{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T02:58:59Z","timestamp":1791082739828,"version":"4.1.0"},"update-to":[{"DOI":"10.12688\/f1000research.145493.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T00:00:00Z","timestamp":1715040000000}}],"reference-count":105,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T00:00:00Z","timestamp":1715040000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns7:p>Advanced hepatocellular carcinoma (HCC) is traditionally associated with limited treatment options and a poor prognosis. Sorafenib, a multiple tyrosine kinase inhibitor, was introduced in 2007 as a first-in-class systemic agent for advanced HCC. After sorafenib, a range of targeted therapies and immunotherapies have demonstrated survival benefits in the past 5 years, revolutionizing the treatment landscape of advanced HCC. More recently, evidence of novel combinations of systemic agents with distinct mechanisms has emerged. In particular, combination trials on atezolizumab plus bevacizumab and durvalumab plus tremelimumab have shown encouraging efficacy. Hence, international societies have revamped their guidelines to incorporate new recommendations for these novel systemic agents. Aside from treatment in advanced HCC, the indications for systemic therapy are expanding. For example, the combination of systemic therapeutics with locoregional therapy (trans-arterial chemoembolization or stereotactic body radiation therapy) has demonstrated promising early results in downstaging HCC. Recent trials have also explored the role of systemic therapy as neoadjuvant treatment for borderline-resectable HCC or as adjuvant treatment to reduce recurrence risk after curative resection. Despite encouraging results from clinical trials, the real-world efficacy of systemic agents in specific patient subgroups (such as patients with advanced cirrhosis, high bleeding risk, renal impairment, or cardiometabolic diseases) remains uncertain. The effect of liver disease etiology on systemic treatment efficacy warrants further research. With an increased understanding of the pathophysiological pathways and accumulation of clinical data, personalized treatment decisions will be possible, and the field of systemic treatment for HCC will continue to evolve.<\/ns7:p>","DOI":"10.12688\/f1000research.145493.2","type":"journal-article","created":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T12:20:18Z","timestamp":1715084418000},"page":"104","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Hepatocellular carcinoma: Advances in systemic therapies"],"prefix":"10.12688","volume":"13","author":[{"given":"Trevor Kwan-Hung","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rex Wan-Hin","family":"Hui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lung-Yi","family":"Mak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Fung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wai-Kay","family":"Seto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7985-7725","authenticated-orcid":false,"given":"Man-Fung","family":"Yuen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2024,5,7]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"209-249","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.","volume":"71","author":"H Sung","year":"May 2021","journal-title":"CA Cancer J. 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It will provide a clear overview of the current status of expanding indications of systemic therapies.<\/b>  Response: Thank you for your\n<b> <\/b>helpful comment. We have added a table to provide description on the major trials on neoadjuvant, adjuvant and combination regimens. We agree that this will make it clearer for readers. (Table 3)  \n<b>Comment #2:&nbsp;There are real-world studies and meta-analyses comparing immunotherapy-based treatment with TKIs in both 1st line and 2nd line or beyond settings. Summarising these studies would enhance the manuscript.<\/b>  Response: Thank you for your comments. We have added a description on meta-analysis data about immunotherapy + TKI in 1\n<sup>st<\/sup> line\/ 2\n<sup>nd<\/sup> line settings. (Combination regimens involving immunotherapy section: last paragraph)  \n<b>Comment #3:&nbsp;Please distinguish between the STAH trial, which evaluated the efficacy of TACE plus sorafenib and did not show an extension in OS, and the LAUNCH trial, which evaluated the efficacy of TACE plus lenvatinib and confirmed an extension in OS, compared with each TKI monotherapy.<\/b>  Response: Thank you for your comments. We have now specifically mentioned the comparison between the STAH trial and the LAUNCH trial in our section on combination therapy. (Combination of systemic therapies with loco-regional therapy section: 3\n<sup>rd<\/sup> paragraph)  \n<b>Comment #4:&nbsp;Sorafenib, regorafenib, and lenvatinib also exhibit VEGF inhibition effects. Please modify the Figure 1 accordingly.<\/b>  Response: Thank you for your comments. We have updated Figure 1 accordingly.","URL":"https:\/\/f1000research.com\/articles\/13-104\/v2#referee-comment-11453","order":1,"name":"referee-comment-11453","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.165333.r274812, Shang-Chin Huang, National Taiwan University Hospital Beihu Branch, Taipei City, Taipei City, 16 May 2024, version 2, indexed","URL":"https:\/\/f1000research.com\/articles\/13-104\/v2#referee-response-274812","order":2,"name":"referee-response-274812","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.159449.r254024, Leonardo Stella, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Rome, 17 Apr 2024, version 1, 3 approved with reservations","URL":"https:\/\/f1000research.com\/articles\/13-104\/v1#referee-response-254024","order":3,"name":"referee-response-254024","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Man-Fung Yuen<\/b>; \n<i>Posted: 19 Apr 2024<\/i>; \n<b>On the other side, the review lacks of specific real-world data on systemic treatment in diverse patient subgroups, and authors should underline how comparative analysis of efficacy and safety among different therapies is also insufficient, limiting insights for treatment selection.<\/b>  Response: Thank you for your comments. We agree that there is a lack of real-world data in specific patient subgroups, and there is a lack of head-to-head studies between systemic therapy options. We have added additional discussion points in our article, highlighting the importance of further real-world data in guiding our treatment decisions. (Discussion section: Paragraph 1)  \n<b>Additionally, there's a call for deeper exploration of liver disease etiology's influence on treatment outcomes and the necessity for further research to elucidate optimal therapy utilization and long-term effects.<\/b>  Response: Thank you very much for your insightful comments. We agree that the role of liver disease etiology on treatment outcomes is a critical area of research. We have expanded our Discussion section to further discuss the role of disease etiology on HCC treatment outcomes, highlighting the need for mechanistic studies and real-life data in this area. (Discussion section: 2\n<sup>nd<\/sup> paragraph)  \n<b>There aren't major concerns. Some minor points are: - Authors should add last evidence on phase I\/II studies who are leading to upcoming phase III trial on double ICI + bevacizumab are lacking, so I suggest including recent studies about double ICI + anti-VEGF: *Tiragolumab + Atezolizumab\/Bevacizumab (Finn R, et. al., 2023 [Ref1 ]) *Relatlimab + Nivolumab\/Bevacizumab (Sangro B,&nbsp;et. al., 2023 [Ref 2])<\/b>  Response: Thank you for your comments. We have now added additional description about these 2 trials. (Combination regimens involving immunotherapy: 6\n<sup>th<\/sup> paragraph)  \n<b>- Authors should expand the paragraph about triple combination (locoregional + TKI + ICI), and to write down latest news about Chinese studies about HAIC + TKI + ICI.<\/b>  Response: Thank you for your comments, we have now expanded the paragraph on locoregional therapy + systemic therapy, and also included description on the Chinese studies on HAIC. (Combination of systemic therapies with loco-regional therapy section: 6\n<sup>th<\/sup> paragraph)","URL":"https:\/\/f1000research.com\/articles\/13-104\/v2#referee-comment-11455","order":4,"name":"referee-comment-11455","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The author(s) declared that no grants were involved in supporting this work","order":5,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}