{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T14:01:48Z","timestamp":1789999308755,"version":"4.0.1"},"reference-count":35,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Hepatocellular carcinoma (HCC) arises in the context of underlying cirrhosis in approximately 85% of cases, making hepatic reserve a major determinant of systemic treatment tolerance and clinical outcomes. Despite this, patients with impaired liver function but a life expectancy sufficient to potentially derive benefit from systemic therapy remain underrepresented in pivotal phase III trials, which enroll patients with well-preserved liver function (Child\u2013Turcotte\u2013Pugh [CTP] A). This discrepancy has created a substantial evidence gap, with treatment decisions in clinical practice relying on retrospective reports, small prospective trials, and observational registry data. Evidence Summary: Current evidence suggests that immune checkpoint inhibitors (ICIs) may represent a rational therapeutic approach in selected patients with impaired hepatic function, given their minimal dependence on hepatic metabolic pathways and the available safety and efficacy data in patients with CTP-A and ALBI grade 2\/3 or selected CTP-B disease. Cohort 5 of the CheckMate 040 nivolumab trial included selected patients with CTP-B7\/B8 disease and demonstrated modest efficacy, with an objective response rate of 12% and a median overall survival of 7.6 months. Additionally, the phase 3b single-arm SIERRA study reported a manageable safety profile for durvalumab plus tremelimumab (STRIDE regimen) in the CTP-B population. In contrast, regimens incorporating vascular endothelial growth factor (VEGF) inhibition, such as atezolizumab\u2013bevacizumab and tyrosine kinase inhibitors (TKIs), may require cautious use due to an increased risk of bleeding or hepatic decompensation. TKIs, including sorafenib, lenvatinib, regorafenib, and cabozantinib, are metabolized by hepatic CYP450 pathways and require careful patient selection, monitoring, and dose optimization. Among TKIs, sorafenib has the most robust observational evidence in patients with impaired liver function, although survival is reduced due to concurrent liver disease. Conclusions: Clinical management should prioritize assessment of hepatic reserve, including bilirubin, albumin, ascites, variceal bleeding risk, portal hypertension, and encephalopathy, alongside performance status. Systemic treatment selection should favor clinical trial enrollment when feasible or, alternatively, immunotherapy-based approaches in selected CTP-B patients, with close monitoring for decompensation. Decreased liver reserve represents a heterogeneous clinical state, and treatment benefits depend on maintaining treatment duration without precipitating hepatic decompensation. Future research must prospectively incorporate populations with impaired liver function to better define efficacy, safety, and endpoints related to hepatic deterioration in this high-risk group.<\/jats:p>","DOI":"10.3390\/cancers18183048","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T12:50:03Z","timestamp":1789995003000},"page":"3048","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Systemic Therapy for Advanced Hepatocellular Carcinoma with Impaired Liver Function: Navigating the Evidence Gap"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9024-6589","authenticated-orcid":false,"given":"Arathi","family":"Mohan","sequence":"first","affiliation":[{"name":"Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nataliya","family":"Razumilava","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Abraham","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maisha","family":"Anika","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8602-8309","authenticated-orcid":false,"given":"Oxana V.","family":"Crysler","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.jhep.2024.08.028","article-title":"EASL Clinical Practice Guidelines on the Management of Hepatocellular Carcinoma","volume":"82","author":"Sangro","year":"2025","journal-title":"J. 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