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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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Assessing the quality of reports of randomized clinical trials: Is blinding necessary?
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Sorafenib in advanced hepatocellular carcinoma
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Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma
Finn, R. S., Qin, S., Ikeda, M., Galle, P. R., Ducreux, M., Kim, T.-Y., Kudo, M., Breder, V., Merle, P., Kaseb, A. O., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1915745 · Cited by 7,470
Self-citationLlovet, J. M., Kelley, R. K., Villanueva, A., Singal, A. G., Pikarsky, E., Roayaie, S., Lencioni, R., Koike, K., Zucman-Rossi, J., & Finn, R. S. (2021) · Nature Reviews Disease Primers · doi:10.1038/s41572-020-00240-3 · Cited by 7,055
Self-citationA New Era of Systemic Therapy for Hepatocellular Carcinoma with Regorafenib and Lenvatinib
Kudo, M. (2017) · Liver Cancer · doi:10.1159/000462153 · Cited by 5,974
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Self-citationEASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma
European Association for the Study of the Liver, & European Organisation for Research and Treatment of Cancer (2012) · Journal of Hepatology · doi:10.1016/j.jhep.2011.12.001 · Cited by 5,218
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Research works printed but not linked: 1
- Genentech. Genentech’s Tecentriq plus avastin is the first treatment combination to reduce the risk of cancer returning in people with certain types of early-stage liver cancer in a phase III trial. Press release. January 18, 2023. Accessed February 16, 2023. https://www.gene.com/media/press-releases/14981/2023-01-18/genentechs-tecentriq-plus-avastin-is-the
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Singal, A. G., Kanwal, F., & Llovet, J. M. (2023) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-023-00825-3 · Cited by 1,029
Self-citationAdjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma
Llovet, J. M., Pinyol, R., Yarchoan, M., Singal, A. G., Marron, T. U., Schwartz, M., Pikarsky, E., Kudo, M., & Finn, R. S. (2024) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-024-00868-0 · Cited by 391
Self-citationHepatocellular carcinoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up
Vogel, A., Chan, S. L., Dawson, L. A., Kelley, R. K., Llovet, J. M., Meyer, T., Ricke, J., Rimassa, L., Sapisochín, G., Vilgrain, V., et al. (2025) · Annals of Oncology · doi:10.1016/j.annonc.2025.02.006 · Cited by 338
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Hepatitis B virus DNA integration: Implications for diagnostics, therapy, and outcome
Zoulim, F., Chen, P., Dandri, M., Kennedy, P. T. F., & Seeger, C. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.06.037 · Cited by 125
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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