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Critical Appraisal of Guideline Recommendations on Systemic Therapies for Advanced Hepatocellular Carcinoma: A Review
Open accessAbstract
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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“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]
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“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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“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
Yu, Y., Jiang, Y., Yang, Y., Glandorff, C., Fang, W., & Sun, M. (2025) · Global Challenges · doi:10.1002/gch2.202500247 · Cited by 3
Yang, T., Han, Y., Wang, Y., Li, R.-Y., Zhang, X.-N., Zhang, X.-X., Xu, X., Xu, J., Li, X.-Y., Lin, C.-H., et al. (2026) · Journal of experimental & clinical cancer research : CR · doi:10.1186/s13046-025-03622-1 · Cited by 3
“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
Hu, Z., Lv, W., Wen, T., Sun, J., Ji, G., Ru, S., Sun, X., Wang, Z., Ren, H., Zhang, Y., et al. (2026) · Nature Chemical Biology · doi:10.1038/s41589-026-02229-7 · Cited by 3
A real-world pharmacovigilance study of Sorafenib based on the FDA Adverse Event Reporting System
Zhang, D., Cai, Y., Sun, Y., Zeng, P., Wang, W., Wang, W., Jiang, X., & Lian, Y. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1442765 · Cited by 3
Ma, X., & Qin, X. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1595653 · Cited by 3
Li, J., Liu, Y., Qiu, Y., Qu, C., & Li, J. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1487353 · Cited by 3
Zhou, Q., Li, R., Wu, S., Zhang, Y., Wang, W. J., Zhu, K., Wang, M., Huang, Z., & Duan, F. (2024) · La radiologia medica · doi:10.1007/s11547-024-01907-7 · Cited by 3
Liu, G., Guo, R., & Xu, J. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1520055 · Cited by 2
Wang, H., Zhang, X., Zhu, K., Jiang, S., Liu, T., Feng, R., Dou, X., Xu, L., He, J., Shi, F., et al. (2025) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359251334538 · Cited by 2
Luo, Y., Yang, Q., Qin, X., Yu, B., Jiang, S., & Liu, Y. (2025) · Molecular Imaging and Biology · doi:10.1007/s11307-025-02005-4 · Cited by 2
Zhang, Y., Shi, K., Li, Y., Liu, Y., Feng, Y., & Wang, X. (2025) · Chinese Journal of Integrative Medicine · doi:10.1007/s11655-025-3835-8 · Cited by 2
Yu, D., Chen, H., & Wang, L. (2025) · Cancer Reports · doi:10.1002/cnr2.70244 · Cited by 2
Li, Q., Wang, Y., & Zou, J. (2025) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-025-06300-z · Cited by 2
Li, H., Si, T., Li, R., Xie, X., Liu, Y., Fu, L., Bai, Y. Z., Yao, J., Zhang, X., Yang, M., et al. (2025) · Cancers · doi:10.3390/cancers17193235 · Cited by 2
“ICIs and combined anti-angiogenic medicines have changed the therapeutic strategy for advanced HCC [32–34].”
Shi, Y., Bai, Y., Wu, J., Yu, Y., Yang, X., Yang, H., Jian, W., & Qing, J. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1693028 · Cited by 2
Sabbioni, S., Guerriero, P., Shankaraiah, R. C., Masatti, L., Michilli, A., Bassi, C., D’Abundo, L., Moshiri, F., Siena, B. D., Simoni, E., et al. (2026) · Cell Death Discovery · doi:10.1038/s41420-026-02940-3 · Cited by 2
“Hence, sorafenib remains a fi rst-line therapy option in patients with contraindications for immunotherapy [8, 9].”
Li, H.-L., Zhou, H., Zhang, Y.-Y., Lai, J.-T., Zhou, Z.-Z., Huang, J.-Y., Guo, S., Wang, Y. F., Huang, W.-J., & Tian, X.-P. (2026) · Science China Life Sciences · doi:10.1007/s11427-025-3093-8 · Cited by 2
Tian, J., Pan, S., Wang, Y., Yu, Y., Wang, S., Shen, Y., Yang, L., Liu, X., Qiu, Q., Luan, J., et al. (2024) · Biomedicines · doi:10.3390/biomedicines12122769 · Cited by 2
“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].”
Naganuma, A., Makita, F., Sugimoto, R., Kikuchi, M., Furuta, K., Iwamoto, S., Sakamori, R., Kouno, H., Ario, K., & Yatsuhashi, H. (2024) · Clinical Nutrition ESPEN · doi:10.1016/j.clnesp.2024.12.005 · Cited by 2
Zhou, Q., Li, H., Ye, L., Li, R., Wang, X., Wang, W., Liu, M., Duan, F., & Huang, Z. (2025) · La radiologia medica · doi:10.1007/s11547-025-01975-3 · Cited by 2
Bahirwani, J. T., Ahuja, S. J. K., Changela, M., Patel, H. D., Patel, N., Kaneriya, M., & Patel, V. N. (2025) · Cancer Pathogenesis and Therapy · doi:10.1016/j.cpt.2025.04.003 · Cited by 2
“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].”
Köstek, O., Demirel, A., Hacıoğlu, M. B., Taştekin, D., Karabulut, S., Gündoğdu, A., Sever, N., Ayhan, M., Çelebi, A., Majidova, N., et al. (2024) · Journal of Chemotherapy · doi:10.1080/1120009x.2024.2305066 · Cited by 2
Errors in the Abstract, Table 1, Text, and Reference List
(2024) · JAMA Oncology · doi:10.1001/jamaoncol.2023.6378 · Cited by 2
Tu, H., Feng, S., Chen, L., Huang, Y., Zhang, J.-Z., Peng, S.-Y., Lin, D., & Ye, X. (2025) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v17.i5.105872 · Cited by 1
Yan, D., Guo, C., Wang, Y., & Wei, Y. (2025) · Biomedical Materials · doi:10.1088/1748-605x/adebd1 · Cited by 1
Cheng, J., Zheng, Q.-Y., Huang, Y.-L., Chen, Y., & Du, S. (2025) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2025.189406 · Cited by 1
Jiang, T., Shi, L., Peng, X., Zheng, S., Chen, Q., Lan, J., & Pan, W. (2025) · Scientific Reports · doi:10.1038/s41598-025-18875-1 · Cited by 1
“…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
Osmański, R., Mardas, M., Radomyski, P., Litwiniuk, M. M., & Stelmach-Mardas, M. (2025) · Supportive Care in Cancer · doi:10.1007/s00520-025-09975-9 · Cited by 1
Kuo, Y., Teng, W., Lin, P., Chen, Y., Su, C., Shen, E. Y.-L., Huang, B.-S., Wu, T., Cheng, J.-Y., Hsieh, Y., et al. (2025) · Liver International · doi:10.1111/liv.70465 · Cited by 1
“Sorafenib, the first systemic standard for advanced HCC, confers only modest benefit [3].”
Lin, L.-W., Chen, Q., Hu, H.-T., Zhou, G., Jin, Z.-C., Zhou, Y., Chen, J.-J., Ji, J., Zhu, X., Huang, M. X., et al. (2025) · International Journal of Surgery · doi:10.1097/js9.0000000000004144 · Cited by 1
Chen, Y., Fu, L., Song, P., Tan, Y., & Jin, Y. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1728098 · Cited by 1
“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
Zhang, X., Kuang, J., Li, N., Pan, W., & Tang, B. (2026) · ACS Materials Letters · doi:10.1021/acsmaterialslett.5c01379 · Cited by 1
Metadata
- 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
- 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
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