S-1 as a core anticancer fluoropyrimidine agent.

Area of Science:

• Gastrointestinal Oncology
• Pharmacology
• Cancer Therapeutics

Background:

• 5-Fluorouracil (5-FU) is a cornerstone chemotherapy for gastrointestinal and other cancers.
• Infusional 5-FU regimens are standard, but oral prodrugs offer potential for improved efficacy and reduced side effects.

Purpose of the Study:

• To evaluate the efficacy and safety of S-1, an oral fluoropyrimidine prodrug, as an alternative to traditional 5-FU regimens.
• To explore the benefits of alternate-day S-1 administration in managing cancer treatment toxicity.

Main Methods:

• S-1, a combination prodrug including a dihydropyrimidine dehydrogenase (DPD) inhibitor (CDHP) and orotate phosphoribosyltransferase (OPRT) inhibitor (Oxo), was administered orally.
• Alternate-day dosing of S-1 was investigated to mitigate gastrointestinal and myelotoxicities.
• Pharmacokinetic profiles and adverse event rates were assessed.

Main Results:

• S-1 administration results in sustained high plasma 5-FU concentrations with minimal inter-patient variability.
• Specific components of S-1 (Oxo) reduce gastrointestinal toxicities, while low FBAL Cmax minimizes side effects like hand-foot syndrome and neurotoxicity.
• Alternate-day S-1 administration effectively reduces GI and myelotoxicities without compromising anticancer efficacy, allowing for prolonged treatment (6-12 months).
• S-1 is safe for patients with DPD deficiency.

Conclusions:

• Alternate-day S-1 administration is a recommended replacement for infusional 5-FU and other fluoropyrimidines.
• This oral regimen maintains or enhances 5-FU's anticancer efficacy and dose intensity.
• It offers a more tolerable and efficient treatment option for patients with GI malignancies.