Purpose. 5-Fluorouracil is still the mainstay in adjuvant protocols for colorectal cancers, alone or in combination with other antineoplastic agents. Several studies have investigated the disease free survival (DFS) improvement after fluoropyrimidine-based adjuvant chemotherapy, despite data concerning the possible role of 5-FU exposure on DFS are not yet available. Therefore the aim of the present study was to evaluate any correlation between 5-FU pharmacokinetics, including that of the first inactive metabolite 5-fluoro-5,6-dihydrouracil (5-FDHU), and DFS in colorectal cancer patients candidate to receive 5-FU-based adjuvant chemotherapy. Experimental design. From January, 1997 to December, 1999, 85 consecutive colorectal cancer patients, 54 men and 31 women (mean±standard deviation age, 62.3±9.2 and 58.8±9.2 years, respectively), were enrolled. Planned treatment consisted of six cycles of L-leucovorin 100 mg/sqm and 5-FU 370 mg/sqm administered as iv boluses for 5 consecutive days every 4 weeks. Blood samples were withdrawn for up to 3 hours after drug administration on day 1 of the first cycle, and 5-FU and 5-FDHU plasma levels were determined by using a validated UV-HPLC method. Individual plasma concentrations of drug and catabolite were fit according to a 2-compartment open model with the use of APO2PR computer software (Mediware, Groeningen) and the area under the time/concentration curve (AUC) value was calculated. Staging of tumors according to Duke’s classification and their histological grade were recorded, as well as relevant clinical and laboratory information during the entire course of planned chemotherapy. Results. In this study, 41 patients (29 males and 12 females) experienced disease recurrence, and in 90% of them the disease recurred within 3 years of study entry. Tumor staging and histological grade did not affect significantly DFS among patients. On the contrary, pharmacokinetic analysis demonstrated a significant association between 5-FU exposure and DFS. In fact, 5-FU AUC and 5-FU/5-FDHU AUC ratio were significantly lower in patients who experienced a recurrence (7.37±3.54 hxmg/l and 0.73±0.33, respectively) compared to other subjects (9.09±4.13 hxmg/l and 0.96±0.59, respectively). Moreover, the planned chemotherapy was not completed in 17 patients: 8 out of them experienced a recurrence (median value, 88 days) and displayed a reduced 5-FU AUC mean value (6.53±3.16 hxmg/l), whereas the remaining 9 subjects did not (AUC value, 8.32±2.64 hxmg/l). Conclusions. Although the large interpatient variability observed in the present study, analysis performed on pharmacokinetic data demonstrate that reduced 5-FU AUC values are significantly associated with decreased DFS in colorectal cancer patients.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]