Prospective evaluation of combination oral S-1 and intravenous cisplatin in cancer patients with severe hepatic dysfunction – a feasibility, safety, and pharmacokinetic study
- 1Department of Haematology-Oncology, National University Cancer Institute
Abstract
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).
Related
- Mapping the subcellular pharmacokinetic-pharmacodynamic landscape: a systems-pharmacology framework for predicting combination therapies against intracellular bacterial infections
- Safety and Recovery Profile of Propofol-Based Intravenous Sedation for Endoscopic Retrograde Cholangiopancreatography in Adults: A Prospective Single-Center Observational Study
- High-Dose Intravenous Vitamin C and Mistletoe Therapy in Breast Cancer: A Prospective Cohort Study on Overall Survival in Palliative Care
- High-Dose Intravenous Vitamin C and Mortality and Organ Dysfunction in Severe Burn Injury
- Evaluation of the Efficacy and Safety of Combination Therapy of Vamha and Myrha in the Management of PMOS: An Open-Label, Randomized, Multicentre, Comparative, Prospective Clinical Study
BibTeX
@article{gwee2026prospective,
title = {{Prospective evaluation of combination oral S-1 and intravenous cisplatin in cancer patients with severe hepatic dysfunction – a feasibility, safety, and pharmacokinetic study}},
author = {Yong Xiang Gwee and Andrea Li Ann Wong and Boon Cher Goh and Ross Andrew Soo and Wei Peng Yong and David Shao Peng Tan and Cheng Ean Chee and Siew Eng Lim and Yvonne Ang and Yiqing Huang and Wan Qin Chong and Joline Lim and Gloria Chan and Natalie Ngoi and Samuel Ow and Rachel Wong and Kenneth Sooi and Joan Choo and Soo Chin Lee},
journal = {Frontiers in Oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.1948986},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1948986/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Prospective evaluation of combination oral S-1 and intravenous cisplatin in cancer patients with severe hepatic dysfunction – a feasibility, safety, and pharmacokinetic study
AU - Yong Xiang Gwee
AU - Andrea Li Ann Wong
AU - Boon Cher Goh
AU - Ross Andrew Soo
AU - Wei Peng Yong
AU - David Shao Peng Tan
AU - Cheng Ean Chee
AU - Siew Eng Lim
AU - Yvonne Ang
AU - Yiqing Huang
AU - Wan Qin Chong
AU - Joline Lim
AU - Gloria Chan
AU - Natalie Ngoi
AU - Samuel Ow
AU - Rachel Wong
AU - Kenneth Sooi
AU - Joan Choo
AU - Soo Chin Lee
PY - 2026
DA - 2026/10/16
JO - Frontiers in Oncology
DO - 10.3389/fonc.2026.1948986
UR - https://www.frontiersin.org/articles/10.3389/fonc.2026.1948986/full
AB - 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).
SN - 2234-943X
ER -