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Evidence-Based Management of Hepatocellular Carcinoma: Systematic Review and Meta-analysis of Randomized Controlled Trials (2002–2020)
Open accessAbstract
Background & aims Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, with a rapidly changing landscape of treatments. In the past 20 years, numerous randomized controlled trials (RCTs) have aimed at improving outcomes across disease stages. We aimed to analyze the current evidence and identify potential factors influencing response to therapies.Methods We conducted a systematic review of phase III RCTs (2002-2020) across disease stages. A meta-analysis was designed to examine the relationship between etiology and outcome after systemic therapies with either tyrosine-kinase inhibitor (TKI)/antiangiogenic or immune checkpoint inhibitor (ICI) therapy.Results Out of 10,100 studies identified, 76 were phase III RCTs. Among them, a rigorous screening algorithm identified 49 with high quality including a total of 22,113 patients undergoing adjuvant (n = 7) and primary treatment for early (n = 2), intermediate (n = 7), and advanced (first-line, n = 21; second-line, n = 12) stages of disease. Nine of these trials were positive, 6 treatments have been adopted in guidelines (sorafenib [2 RCTs], lenvatinib, atezolizumab+bevacizumab, regorafenib, cabozantinib and ramucirumab), but 2 were not (adjuvant CIK cells and sorafenib plus hepatic arterial infusion with FOLFOX). Meta-analysis of 8 trials including 3739 patients revealed ICI therapy to be significantly more effective in patients with viral hepatitis compared with nonviral-related HCC, whereas no differences related to etiology were observed in patients treated with TKI/anti-vascular endothelial growth factor.Conclusions Among 49 high-quality RCTs conducted in HCC during 2002-2020, 9 resulted in positive results. A meta-analysis of systemic therapies suggests that immunotherapies may be more effective in viral etiologies.
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“those testing such approaches in HCC after potentially curative resection or local ablation have not yielded positive results over the preceding decades11.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [11]
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“In summary, most of the studies failed to identify any clinical benefit and, among the positive studies, validation in trials conducted in Western countries is awaited.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [11]
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“In KEYNOTE-240, OS benefits seem numerically greater in patients with HBV-HCC (HR 0.57 [0.35–0.94]) treated with pembrolizumab compared to placebo, while the HR of patients with non-viral HCCs was 0.88 (0.64–1.20) [46].”
From Etiology-Based Treatment for Unresectable/Advanced Hepatocellular Carcinoma: Focus on Viral Hepatitis and Metabolic Dysfunction-Associated Steatohepatitis (2025) · cites this paper as [46]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“In KEYNOTE-240, OS benefits seem numerically greater in patients with HBV-HCC (HR 0.57 [0.35–0.94]) treated with pembrolizumab compared to placebo, while the HR of patients with non-viral HCCs was 0.88 (0.64–1.20) [46].”
From Etiology-Based Treatment for Unresectable/Advanced Hepatocellular Carcinoma: Focus on Viral Hepatitis and Metabolic Dysfunction-Associated Steatohepatitis (2025) · cites this paper as [46]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“However, the HR for PFS was similar (0.70 [0.44–1.13] and 0.75 [0.56–1.01]) respectively.”
From Etiology-Based Treatment for Unresectable/Advanced Hepatocellular Carcinoma: Focus on Viral Hepatitis and Metabolic Dysfunction-Associated Steatohepatitis (2025) · cites this paper as [46]
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“in CheckMate-459, KEYNOTE-240, and COSMIC-312, the apparent reduced benefit from ICIs for patients with non-viral HCCs was likely a major cause for the negative OS outcomes, despite a clear benefit for patients with HBV-HCCs [27, 35, 46]”
From Etiology-Based Treatment for Unresectable/Advanced Hepatocellular Carcinoma: Focus on Viral Hepatitis and Metabolic Dysfunction-Associated Steatohepatitis (2025) · cites this paper as [46]
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“Results from other studies suggest that a metabolic-related fatty liver disease-related aetiology might be related to a decreased response owing to unique immunological traits hampering antitumoural surveillance11,101.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [11]
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“Only a small number of patients with HCV-HCC were recruited (15.5% of all).”
From Etiology-Based Treatment for Unresectable/Advanced Hepatocellular Carcinoma: Focus on Viral Hepatitis and Metabolic Dysfunction-Associated Steatohepatitis (2025) · cites this paper as [46]
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Liberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Gotzsche, P. C., Ioannidis, J. P. A., Clarke, M., Devereaux, P. J., Kleijnen, J., & Moher, D. (2009) · BMJ · doi:10.1136/bmj.b2700 · Cited by 17,648
Sorafenib in advanced hepatocellular carcinoma
Llovet, J. M., Ricci, S., Mazzaferro, V., Hilgard, P., Gane, E., Blanc, J.-F., de Oliveira, A. C., Santoro, A., Raoul, J.-L., Forner, A., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0708857 · Cited by 13,097
Self-citationEASL Clinical Practice Guidelines: Management of hepatocellular carcinoma
Galle, P. R., Forner, A., Llovet, J. M., Mazzaferro, V., Piscaglia, F., Raoul, J.-L., Schirmacher, P., & Vilgrain, V. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2018.03.019 · Cited by 11,406
Self-citationAtezolizumab 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
Mazzaferro, V., Regalia, E., Doci, R., Andreola, S. A., Pulvirenti, A., Bozzetti, F., Montalto, F., Ammatuna, M., Morabito, A., & Gennari, L. (1996) · New England Journal of Medicine · doi:10.1056/nejm199603143341104 · Cited by 7,173
Llovet, 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-citationCheng, A.-L., Kang, Y.-K., Chen, Z., Tsao, C.-J., Qin, S., Kim, J. S., Luo, R., Feng, J., Ye, S., Yang, T.-S., et al. (2009) · The Lancet Oncology · doi:10.1016/s1470-2045(08)70285-7 · Cited by 5,832
Sorafenib in Advanced Hepatocellular Carcinoma
정, 재. (2008) · Cited by 5,586
Kudo, M., Finn, R. S., Qin, S., Han, K.-H., Ikeda, K., Piscaglia, F., Baron, A., Park, J.-W., Han, G., Jassem, J., et al. (2018) · The Lancet · doi:10.1016/s0140-6736(18)30207-1 · Cited by 5,497
Marrero, J. A., Kulik, L., Sirlin, C. B., Zhu, A. X., Finn, R. S., Abecassis, M. M., Roberts, L. R., & Heimbach, J. K. (2018) · Hepatology · doi:10.1002/hep.29913 · Cited by 4,597
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AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma
Singal, A. G., Llovet, J. M., Yarchoan, M., Mehta, N., Heimbach, J. K., Dawson, L. A., Jou, J. H., Kulik, L. M., Agopian, V. G., Marrero, J. A., et al. (2023) · Hepatology · doi:10.1097/hep.0000000000000466 · Cited by 2,052
“[160] Despite higher rates of perioperative complications (post-hepatectomy liver failure, prolonged length of hospitalization) and morbidity, a meta-analysis of nine studies comparing outcomes of curative therapy in NAFLD and non-NAFLD HCC reported improved disease-free and OS after liver…”
Self-citationImmunotherapies for hepatocellular carcinoma
Llovet, J. M., Castet, F., Heikenwalder, M., Maini, M. K., Mazzaferro, V., Pinato, D. J., Pikarsky, E., Zhu, A. X., & Finn, R. S. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00573-2 · Cited by 1,843
Self-citationSingal, A. G., Kanwal, F., & Llovet, J. M. (2023) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-023-00825-3 · Cited by 1,029
Self-citationEvolving therapeutic landscape of advanced hepatocellular carcinoma
Yang, C. G., Zhang, H., Zhang, L., Zhu, A. X., Bernards, R., Qin, W., & Wang, C. (2022) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-022-00704-9 · Cited by 747
The liver cancer immune microenvironment: Therapeutic implications for hepatocellular carcinoma
Donné, R., & Lujambio, A. (2022) · Hepatology · doi:10.1002/hep.32740 · Cited by 659
Metadata
- Authors
- Haber, P. K., Puigvehí, M., Castet, F., Lourdusamy, V., Montal, R., Tabrizian, P., Buckstein, M., Kim, E., Villanueva, A., Schwartz, M., & Llovet, J. M.
- Affiliations
- Tisch Cancer Institute (US)
- Universitat Autònoma de Barcelona (ES)
- Hospital Clínic de Barcelona (ES)
- Hospital Universitari Arnau de Vilanova (ES)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Corresponding author
- Llovet, Josep M.
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2021-09
- Volume
- 161
- Issue
- 3
- Pages
- 879-898
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC12276942
- OpenAlex
- W3169705253
- Cited by
- 248
- References
- 82
- Citations by year
- 2026: 33 · 2025: 42 · 2024: 52 · 2023: 67 · 2022: 39 · 2021: 13
- FWCI
- 5.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion)
- Funders
- U.S. Department of Defense (CA150272P3)
- National Cancer Institute (P30 CA19652, R01 CK 128289-01)
- Samuel Waxman Cancer Research Foundation
- California Department of Fish and Game
- Agència de Gestió d'Ajuts Universitaris i de Recerca (SGR-1358)
- Ministerio de Ciencia e Innovación (SAF-2016-76390)
- Deutsche Forschungsgemeinschaft (HA 8754/1-1)
- Fundación Científica Asociación Española Contra el Cáncer
- Generalitat de Catalunya
- Asociación Española para el Estudio del Hígado
- Cancer Research UK
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Renal cell carcinoma treatment
- Keywords
- hepatocellular carcinoma, systemic therapy, tyrosine kinase inhibitors, immune checkpoint inhibitors, viral hepatitis etiology, sorafenib, lenvatinib, atezolizumab, bevacizumab, regorafenib, cabozantinib, ramucirumab, adjuvant therapy, treatment response
- MeSH terms
- Progression-Free Survival, Immune Checkpoint Inhibitors, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Hepatocellular, Humans, Immunotherapy, Liver Neoplasms, Neoplasm Staging, Time Factors, Randomized Controlled Trials as Topic, Chemoembolization, Therapeutic, Chemotherapy, Adjuvant, Clinical Trials, Phase III as Topic, Disease Progression, Radiopharmaceuticals, Evidence-Based Medicine, Neoadjuvant Therapy, Ablation Techniques
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