4. PK/PD of 5-fluorouracil during neoadjuvant chemoradiotherapy in locally advanced rectal carcinoma
Abstract
Background and Purpose: The main goal of the present study was to estimate the early patientśresponse 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 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.