Pre-treatment serum total bilirubin level as an indicator of optimal CPT-11 dosage.

BACKGROUND: Irinotecan (CPT-11), a highly effective chemotherapeutic agent, can cause severe neutropenia and diarrhea. The area under the curve of plasma levels over time of SN-38, an active metabolite of CPT-11, was previously reported to correlate with the pre-treatment serum total bilirubin level (PTB). However, there are no established criteria for selecting CPT-11 dose on the basis of PTB. Therefore, we evaluated PTB as an indicator for the optimal CPT-11 dose. METHODS: Retrospective analyses were conducted in patients administered CPT-11 as a single agent at the Osaka National Hospital from June 2006 to July 2013. Data obtained during the first 28 days following CPT-11 administration were analyzed to compare PTB between patients with and without grade 3-4 neutropenia and grade 3-4 diarrhea. Receiver operating characteristics (ROC) curve analysis was performed to determine the optimal PTB cutoff value for PTB-associated toxicity. Subgroup analysis was performed comparing the incidence of toxicity in patients with PTB values below or above the cutoff value. RESULTS: Although PTB incidence was significantly higher in patients who developed grade 3-4 neutropenia than in those who did not, PTB was not associated with grade 3-4 diarrhea. The PTB cutoff value for association with grade 3-4 neutropenia occurrence was set at 0.8 mg/dL. The incidence of febrile neutropenia (FN) significantly elevated to 21% in patients with PTB ≥0.8 mg/dL, whereas that of patients with PTB <0.8 mg/dL was 4%. In the subgroup analysis, no difference was found in the neutropenia incidence between patients treated with a dose below 80 mg/m(2) and those treated on a weekly schedule. CONCLUSIONS: PTB can be used as a predictive marker of CPT-11-induced severe neutropenia and FN. In patients with PTB ≥0.8 mg/dL, the CPT-11 dose should be reduced to less than 80 mg/m(2) with weekly dosing.

[Combined determination of urine uracil levels and plasma 5-FU clearance for a simple order-made treatment with anticancer agents of FU derivative].

Individual differences exist in the pharmacodynamics of fluorouracil-derived anticancer agents, with circadian variability even in the same patient probably due to individual differences in the distribution of dihydrophrimidine dehydrogenase (DPD), a decomposing enzyme. Though DPD activity is usually determined in the liver or blood, a more simplified estimation of DPD activity has been recently attempted using urine uracil levels. However, because urine uracil level has the drawback of being easily affected by food ingestion or kidney function, in this study it was determined simultaneously with the determination of plasma 5-FU clearance after sustained instillation of 250 mg 5-FU, in order to estimate DPD activity more accurately. A correlation was observed between urine uracil levels and 5-FU clearance. In cases showing a baseline urine uracil level below 25.1 mumol/g. Creatinine, the blood concentration decreased due to large 5-FU clearance, with a tendency for diminished efficacy of FU-derived anticancer agents. In cases showing a baseline urine uracil level above 99.9 mumol/g. Creatinine, on the other hand, adverse reactions due to FU anticancer agents tended to become more serious. Since urine uracil level can be determined easily, it could be the first choice in screening to detect abnormal metabolism of fluorouracil-derived anticancer agents under present circumstances. By combining determination of urine uracil level with 5-FU clearance, it seems possible to predict adverse effects and the effective rate of these agents more accurately. Under existing circumstances, where genetic analysis remains unavailable as a general practice, the combined determination of urine uracil levels and plasma 5-FU clearance may be beneficial in developing order-made treatments in cancer chemotherapy.

[Support of TS-1, 5-FU preparation containing potent DPD inhibitor by determination of urinary uracil/serum 5-FU clearance].

Though FU-derived anticancer agents are metabolized and detoxicated by dihydropyrimidine dehydrogenase (DPD), its wide distribution of activity is concerned primarily in the antitumor effects or side effects of 5-FU. In recent years, it has become possible to predict the metabolism of FU-derived anticancer agents by DPD activity through the determination of urinary uracil levels. In the present study, therefore, we examined whether or not urinary uracil levels could be used as a predictor for as certaining the efficacy and/or side effects of TS-1, which contains a potent DPD inhibitor. Consequently, the following relationship was revealed to exist between urinary uracil levels and clinical effects of TS-1: 1) The effect of TS-1 administration was generally good in patients whose uracil level was within the standard values with no presentation of serious side effects. 2) The administration of TS-1 was also useful even in patients whose uracil levels were below the standard value. 3) Though no side effects were observed when a conventional FU-derived anticancer agent was administered to patients showing an urinary uracil level below the standard value, some side effects appeared when TS-1 was administered. Under present circumstances where understanding of genome diagnosis and establishment of informed consent are rather difficult, this approach of predicting DPD activities through the determination of urinary uracil levels seems to be of help for deciding a therapeutic regimen based on the patient's constitutional features when a cancer chemotherapy with TS-1 is performed.