Effect of dose-escalation of 5-fluorouracil on circadian variability of its pharmacokinetics in Japanese patients with Stage III/IVa esophageal squamous cell carcinoma

Abstract

Objective: The effects of dose-escalation of 5-fluorouracil (5-FU) on the clinical outcome and pharmacokinetics of 5-FU were investigated in Japanese patients with Stage III/IVa esophageal squamous cell carcinoma.Methods: Thirty-five patients with Stage III/IVa were enrolled, who were treated with a definitive 5-FU/cisplatin-based chemoradiotherapy. A course consisted of continuous infusion of 5-FU at 400 mg/m2/day (the standard dose group, N=27) or 500-550 mg/m2/day (the high dose group, N=8) for days 1-5 and 8-12, infusion of cisplatin at 40 mg/m2/day on days 1 and 8, and radiation at 2 Gy/day on days 1 to 5, 8 to 12, and 15 to 19, with a second course repeated after a 2-week interval. Plasma concentrations of 5-FU were determined by high performance liquid chromatography at 5:00 PM on days 3, 10, 38 and 45, and at 5:00 AM on days 4, 11, 39 and 46.Results and conclusions: No patient with Stage IVa achieved a complete response in the standard dose group, whereas a complete response was observed at a rate of 50% in the high dose group, and this can be explained by a higher plasma concentration of 5-FU. The circadian rhythm in the concentrations found at the standard dose was not observed for a higher dose.

Recombinant human endostatin combined with definitive chemoradiotherapy as primary treatment for patients with unresectable but without systemic metastatic squamous cell carcinoma of the oesophagus

“…The major acute toxicities reported were leukocytopaenia and oesophagitis. In the studies of 5-FU/ CDDP-based CRT, the rate of grade 3 and 4 leukopaenia ranged from 24% to 50% [20][21][22][23][24]. In this study, the rates of grade 3 and 4 leukopaenia in two groups were 25.0% (5/ 20) and 27.8% (5/18), respectively (p50.568), a significant improvement over earlier studies [20][21][22][23][24].…”

“…In the current study, the CR rate of 30% (6/20) in the CRTalone group was lower than 37.5%, and MST of 11.6 months in the CRT-alone group was also slightly lower than 12 months. The difference can be explained by a higher plasma concentration of 5-FU because the latter study modified the treatment schedule and increased the dose of 5-FU [22]. To improve both local and distant control in patients with unresectable but without systemic metastatic SCC of the oesophagus (T4 or Stage IVA), new regimens must be developed.…”

“…In the studies of 5-FU/ CDDP-based CRT, the rate of grade 3 and 4 leukopaenia ranged from 24% to 50% [20][21][22][23][24]. In this study, the rates of grade 3 and 4 leukopaenia in two groups were 25.0% (5/ 20) and 27.8% (5/18), respectively (p50.568), a significant improvement over earlier studies [20][21][22][23][24]. In the reports evaluating the effect of 5-FU/CDDP-based CRT, the rate of oesophagitis ranged from 10.0% to 37.5%.…”

“…Some of these have demonstrated that CRT was of significant benefit to the patients with unresectable but without systemic metastatic SCC of the oesophagus (T4 or Stage IVA) and concluded that these patients should not be excluded from potentially definitive and curative treatment [19][20][21][22][23][24][25]. For these patients a definitive 5-FU/CDDP-based CRT is one of the most promising ways to achieve a complete therapeutic response.…”

“…For these patients a definitive 5-FU/CDDP-based CRT is one of the most promising ways to achieve a complete therapeutic response. In the studies of chemoradiotherapy with 5-FU, CDDP and 60 Gy of radiotherapy, the CR rate ranged from 15.0% to 37.5%, with an MST of 9-12 months [20][21][22][23][24], but with significant toxicity. The differences in treatment outcomes are probably due to different doses of chemotherapeutic agents.…”