trajectory on the waitlist, to align efficiency with
equity in organ distribution.[133]
When LT is not an option, patients with preserved function should receive TACE as
default, supported by RCT evidence.[150,151] Conventional and DEB techniques
provide comparable tumor control [150] and survival estimates coming largely from
cohort and phase II studies.[85,152–154] STOPPER enrolled BCLC-A/B candidates
for TACE with preserved liver function.[143] The TACTICS trial enrolled patients
across BCLC stages A, B, and C, with the majority being BCLC-B, and smaller subsets
representing early and selected advanced stages.[155]
If TACE is not feasible due to excessive tumor burden, systemic therapy should be
considered. Alternatively, if TACE is not performed for technical reasons rather than

26
tumor burden, other locoregional options such as TARE or EBRT may be used to
delay systemic therapy and preserve it for progression.
Although retrospective studies showed higher tumor response and longer TTP with
TARE versus TACE in this population, no survival benefit difference has been
demonstrated.[156–158] TRACE, the only randomized trial, included patients with
ascites and ECOG-PS 1, which led to early mortality in the TACE arm and raising
concerns about its validity.[90] OS in the TACE arm was unexpectedly low—close to
the natural history of BCLC-B[159]—even though the study also included BCLC-A
cases, which limits the robustness and clinical interpretation of these findings.
More reliable benchmarks come from larger non-randomized cohorts: in 1,000

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patients treated with TARE,[160] median OS for BCLC-B was 19 months overall, but

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38.5 months in ALBI-1 patients, underscoring the prognostic relevance of liver

compensated BCLC-B treated with TARE.

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function. These results suggest that 3 years[161] serve as a benchmark for well-
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Separately, the Kuehnle et al. [162] meta-analysis of three prospective randomized
trials comparing EBRT with TACE found no difference in OS or grade ≥3 toxicity, but
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applicability to BCLC-B is constrained by small stage-specific numbers and modality

heterogeneity (protons vs photons for EBRT; cTACE, DEB-TACE, and TAE on the
na

embolization side). Encouraging results have also emerged for EBRT in BCLC-B.
ur

Moon et al. [84] reported favorable OS in an unselected cohort, with particularly long
survival in treatment-naïve patients and those with ALBI grade 1(4.5 years). However,
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unclear selection criteria limit generalizability and hinder identification of patients most
likely to benefit. Sorin et al. likewise reported favorable multi-year survival with EBRT
in BCLC-B,[163] but these retrospective, small-cohort data are best considered
descriptive rather than comparative.
In summary, OS data on TAE are not robust enough to replace TACE in well-selected
BCLC-B patients. TARE, EBRT may be considered for patients who are not
candidates for TACE, but no data support its use as a first-line option based on OS. If
considering TARE, the DOSISPHERE-01 trial showed that personalized dosimetry
improves outcomes and should be standard practice.[164]
The current BCLC strategy still does not support TARE or SBRT as first line
alternatives to TACE in this context, as the available data on these therapies in non-
TACE candidates primarily involve patients with BCLC-A disease. These modalities

27
could serve to delay the initiation of systemic therapy and preserve it as a subsequent
option in the event of disease progression.

Treatment tage Migration

While outcomes are commonly stratified by liver function or prior therapy, few studies
address individual profiles (e.g., BCLC-B/C with diabetes or other comorbidities). This
gap underscores the need for granular data to guide therapy beyond OS-based
choices. CUSE highlights the importance of considering the reason for TSM (Figure

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3), ensuring that subsequent decisions reflect evolving clinical status and patient

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goals. Figure 4 (dotted arrow) illustrates that sequences may occasionally bypass

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systemic therapy; however, this is not a general recommendation and reflects
temporary decisions in settings of uncertainty.
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TACE-based combinations:
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Phase III trials have evaluated TACE plus systemic therapy in unresectable HCC.
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Multiregional studies with immunotherapy (EMERALD-1,[165] LEAP-012,[166]

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TALENTACE[167]) improved PFS (HR 0.64–0.77) but OS data remain immature, with
stage-specific results reported only in TALENTACE. Three large RCTs in China—
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LAUNCH, (lenvatinib + TACE)[168] TACE + apatinib,[169] and DEB-TACE +

apatinib[170]—each showed OS and PFS benefit, but lack validation in other
populations. Differences in trial design, BCLC composition, and geographic coverage
preclude firm conclusions. At present, TACE-based combinations cannot be
recommended outside clinical trials. This exemplifies the value of CUSE in
contextualizing signals of efficacy against heterogeneity, scope, and evidence
maturity. (SUP-C). Beyond these specific trials, we stress that interpretation of
immature or heterogeneous evidence requires a structured approach. As detailed in
Supplementary A (BCLC CUSE 2025 literature interpretation), we advocate
contextualizing these signals of efficacy within MTBs, weighing safety, feasibility, and
patient values before recommending implementation outside clinical trials.

28
Advanced stage (BCLC-C)

This stage includes patients with macrovascular invasion and/or extrahepatic spread,
regardless of intrahepatic tumor burden, which in Figure 4 is indicated as “any
intrahepatic burden” to denote its coexistence with macrovascular vascular invasion
or extrahepatic spread. They have preserved liver function and a maintained
performance status (ECOG PS 0–2) and should be considered for systemic therapy.
For first-line treatment, immune-based combinations—atezolizumab plus
bevacizumab[171], tremelimumab plus durvalumab[172] , ipilimumab plus nivolumab
[173], and camrelizumab plus rivoceranib (with only 17% of patients from non-Asian

f
countries)[174]—have all demonstrated superior OS compared to sorafenib (or

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sorafenib/lenvatinib in the case of ipilimumab plus nivolumab) across multiple
geographic regions (SUP-B).
pr
These trials included patients with unresectable HCC, mostly stage BCLC C but also
-
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A and B in variable proportions, contributing to outcome. Other treatments such as
lenvatinib,[175] durvalumab[172] or tislelizumab[176] were non-inferior to
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sorafenib[177,178] which itself improved OS versus placebo.

Other regimens (SUP-C) such as anlotinib plus penpulimab,[179] HAIC-
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FOLFOX,[180,181] donafenib[182], TACE plus lenvatinib,[168] sintilimab plus

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bevacizumab biosimilar,[183] and toripalimab plus bevacizumab[184] demonstrated

OS benefit over sorafenib or lenvatinib. However, these RCTs were conducted
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exclusively in Asia (primarily China).

Phase III trials (SARAH,[185] SIRveNIB,[186] and SORAMIC[187]) comparing TARE
alone or in combination with sorafenib versus sorafenib were negative, and by the time
immunotherapy became the standard first-line treatment, no randomized trial had
demonstrated a survival benefit for TARE in this setting. Additionally, several studies
have assessed whether the degree of vascular invasion should inform treatment
selection. A recent systematic review and meta-analysis of 73 studies (10,329 patients
with macrovascular invasion) further evaluated this subgroup. Despite a rigorous
identification process, substantial heterogeneity persisted for most modalities (I²
>80%), precluding robust pooling. TARE was the only treatment for which 1-year OS
as the most comparable endpoint across modalities, achieving a pooled 1-year OS of
34%, with wide confidence intervals (95% CI, 2–48%; I²= 0%). In contrast, surgery,

29
TACE, EBRT, and sequential strategies were confounded by indication and immortal-
time bias, and survival data beyond 12 months were largely incomplete.[188]
These findings underscore that systemic therapy remains the standard for BCLC-C,
while TARE may represent an alternative in selected patients when systemic therapy
is contraindicated or not feasible, and highlight the need for stratified head-to-head
trials of it against immunotherapy. Because no head-to-head trials directly compare
the available immunotherapy-based combinations, current guidance is to select one
as initial systemic therapy, tailoring this choice through the CUSE framework.

Systemic Treatment Sequence

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Among first-line therapies, only sorafenib[178,189] supports an evidence-based

lacking.
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sequencing strategy since validated pathways after other first-line regimens are
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Patients progressing to the second-line may benefit from regorafenib,[190,191]
cabozantinib regardless of prior sorafenib tolerance,[192] or ramucirumab if AFP >400
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ng/mL,[193] irrespective of prior tolerance. Cabozantinib has also demonstrated

efficacy as a third line option.[192] In the field of immunotherapy, data are limited. A
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Western trial of pembrolizumab versus placebo in the second line did not meet its
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primary OS endpoint,[194] whereas an Asian trial in a similar population reported a

significant OS improvement.[195] The recently published meta-analysis including both
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trials found that pembrolizumab improved OS (HR 0.79, 95% CI 0.67–0.93).[196]

However, the control arms differed slightly, as the Asian trial also included patients
who had progressed on or were intolerant to oxaliplatin-based chemotherapy.[195]
As mentioned, the optimal post–checkpoint inhibitor (ICI) sequence in BCLC-C is not
established: non-randomized data and indirect comparisons suggest TKI activity after
IO without proven superiority of any sequence. We recommend prioritizing
preservation of liver function, tolerability, and clinical-trial enrollment. SUP-B&C
describes outcomes according to different treatment options.

CUSE-tailored approach in BCLC-C patients

30
As of August 5, 2025, SUP-B summarizes available data to guide first-line decisions.
In brief, five positives multiregional RCTs and more than 30 sub-analyses of pivotal
studies have characterized populations, updated OS, or described quality of life. Over
1,400 real-world data (RWD) publications are also available, although cohort overlap
cannot be reliably excluded. Four RCTs conducted in China have reported
encouraging results. However, OS benefits have not been demonstrated in
multiregional populations, precluding a general recommendation.
Regarding second-line therapy, RCTs are available only for those patients who
received sorafenib as first-line treatment. [190,192,193] No phase III multiregional
RCT has evaluated patients previously treated with immune-based regimens. In total,

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6 phase II trials have analyzed outcomes with cabozantinib[197,198],

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regorafenib[199], regorafenib-nivolumab[200], regorafenib-pembrolizumab, [201] and

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lenvatinib.[202] Finally, >30 RWD studies describe outcomes in this population.See
SUP-B for RWD details by country, specific condition, and treatment line.
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First-line therapy selection according to CUSE 2025
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Selecting first-line therapy requires balancing multiple elements: evidence from pivotal
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trials (eligibility criteria and survival benefits);[171,173,174,203] safety data from trials
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and real-world studies; patient comorbidities; access to treatment;[204]; expected

response and progression rates including progression patterns[28,205–211] long-term
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outcomes; biological rationale; and quality-of-life metrics, including the granularity of

outcome measures to predict the individual course (SUP-B).
When more than one regimen has shown survival benefit, pragmatic considerations—
such as time toxicity,[212] indirect costs,[213] patient experience[214]— may influence
the choice, although such analyses are rarely reported in clinical trials or post-approval
studies, including patient preference data.[215] In the absence of head-to-head
comparisons or when availability is limited, decisions should be individualized. Within
the CUSE framework, treatment selection is guided by predefined priorities that extend
beyond OS to encompass safety, ORR, PFS, durable response, and other outcomes.
Because no universal hierarchy exists, the multidisciplinary team and the patient
should first agree on primary goals. Accordingly, the BCLC model emphasizes
assembling the full safety–efficacy dataset and weighting endpoints within a CUSE-

31
guided discussion, ensuring that the final plan reflects both clinical judgment and the
goals and values of the person living with HCC.
A profile of special interest within BCLC-C is vascular invasion. Isolated cases are
extremely rare[188,216,217] the typical presentation is intrahepatic HCC with
concomitant macrovascular invasion. Although immunotherapy is the general
recommendation for BCLC-C, current evidence in patients with vascular invasion
comes mainly from subgroup analyses of pivotal trials[218] and observational
cohorts,[216,217] particularly Japanese series with atezolizumab–
bevacizumab.[217,219] These studies confirm the prognostic impact of liver function
and show heterogeneous survival depending on invasion extent, but cohort

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heterogeneity and high rates of missing long-term data limit generalizability.

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Comparisons with TARE suggest lower 12-month survival, yet wide confidence

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intervals and divergent populations preclude indirect inference.[188]
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The DOSISPHERE-01 phase II trial further informs this setting. Patients were
randomized (1:1) to personalized dosimetry (PDA; ≥205 Gy to the index lesion, up to
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250–300 Gy when feasible) or standard dosimetry (SDA; 120–150 Gy to the treated

volume). In the portal tumour invasion subgroup (n=39), median OS was 22.0 months
na

(95% CI, 10.3–36.5) with PDA (n=18) versus 9.4 months (95% CI, 5.3–17.6) with SDA
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(n=21) (HR 0.52; 95% CI, 0.26–1.01; p=0.058). Post hoc analyses confirmed a dose–
response effect in this subgroup of patients median OS was 22.9 months (95% CI,
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11.0–48.1) with tumor dose ≥205 Gy versus 10.3 months (95% CI, 5.9–17.6) with <205
Gy (HR 0.42; 95% CI, 0.22–0.81; p=0.010).[220]
There is increasing interest in EBRT in patients with vascular invasion in combination
with systemic therapy. A seminal RCT phase III study (RTOG 1112) compared
sorafenib to sorafenib with SBRT, patients were stratified by the presence and degree
of vascular invasion.[221] Of the 177 patients eligible for analysis, 74% had
macrovascular invasion and results showed that the vascular HCC response was 9%
(95% CI, 2-16) with sorafenib alone compared to 38% (95% CI, 26-49) with sorafenib
plus SBRT (P < 0.001). This data refers exclusively to vascular response and is
presented for descriptive purposes. Of note, OS and PFS remain the main endpoints
of the trial.

32
These favorable results from prospective trials suggest EBRT can be considered in
appropriate patients with macrovascular invasion and should be studied in future trials
that incorporate modern systemic therapies.
In addition to the Fortuny et al metanalysis[188] on the role of surgery in this
population, observational series consistently reflect treatment-selection bias[217,219]:
apparent advantages of resection largely disappear once disease burden, liver
function, and propensity-adjusted methods are accounted for. Overall, in the absence
of RCT evidence, survival differences across modalities must be interpreted with
caution, acknowledging residual confounding and the non-exchangeability of
treatment cohorts. Systemic therapy is the preferred first-line option for patients with

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macrovascular invasion (Vp1–Vp4). If contraindicated or not feasible, TARE

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(DOSISPHERE-01)[164,220] or EBRT (RTOG 1112)[221] may be considered within

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the CUSE framework, however, evidence in patients with portal vein invasion remains
limited, with only 18 such cases included in DOSISPHERE-01, and these options are
-
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therefore not yet robustly proven.
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Evaluating immunotherapy suitability and management

na
ur

Assessing suitability for immunotherapy —and identifying absolute

contraindications— requires thorough pretreatment evaluation of the risk for irAEs.
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Equally critical is prompt recognition and management of immune related adverse

events[26,222,223] throughout care, including admission into intensive care
units.[224] This underscores the need for targeted education of both health
professionals and persons living with HCC. Specialized oncology nurses play a pivotal
role in patient teaching, monitoring, and care coordination.[1,26,225,226]
The principal drivers of systemic therapy management are therapy-related adverse
events, complications of cirrhosis, progression of HCC with or without
decompensation, and patient adherence (SUP-B). In patients with cirrhosis, careful
differential diagnosis of irAEs and other non–immune-related causes should guide
cautious and rational use of steroids. Extrapolating recommendations from non-
cirrhotic populations may increase the risk of decompensation or bacterial infections.
.[222]. Additional challenges arise in special populations—people living with HIV,[227–

33
230] candidates for LT,[133,231–235] or patients on dialysis.[236,237] Given the
limited evidence base, universal recommendations cannot be made.

Second- and later-line selection according to CUSE 2025

In the second-line setting and beyond, clinical trial enrollment remains the preferred
option for patients with HCC. When trial participation is not feasible, treatment
selection must be guided by the CUSE framework. Robust evidence for sequential
therapy exists primarily after sorafenib.[190,192,193] Recommendations after

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immunotherapy or lenvatinib are based on phase I/II trials, cohort studies, and expert

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consensus. Alternative strategies—including immunotherapy rechallenge, tyrosine

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kinase inhibitors, locoregional therapies (TARE, EBRT), or phase II–based
combinations—may be considered, but are not validated as standard second-line
-
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options (see SUP-C).
Key uncertainties arise when discontinuing first-line therapy without a defined
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subsequent strategy, such as stopping after complete response, escalating to ablative

intent (ablation or surgery), or continuing despite progression or toxicity.[238]
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Decisions should weigh clinical status, tolerance, and patient goals (see SUP-C). In
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patients with absolute contraindications or no access to systemic therapy, non-

systemic approaches (TARE, EBRT) may be considered within CUSE despite limited
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evidence.

Downsizing, downstaging and conversion approach through locoregional

treatment

Effective treatments can reduce tumor burden, yielding complete or partial responses
according to different criteria (RECIST 1.1[239] EASL,[240]
RECICL,[241]mRECIST,[242] Choi criteria[243], iRECIST,[244] imRECIST[245] and
LIRADS[246]). In such instances, follow-up staging may show that observed
downsizing (reduced tumor burden) translates into a downstaging that permits the
consideration of the potential benefit of treatments that have been discarded at
baseline. The downstaging via locoregional approaches (TACE and TARE) has been
developed and validated for LT.[108,147] Thereby, patients who would exceed listing
34
criteria but respond to therapy and fulfill such criteria may benefit from transplantation
and the outcome is optimal. The UNOS‑DS criteria are the most validated (single 5–
8 cm, 2–3 lesions ≤5 cm with total ≤8 cm, or 4–5 lesions ≤3 cm with total ≤8 cm, plus
AFP <1000 ng/mL).[108,247] The XXL RCT showed superior 5‑year OS with LT
versus best alternative therapy after successful downstaging (77.5% vs 31.2%;
HR,0.32; p=.035).[147] The key issues to explore are the upper tumor burden limits to
enter a downstaging protocol to reach effective transplantation and the post-treatment
criteria (Milan, UCSF) to fulfill for listing.[248] Optimal tumor/AFP thresholds, response
duration, and success definitions remain unsettled and preclude universal
recommendations.[249]

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Treatable Tumor Regression: Downsizing, Downstaging, and Conversion
Approach with Systemic Treatment
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Beyond locoregional strategies, systemic therapies are being investigated as tools to
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achieve tumor regression and potential downstaging. Downstaging with
immunotherapy has recently been explored, and early data are suggestive.[250,251]
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Prospective studies are needed to define intention-to-treat outcomes and safety.[133]

ICI exposure could increase rejection risk, particularly with a washout <30 days. A
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meta-analysis suggests at least a 3‑month interval.[252] Details of individual clinical

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reports, are summarized in SUP-A&B&C.

The concept of conversion approach—using systemic or combined treatment to
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achieve potential cure after major response—remains unproven and is categorized as

an alternative sequence in BCLC 2025. Most publications are case reports, with only
eight phase II trials and retrospective series.[253–260] Reported conversion rates vary
(2–60%), reflecting heterogeneity in criteria, response assessment, and sequencing.
Prospective studies are needed to define baseline thresholds, treatment strategies,
response evaluation, and timing of clinical decisions.

End stage (BCLC-D)

Individuals with HCC who present with major cancer-related symptoms (ECOG PS
>2) or severe liver dysfunction and are not candidates for LT due to tumor burden or
non-oncologic contraindications, they have poor short-term survival.[2,261]

35
In selected scenarios, particularly when decompensation is potentially reversible—
such as HBV-related cirrhosis or alcohol-induced cirrhosis with sustained
abstinence—patients may achieve hepatic recompensation,[262–264] defined per
Baveno VII criteria.[44] Studies have shown that alcohol-related cirrhosis achieves
recompensation in approximately 15–20% of patients with sustained abstinence,
translating into a marked reduction in liver-related mortality.[265,266] In HBV-related
disease, antiviral therapy can induce recompensation in a substantial proportion of
patients.[267]
Recent data in HCV patients report recompensation rates ranging from 36% to 64%

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across cohorts.[268,269] Achieving recompensation is associated with improved

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prognosis and, in some cases, may allow re‑evaluation for systemic therapy or liver

progress while awaiting recompensation.

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transplantation. Prospective studies should define the extent to which the tumor may
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In practice, only 7% of patients meet Baveno VII criteria of recompensation supporting
our statement that most BCLC-D patients will not achieve recompensation, and for
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them tumor-directed therapy provides no meaningful survival benefit. Even when

considering expanded criteria, only up to 37% of patients qualify, and none of them
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had HCC,[20] and for them tumor-directed therapy provides no meaningful survival
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benefit. Therefore, the priority shifts to symptom control—for example, radiotherapy

for metastases[270]—along with supportive measures and coordinated palliative care.
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CUSE-tailored approach in BCLC-D patients

Patients receiving best supportive care represent a heterogeneous group, as some

are not true BCLC-D because of very advanced cancer stage or impaired liver
function, but earlier-stage cases managed conservatively due to comorbidities or
patient choice. Clear distinction is essential: whereas patients fulfilling the strict
definition of BCLC-D have a prognosis of median OS <3 months, while others may
experience longer survival (SUP-B). Hence, the expected median OS for BCLC-D in
Figure 4 has been revised to <12 months.

36
Conclusion
The 2025 BCLC update reflects the challenge of managing HCC within an expanding
yet uneven evidence base. CUSE addresses this need by providing open-access
staging and treatment support that adapts to evolving data. This version preserves the
simplicity of BCLC staging while embedding CUSE to guide individualized care in
today’s complex therapeutic landscape. As a conceptual framework, CUSE
implementation may vary across settings with different resources. Its strength is in
making uncertainty explicit and creating a shared language, while future studies
should assess its impact on clinical practice and outcomes. To support
implementation, the open-access platform (www.bclccuse.ai) has been developed as

f
a decision-support tool, grounded in the CUSE framework and designed to

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standardize the decision-making process.

Abbreviations:
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HCC: Hepatocellular Carcinoma; BCLC: Barcelona Clínic Liver Cancer; TACE:
Transarterial Chemoembolization; TARE: Transarterial Radioembolization; EBRT:
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External Beam Radiotherapy; ALBI: Albumin–Bilirubin; AFP: Alpha-Fetoprotein;

CUSE: Complexity, Uncertainty, Subjectivity, Emotion; CP: Child–Pugh; MELD: Model
na

for End-Stage Liver Disease; ECOG PS: Eastern Cooperative Oncology Group
ur

Performance Status; OS: Overall Survival; RFA: Radiofrequency Ablation; MW:

Microwave Ablation; LR: Liver Resection; LT: Liver Transplantation; MTM:
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Macrotrabecular-Massive; VETC: Vessels-Encapsulating Tumor Clusters; MC: Milan

Criteria; RCT: Randomized Controlled Trial; IPDM: individual patient data meta-
analyses; IPTW: Inverse-Probability of Treatment Weighting; PFS: Progression-Free
Survival; TTF: Time to Treatment Failure; DoR: Duration of Response; QALY/QALD:
Quality-Adjusted Life Year/Day; PPS: Post-Progression Survival; CPR: Complete
Pathological Response; DEB-TACE: Drug-Eluting Beads Transarterial
Chemoembolization; TAE: Transarterial Embolization; LAMWA: Laparoscopic
Microwave Ablation; UTP: Untreatable Progression; TSM: Treatment Stage Migration;
ICI: Immune Checkpoint Inhibitor; TKI: Tyrosine Kinase Inhibitor; RWD: Real-World
Data; irAEs: Immune-Related Adverse Events; UNOS-DS: United Network for Organ
Sharing–Downstaging;
HVPG: Hepatic Venous Pressure Gradient; SBRT – Stereotactic Body Radiation
Therapy.
37
Acknowledgements
English Editing Assistance: During the preparation of this work, the author(s) used
OpenAI’s ChatGPT (GPT-5, subscription version, temporary session) to improve the
fluency of the English language and enhance conciseness. The final version of the
manuscript was reviewed using this tool. After its use, the author(s) carefully revised
and edited the content, and take full responsibility for the final text.

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Figure legends

Figure 1a. CUSE approach: Framing Optimal, Person-Centered Decisions Amid

Uncertainty
69
The CUSE framework supports person-centered decision-making in HCC by
integrating four dimensions—Complexity (multifactorial disease and treatment
options), Uncertainty (ambiguous prognosis and evolving evidence), Subjectivity
(individual variability and preferences), and Emotion (previous experiences, hopes,
and personal beliefs/values)—with contextual factors such as values, regulations, and
health-system capacity.
The world map illustrates regional differences in contextual factors that shape the
implementation of CUSE globally.
Evidence tiers (right panel) span from no evidence to phase III trials with OS, ensuring

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safety at every level. CUSE advocates defining choices as ‘optimal’ rather than ‘best’

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when evidence is lacking—avoiding false certainty—and promotes explicit acceptance

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of uncertainty through time-bound, reviewable decisions with clear objectives. This
ensures that each person’s unique profile guides therapy beyond trial data alone.
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Figure 1b. CUSE framework process
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The CUSE process (co-designed) provides a structured pathway for clinical decision-
making in hepatocellular carcinoma. It involves: (1) establishing the goals of care; (2)
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assessing the clinical and social context, including hepatic reserve, performance
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status, frailty, comorbidities, deliverability, affordability, and caregiver capacity; (3)

evaluating the evidence by level of certainty and applicability, translating population
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data into person-level choices, and communicating options in plain language using
absolute numbers; (4) deliberating within the multidisciplinary team; (5) making a
shared decision documented with rationale and consent; and (6) iterating the plan to
reflect changing goals, clinical status, and evolving evidence, incorporating interim
decisions in ambiguous scenarios (e.g., time-limited therapy used in downstaging)
and predefined review points.

Figure 2. Accessing the BCLC Treatment Flowchart

Fig. 2. Accessing the BCLC Treatment Flowchart. A stepwise framework for staging
and prognostication in people with HCC. First, each person is assessed for
compensated cirrhosis; if cirrhosis is compensated, prognosis is guided primarily by
tumor biology and stage, and the person is classified as BCLC stage 0/A–D. If
cirrhosis is decompensated, prognosis reflects both residual liver function and tumor
70
burden. People who meet radiologic liver transplant (LT) criteria and have no
comorbid contraindications are considered for liver transplantation (BCLC 0/A–B).
Patients with decompensated cirrhosis who do not qualify for, or have
contraindications to, LT and do not achieve recompensation are referred for best
supportive care (BCLC-D). In all cases, significant cancer-related symptoms may
also place a person in BCLC-D, regardless of tumor burden. The dotted arrow
indicates that recompensation may allow re-entry into specific treatment pathways, in
line with the CUSE framework.

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Figure 3. Treatment-Stage Migration and CUSE-Defined Clinical Dilemmas

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Treatment-stage migration in HCC occurs when patients move between therapeutic

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categories due to factors such as comorbidities or age, feasibility constraints,
untreatable tumor progression, major treatment response, or patient decisions and
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values. These shifts give rise to clinical dilemmas that the CUSE framework seeks to
define and address. Comorbidities/Age, competing health conditions or advanced age;
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Feasibility, logistical or anatomical factors limiting intervention;

Untreatable Progression, disease advancement beyond current therapy’s scope;
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Major Response, substantial tumor regression prompting reconsideration of stage-

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appropriate care; Patient Decision/Values, individual preferences and life goals

guiding treatment choice.
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Figure 4. BCLC staging and treatment strategy in 2025.

The BCLC system establishes a prognosis in accordance with the 5 stages that are
linked to first-line treatment recommendation. The expected outcome is expressed as
median survival of each tumor stage according to the available scientific evidence.
Individualized clinical decision-making, according to the available data on August 5th,
2025, is defined by teams responsible for integrating all available data with the
individual patient’s medical profile. Note that liver function should be evaluated beyond
the conventional Child-Pugh score.
AFP, alpha-fetoprotein; ALBI, albumin-bilirubin; BCLC, Barcelona Clínic Liver Cancer;
BSC, best supportive care; CUSE approach, Complexity, Uncertainty, Subjectivity,
and Emotion factors involved in the clinical decision-making process.
EBRT, External Beam Radiotherapy; ECOG PS, Eastern Cooperative Oncology
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Group-performance status; LT, liver transplantation; MELD, model of end-stage liver
disease; TACE, transarterial chemoembolization; TARE, transarterial
radioembolization; ST, systemic therapy.
*Except for those with tumor burden acceptable for Transplant ^ Resection for single
peripheral HCC with adequate remnant volume should, when feasible, be performed
minimally invasively; çTACE is classified as non-ablative; & EBRT or resection may be
considered prior to systemic treatment in BCLC-A; #TACE, TARE, EBRT, resection,
or LT post-ICI after major response fall in this category.
Dotted arrow into the clinical decision-making chapter illustrates that treatment
sequences may occasionally bypass systemic therapy; however, this strategy is not a

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general recommendation and highlights the need for temporary decisions in the face

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of uncertainty and limited evidence.

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Figure 5. Limitations of Progression-Free Survival as a Surrogate for Overall
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Survival
The same PFS interval can herald very different outcomes depending on its defining
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event. In panel A PFS also ends with progression, but of an indolent pattern that does
not impact long-term survival (OS remains long), In panel B, PFS ends with disease
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progression that directly drives mortality, resulting in short OS. The hatched area in
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panel B represents edema or ascites, depending on the context. In panel C,

progression reflects aggressive tumor biology and is followed by rapid decline in OS.
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In panel D, PFS ends with treatment-related toxicity and death—completely

independent of tumor behavior—underscoring how event type conditions both patient
experience and the ultimate prognosis.
PFS, progression-free survival; OS, overall survival; RTP, radiologic tumor
progression
The hatched area in panel B represents perilesional edema or ascites, depending on
the context, and not cirrhosis complications per se.

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 f
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BCLC figures

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VERSION 2025

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22th October
 FIGURE 1A

Complexity Uncertainty Subjectivity Emotion

• Multifactorial • Prognosis uncertain • Individual variability • Previous experiences
• Multiple options • Evidence gaps • Personal interpretation • Personal hopes
• • Evolving standards • • Personal belief/values
BCLC-CUSE approach

Interdisciplinary Patient preferences

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Patient profile • RCT phase III - end point OS

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www.bclccuse.ai

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• RCT phase III - end point others

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• RCT phase II - end point OS

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• RCT phase II end point others
Values/Culture

Health system
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• Individual Data Metanalysis with OS
• Meta analysis with I2 < =50%

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Safety
•

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Prospective cohorts with OS
• Individual Data Metanalysis without OS
• RCT phase I or Prospective cohorts without OS
• Retrospective cohorts
• Meta analysis with I2 > 50%
• Case reports, case series
• No publication
Regulatory
RCT, Randomized Clinical Trials; i2, I-squared; OS, overall surival

CUSE, Complexity, Uncertainty, Subjectivity, and Emotion factors involved in Clinical-decision making process
 FIGURE 1B

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BCLCCUSE.AI

Values/Culture
FIGURE 2 HCC Diagnosis

What is the PROFILE of the patient?

Baveno VII criteria Yes PROGNOSIS DELINEATED
Compensated cirrhosis? Yes
Re-compensated
By HCC

No

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BCLC 0/A-D

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Clinical Decision-Making
No Meets the LT criteria?

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CUSE framework
(Complexity, Uncertainty, Subjectivity, and Emotion)

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PROGNOSIS DELINEATED
By LIVER FUNCTION

Yes

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Treatment Stage Migration
(Comorbidities, Feasibility,

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Untreatable progression, Major Response,
BCLC -D

Patient Decision)

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BSC Yes COMORBIDITIES that contraindicate LT?

No BCLC 0/A-B

CANDIDATE to LT? PROGNOSIS DELINEATED

No Yes
By LIVER FUNCTION and HCC

BSC, Best Supportive Care; LT, Liver Transplantation, HCC, Hepatocellular Carcinoma
CUSE, Complexity, Uncertainty, Subjectivity, and Emotion are factors involved in Clinical-decision making process
 Figure 3

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Treatment stage migration due to

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Comorbidities/Age/Frailty Feasibility/Availability Untreatable progression Major Response Patient Decision/Values

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Clinical Dilemmas defined by CUSE approach
FIGURE 4 HCC
Based on tumor burden, liver
Prognosis function and Very early stage (0) Early stage (A) Intermediate stage (B) Advanced stage (C) End stage (D)
physical status
Single ≤ 2cm nodule Single or ≤ 3 nodules, each ≤ 3 cm >3 nodules, or up to 3 nodules, with at least 1 > 3 cm Vascular invasion and/or Extrahepatic spread Any tumor burden
Refined by AFP, ALBI score, Preserved liver function*, PS 0 Preserved liver function*, PS 0 Preserved liver function*, PS 0 Any intrahepatic burden End stage liver function, PS 3-4
Preserved liver function, PS 0-2
Child-Pugh, MELD

Potential candidate for LT Single ≤ 3 nodules, Extended Well defined nodules, Diffuse, infiltrative,
Patient characterization

each ≤ 3 cm liver transplant preserved portal flow, extensive bilobar

criteria (size, AFP) selective access liver involvement
No Yes Portal pressure,
bilirubin

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To decide individualized
treatment approach Normal Increased^ Contraindication to LT

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Yes^ No

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1st Treatment Option Ablation Resection Ablation Transplant TACE Systemic Treatment BSC

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Expected Survival > 5 years > 2.5 years > 2 years < 1 year

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CUSE approach MW/RFA 1st Line Atezolizumab-Bevacizumab/Tremelimumab-Durvalumab/
www.bclccuse.ai TARE/EBRT Successful Camrelizumab-Rivoceranib/ Ipilimumab-Nivolumab
Downstaging/ If not feasible Sorafenib /Lenvatinib /Durvalumab/Tislelizumab
Clinical Decision-Making

TACE
Not feasible or failure Bridging therapy
(Complexity, Uncertainty, Regorafenib
Subjectivity, and Emotions) 2nd Line

feasible
(sorafenib-tolerant)

Not

Not feasible or failure

Post Sorafenib Cabozantinib
Not Ramucirumab
TACE/TARE & feasible or (AFP >/=400 ng/mL) Clinical
Treatment Stage Migration Not feasible failure Trials
or failure Post others 1st Line options

feasible
3rd Line

Not
Cabozantinib
(Comorbidities, Age, Frailty,
Feasibility, Availability
Untreatable progression,
Major Response, Patient Decision)
Alternative sequences upon major response or failure may be considered according to CUSE framework but have not been robustly proven#
denotes temporary decisions * Except when tumor burden is within LT criteria ^ Resection for single peripheral HCC with adequate remnant volume should, when feasible, be performed minimally invasively
under uncertainty
& EBRT or resection may be considered prior to systemic treatment in BCLC-A #TACE, TARE, EBRT, resection, or LT after major response fall in this category
FIGURE 5

Compensated Radiological tumor progression with

Death
liver cirrhosis
Preserved liver function
/no cirrhosis complications A PFS

Radiological Progression Death

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NO RTP or Response

B PFS

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Mild-moderate liver dysfunction

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Death

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Symptomatic Progression C PFS

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D PFS
Treatment-related death
Death

Evolutionary events along time