Onkologie. 2012:6(4):214-219

PK/PD of 5-fluorouracil during neoadjuvant chemoradiotherapy in locally advanced rectal carcinoma

Jiří Grim¹, Miloš Hroch², Jaroslav Chládek², Ondřej Slanař³, Jiří Petera¹, Jiřina Martínková²

¹ Klinika onkologie a radioterapie FN Hradec Králové

² Ústav farmakologie, UK v Praze, LF v Hradci Králové

³ Ústav farmakologie 1. LF UK a VFN, Praha

Background and Purpose: The main goal of the present study was to estimate the early patients´response following neoadjuvant

chemoradiotherapy (CHRT) based on 5-fluorouracil (5-FU) with curative aim in relation to plasma concentrations and pharmacokinetic

parameters of 5-FU. Secondary objectives included evaluation of the safety and tolerability of the regimen.

Patients and Methods: This open prospective study enrolles 34 adult patients with locally advanced rectal cancer, who received 5-FU

200 -1000 mg/m2 administered as a continuous i. v. infusion over 4–5 week and radiotherapy delivered with 10–15 MV photon beams

at 1.8 Gy/fraction up o 50.4 Gy in 28 daily fractions for 5 days a week. Surgical resection with curative aim followed 4–6 weeks after the

completion of CHRT and clinical restaging. Pathologic response evaluation and the rate of tumor regression was evaluated using tumor

downstaging by MR, histopathological staging, and expressed as residual disease (%).

Results and Conclusion: The outcome evidenced the correlation between the cumulative 5-FU dose and cumulative AUC of 5-FU

(r = 0.61; p < 0.001). The similar relationship was demonstrated between the cumulative AUC and metabolic ratio (the plasma concentration

od inactive metabolite dihydrofluotouracile 5-FUH2 to 5-FU; r = -0.80; p < 0.0001). The cumulative AUC was correlated with tumor

regression rate (r = -0.53; p < 0.005) and determined toxicity grade. To reach pCR, the daily dose of 5-FU in patient with average metabolic

ratio of 5-FUH2/5-FU should be >350 mg/m2 and the cumulative AUC1–39days > 50 mg/L*h. No mutation of gene for enzyme dihydropyrimidindehydrogenase

(DPD) and mutidrug resistance-1 protein (MDR-1) were identified, although the interindividual variability of

5-FU plasma concentration was high, also with regard to circadial 5-FU pharmacokinetics variability.

Keywords: neoadjuvant chemoradiotherapy, 5-fluorouracil, locally advanced rectal carcinoma, kinetically guided therapy

Published: October 1, 2012  Show citation