Critical Appraisal of Guideline Recommendations on Systemic Therapies for Advanced Hepatocellular Carcinoma: A Review
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Importance: The combination of immune checkpoint inhibitors with antiangiogenic agents has revolutionized the treatment landscape of advanced hepatocellular carcinoma (HCC). However, due to rapid publication of new studies that attained their predefined primary end points, a lack of robust cross-trial comparison of first-line therapies, and diverging clinical guidelines, no clear-cut treatment flowchart and sequence of therapies are available. This critical analysis of the recommendations for the management of advanced HCC from the main scientific societies in the US and Europe adopted an integrated approach to provide information on the clinical benefit (overall survival and progression-free survival) and safety profile of these therapies using the European Society for Medical Oncology (ESMO)–Magnitude of Clinical Benefit Scale (MCBS) score and an ad hoc network meta-analysis. Observations: There is a major consensus among guidelines that atezolizumab plus bevacizumab has a primacy as the recommended first-line treatment of choice in advanced HCC. On progression after immunotherapy-containing regimens and for patients with contraindications for immunotherapies, most guidelines maintain the established treatment hierarchy, recommending lenvatinib or sorafenib as the preferred options, followed by either regorafenib, cabozantinib, or ramucirumab. Thus far, the first-line immune-based regimen of tremelimumab plus durvalumab has been integrated only in the American Association for the Study of Liver Diseases guidance document and the latest National Comprehensive Cancer Network guidelines and has particular utility for patients with a high risk of gastrointestinal bleeding. Overall, in the first-line setting, both atezolizumab plus bevacizumab and sintilimab plus IBI305 (a bevacizumab biosimilar) and durvalumab plus tremelimumab received the highest ESMO-MCBS score of 5, indicating a substantial magnitude of clinical benefit. In a network meta-analysis, no significant differences in overall survival were found among the various combination regimens. However, the newly reported combination of camrelizumab plus rivoceranib was associated with a significantly higher risk of treatment-related adverse events compared with atezolizumab plus bevacizumab (relative risk, 1.59; 95% CI, 1.25-2.03; P < .001). Conclusions and Relevance: This narrative review found that atezolizumab plus bevacizumab is regarded as the primary standard of care for advanced HCC in the first-line setting. These findings from integrating the recommendations from scientific societies’ guidelines for managing advanced HCC along with new data from cross-trial comparisons may aid clinicians in decision-making and guide them through a rapidly evolving and complex treatment landscape.
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Effective systemic therapies, especially immune-checkpoint inhibitors, have substantially improved outcomes for patients with advanced-stage hepatocellular carcinoma.
“Over the past two decades, the development of effective systemic therapies has substantially improved the outcomes of patients with advanced-stage HCC2–6.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [6]
Approval of numerous new systemic agents for advanced HCC has left substantial knowledge gaps about optimal first-line regimen choice and sequencing after progression.
“the approval of numerous new systemic agents for advanced-stage HCC has left substantial knowledge gaps in choosing the optimal first-line regimen and the subsequent sequencing of these agents after disease progression6.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [6]
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“Consequently, multiple expert societies consistently recommend ICIs as first-line systemic therapy for unresectable HCC, unless contraindications are identified [12].”
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“It is important to note, however, that ICIs are currently only approved for use in patients with HCC in combination with other agents [117,118].”
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“To maximize the success of conversion therapy, current strategies frequently combine targeted therapies or ICIs with locoregional treatments such as TACE or hepatic arterial infusion chemotherapy (HAIC) [95].”
NOTCH1 Drives Sexually Dimorphic Immune Responses in Hepatocellular Carcinoma
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Self-citationMolecular Testing and Targeted Therapies in Hepatobiliary Cancers
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Current advances and future directions in combined hepatocellular and cholangiocarcinoma
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“…benefit, safety and accessibility, it is hard for clinical decision-makers to provide the recommendations only based on the published guidelines, 18 and which combination is the most affordable, that would place this treatment in a potential primacy consideration among all the approved…”
BackgroundThe assessment of impaired liver function and prognosis in hepatocellular carcinoma
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Management of Advanced Hepatocellular Carcinoma: A Review and Practical Guide
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Trial design and end points in hepatocellular carcinoma: an EASL–AASLD–ILCA consensus statement
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Self-citationHepatocellular carcinoma systemic treatment update: From early to advanced stage
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“…for patients with unresectable HCC who are unsuitable for locoregional therapy, including patients with intermediate-stage HCC who will not benefit from transarterial chemoembolization (TACE), such as infiltrative, diffuse, and extensive bilobar involvement, and those with advanced-stage HCC [3,4].”
Immunosenescence and immunotherapy in elderly patients with hepatocellular carcinoma
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Lapatinib: A Potential Therapeutic Agent for Colon Cancer Targeting Ferroptosis
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Targeting glypican-3 as a new frontier in liver cancer therapy
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Navigating second-line therapy after immunotherapy in advanced HCC☆
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“4,14,15 To address this gap, network meta-analyses have been employed to integrate direct and indirect comparisons, providing a more comprehensive estimation of treatment efficacy.”
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“However, retrospective studies are at risk of selection bias, and our results, although statistically signi fi cant, need to be validated by more rigorous prospective studies and randomized controlled trials [56, 57].”
Progress in the treatment of advanced hepatocellular carcinoma with immune combination therapy
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“1 6 Although Atezo/Bev combination therapy shows a strong effect, nearly 20% of treated patients show progressive disease (PD).”
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“Advanced-stage diagnosis and limitations of traditional therapies (surgery, radiation, chemotherapy) underscore the need for innovative treatments [2 – 4].”
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“Lenvatinib was recently approved as a targeted therapeutic agent for the management of advanced HCC (4).”
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“Systemic therapy is recommended as a standard first-line option [8], which includes immune checkpoint inhibitors plus molecular-targeted agents (ICI-MTA) and dual immune checkpoint inhibitors [9].”
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“These findings established lenvatinib as a first-line systemic therapy and the preferred tyrosine kinase inhibitor (TKI) for advanced-stage HCC [9].”
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“Systemic therapy for unresectable hepatocellular carcinoma (HCC) has advanced [1–3], involving immune checkpoint inhibitor (ICI)- based regimens for improved treatment outcomes [4–6].”
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Strategies to enhance the response of liver cancer to pharmacological treatments
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The Role of the MiR-181 Family in Hepatocellular Carcinoma
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“Among several factors that contribute to the resistance of Lenvatinib, CSC traits are often mentioned and are considered as one of most significant characteristics [26, 27].”
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“22 The results of a study based on the A+T regimen showed that lenvatinib was the preferred regimen after A+T treatment.”
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Self-citationThe versatile interplay between steatotic liver disease and liver cancer
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Prognostic impact of primary versus secondary resistance to sorafenib in patients with HCC
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Bevacizumab-Related Gastrointestinal Perforation in Hepatocellular Carcinoma Patient: A Case Report
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“In advanced HCC, atezolizumab plus bevacizumab is widely considered the first-line treatment of choice [1].”
Synergistic Strategies in Systemic Therapy for Advanced Hepatocellular Carcinoma
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“Sorafenib remains a foundational systemic therapy; however, its efficacy is limited by a low response rate [5, 6].”
Nuclear OXCT1 attenuates histone β-hydroxybutyrylation-mediated MHC-I transcription
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A real-world pharmacovigilance study of Sorafenib based on the FDA Adverse Event Reporting System
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“ICIs and combined anti-angiogenic medicines have changed the therapeutic strategy for advanced HCC [32–34].”
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“Hence, sorafenib remains a fi rst-line therapy option in patients with contraindications for immunotherapy [8, 9].”
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“However, despite the promise of this combination therapy, a substantial number of patients remain unresponsive or develop resistance, with some experiencing early tumor progression after treatment initiation, leading to poor prognoses [2,6,7].”
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“For instance, the pooled analyses for RRs showed I 2 values of 70% [Table 2] and 83% [Table 4], whereas PFS outcomes demonstrated I 2 values as high as 96 – 99% [Tables 3 and 5].”
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Errors in the Abstract, Table 1, Text, and Reference List
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“…5-fluorouracil (5-FU), sorafenib, lenvatinib, regorafenib, ramucirumab, and cabozantinib could decrease the incidence and mortality of liver cancer 7–9 , they cause fatigue, nausea, emesis, diarrhoea, cutaneous eruptions, hypertension induction, coagulopathies, and hepatic dysfunction 10–14 .”
Changes in nutritional status in hepatocellular carcinoma patients treated with sorafenib
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“Sorafenib, the first systemic standard for advanced HCC, confers only modest benefit [3].”
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Chen, Y., Fu, L., Song, P., Tan, Y., & Jin, Y. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1728098 · Cited by 1 · see citing works
“This pharmacologic distinction translates into differing toxicity pro fi les: hypertension, proteinuria, and gastrointestinal effects are more characteristic of lenvatinib, whereas RAF inhibition – related hyperkeratotic HFSR is more strongly associated with sorafenib-like agents (14).”
A three-gene resistome signature as a prognostic tool in hepatocellular carcinoma
Sánchez-Martín, A., Macı́as, R. I. R., Muñoz-Bellvís, L., González, L. M. A., Forner, A., Reig, M., Marin, J. J. G., & Briz, Ó. (2025) · Annals of Hepatology · doi:10.1016/j.aohep.2025.102179 · Cited by 1 · see citing works
Zhang, X., Kuang, J., Li, N., Pan, W., & Tang, B. (2026) · ACS Materials Letters · doi:10.1021/acsmaterialslett.5c01379 · Cited by 1 · see citing works
- Authors
- Cappuyns, S., Corbett, V., Yarchoan, M., Finn, R. S., & Llovet, J. M.
- Affiliations
- Universitair Ziekenhuis Leuven (BE)
- Tisch Cancer Institute (US)
- Johns Hopkins University (US)
- University of California, Los Angeles (US)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Venue
- JAMA Oncology
- Publisher
- American Medical Association (AMA)
- Published
- 2024-03-01
- Volume
- 10
- Issue
- 3
- Pages
- 395
- ISSN
- 2374-2437 (ISSN-L)
- PMC
- PMC10837331
- OpenAlex
- W4385514156
- Cited by
- 167
- References
- 60
- Citations by year
- 2026: 49 · 2025: 74 · 2024: 41 · 2023: 3
- FWCI
- 7.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA Oncology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Lirias (KU Leuven) (submittedVersion)
- Funders
- Belgian American Educational Foundation
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- Boston Scientific Corporation
- Exelixis
- Incyte
- Seagen
- Cancer Research UK (C9380/A268-13, A26813, 26813)
- Fundación Científica Asociación Española Contra el Cáncer (C9380/A26813)
- Generalitat de Catalunya (SGR‐1358, PID2019)
- Eisai
- Ministerio de Ciencia e Innovación (PID2019, PID2019-105378RB-I00)
- Associazione Italiana per la Ricerca sul Cancro (A26813, C9380/A26813)
- Vlaamse regering
- Ipsen
- National Institutes of Health (RO1DK56621)
- Genentech
- Agència de Gestió d'Ajuts Universitaris i de Recerca (SGR-1358)
- National Cancer Institute (P50CA062924, R01CA285544)
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK056621, R01DK056621, R01DK128289)
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- advanced hepatocellular carcinoma, systemic therapy, first-line therapy, immune checkpoint inhibitors, atezolizumab plus bevacizumab, lenvatinib, sorafenib, regorafenib, cabozantinib, ramucirumab, angiogenesis inhibitors
- MeSH terms
- Bevacizumab, Sorafenib, Carcinoma, Hepatocellular, Humans, Immunotherapy, Liver Neoplasms, Practice Guidelines as Topic
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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