L. ZufÃa(1), A. Aldaz(1), A. Ortega(1), F. Calvo(2), J. Giráldez(1)
(1) Pharmacy Department, University Hospital of Navarra; (2) Oncology Department, Hospital General Universitario Gregorio Marañón
Tegafur (Ftorafur), 1-(tetrahydro-2-furanyl)-5-fluorouracil, a oral prodrug of 5-fluorouracil (known radiopotentiating agent in preclinical models), has an efficacy similar to that of intravenous 5-Fu. Clinical experiences have explored with success the feasibility, tolerance and tumor response rate of oral Tegafur administered simultaneously with preoperative radiotherapy in rectal cancer [ 1] .
Objectives: The aim of this study was to measure Tegafur and 5-Fu concentrations in tissues of rectal cancer patients treated with preoperative chemoradiation and to correlate drug concentrations with cancer downstanging effects. Also was conducted a little stability study.
Patients and methods: Three tissue samples of 16 patients with locally advanced rectal cancer treated with preoperative pelvic irradiation sensitized with oral Tegafur before surgery (5 to 6 weeks after the completion of chemoradiation) were analyzed. Seven patients received a precharge dose of Tegafur 24 hours before surgery. Tegafur and 5-Fu concentrations, were determined according to a high performance liquid chromatography (HPLC) method developed and validated by the pharmacokinetic laboratory of the Pharmacy Department at the University Hospital of Navarra [ 2] . Stability study of processed samples was investigated, as a requirement of the analytical method validation, by reinjecting the samples (hold at room temperature in the auto-injector) at different time intervals during 16 days.
Results: In eight of the nine patients without precharge dose was possible obtained detectable levels of Tegafur but only in one patient 5-Fu levels were detectables. In Tegafur pre-charged patients both Tegafur and 5-Fu were present in all tissue samples with exception of 2 fat samples. Both, Tegafur and 5-Fu levels were higher in tumor samples than other sites and show a clear tendency toward a correlation between degree of 5-Fu present in the residual tumor and cancer downstaging. Stability study showed a progressive increase of 5-Fu levels with time with no change in Tegafur values; so we hypothesize about the presence of a chemically labile metabolic intermediates that spontaneously cleave to 5-Fu.
Conclusion: A prospective study with a larger cohort of patients is necessary to confirm these results and to evaluate if tumor uptake of fluoropyrimidine could be a prognostic indicator of downstanging. Research should also be required to characterize the metabolic intermediates found in the stability study.
References:
[ 1] F.A. Calvo, M. Gomez-Espi, J.A. Diaz-Gonzalez, et al. Intraoperative presacral electron boost following preoperative chemoradiation in T3-4Nx rectal cancer: initial local effects and clinical outcome analysis. Radiother. Oncol. 2002; 62:201-06.
[ 2] L. Zufia, A. Aldaz, C. Castellanos, et al. Determination of 5-fluorouracil and its prodrug Tegafur in plasma and tissue by high-performance liquid chromatography in a single injection: validation for application in clinical pharmacokinetic studies. Ther. Drug Monit. 2003; 25:221-8.
Reference: PAGE 14 () Abstr 825 [www.page-meeting.org/?abstract=825]
Poster: poster