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Life sciences · Journal article
Frontiers in Oncology · October 16, 2026
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Introduction Patients with advanced solid tumors and severe hepatic dysfunction have limited systemic therapy options due to impaired drug metabolism and increased toxicity risks. This population is often excluded from clinical trials, leaving a critical treatment gap. This study evaluates the feasibility, safety, pharmacokinetics and efficacy of S-1, an oral prodrug of 5-fluorouracil (5-FU), plus cisplatin in these patients. Methods Between September 2016 and November 2023, 61 patients were enrolled into four cohorts based on hepatic function per NCI-ODWG criteria: normal (Cohort 1), mild (Cohort 2), moderate (Cohort 3), and severe dysfunction (Cohort 4). Primary endpoints were safety and 5-fluorouracil pharmacokinetics; secondary endpoints included objective response rate (ORR) and 3-month clinical benefit rate (3M-CBR). Results On Cycle 1 day 15, patients with severe hepatic dysfunction (Cohort 4) had lower 5-FU C max and longer T max than those with normal hepatic function (Cohort 1) (p<0.05), though 5-FU AUC remained comparable across cohorts. Safety in Cohort 4 were similar to those in Cohorts 1–3. No grade 5 treatment-related adverse events occurred. In Cohort 4, 22.2% achieved a partial response, 40.7% derived clinical benefit, and 22.2% maintained progression-free survival ≥6 months, providing preliminary evidence of clinical activity in this population. Conclusion Patients with severe hepatic dysfunction had similar 5-FU AUC and toxicities to those with less severe hepatic dysfunction, and preliminary evidence of clinical activity was observed with cisplatin + S-1. These findings provide prospective preliminary evidence that this combination may be feasible in selected patients with severe hepatic dysfunction, a population frequently excluded from clinical trials. Larger studies are needed to further define its safety, pharmacokinetics, and clinical activity in this population. (Clinical Trial Registration: NCT03519074. Retrospectively registered 08 May 2018).