Association between circadian and chemotherapeutic cycle effects on plasma concentration of 5-fluorouracil and the clinical outcome following definitive 5-fluorouracil/cisplatin-based chemoradiotherapy in patients with esophageal squamous cell carcinoma.

Therapeutic drug monitoring (TDM) of 5-fluorouracil (5-FU) is believed to be a clinical option for improving clinical responses. Evaluating the potential factors contributing to plasma 5-FU concentration is important to develop TDM of 5-FU. Our aim was to evaluate the association of the circadian and treatment cycle effects on plasma 5-FU concentration with the clinical response. A population analysis was performed using the plasma concentration of 5-FU and clinical response data, including prognosis from 49 patients with esophageal squamous cell carcinoma after treatment with definitive 5-FU/cisplatin-based chemoradiotherapy, consisting of prolonged infusion of 5-FU at 400 mg/(m·day) for 5 days. The circadian rhythm and treatment cycle were applied as covariates to the model equation. The plasma 5-FU concentration in the evening was 1.3-fold higher compared with the morning, and in the second cycle, it was 1.5-fold increased compared with the first cycle, with relatively small inter-individual variations (23.3 and 16.8%). Clinical efficacy depended on the plasma 5-FU concentration, excluding the covariate effects (P=0.025), which correlated with age and height but not body surface area. Circadian variation did not contribute to the clinical response, and the increase in 5-FU plasma concentration in the second cycle significantly correlated with leucocyte counts obtained before chemoradiotherapy. The higher plasma concentration of 5-FU in the early phase of treatment may be the key determinant of clinical efficacy, whereas the variations in the plasma concentration of 5-FU owing to the time of day and treatment cycle are small contributors.