EVALUATION OF PLASMA 5-FLUOROURACIL NUCLEOSIDE LEVELS IN PATIENTS WITH METASTATIC BREAST-CANCER - RELATIONSHIPS WITH TOXICITIES

This paper describes the relationship between 5-fluorouracil (FUra)-de rived toxicities and plasma levels of the FUra anabolites 5-fluorourid ine (FUrd) and 5-fluoro-2'-deoxyuridine (FdUrd) monitored in patients receiving continuous infusions of FUra (1000 mg/m(2) per 24 h) over 5 days preceded by the administration of cisplatin (100 mg/m(2)). A tota l of 63 courses of this treatment were given as second-line chemothera py to 17 patients with metastatic breast cancer. The active FUra anabo lites FUrd and FdUrd were monitored twice daily in the plasma by high- performance liquid chromatography. Data were analyzed using multiple a nalysis of variance (ANOVA). Only a low proportion of patients exhibit ed measurable plasmatic levels of FUrd (43%) and FdUrd (70%). The area s under the plasma concentration-time curves The areas under the plasm a concentration-time curves (AUC) determined over 120 h for FUrd (AUC( FUrd)) and for FdUrd (AUC(FdUrd)) were found to be statistically signi ficantly different for chemotherapy cycles with and those without myel osuppression. Chemotherapy cycles without neutropenia were associated with low AUC(FUrd) values (mean +/- SEM, 2.9 +/- 0.7 mu g ml(-1) h) an d high AUC(FdUrd) values (14.1 +/- 2.7 mu g ml(-1) h), respectively, w hereas courses with myelosuppression (WHO grades 2-4) showed inverse p rofiles with high AUC(FUrd) values (16.3 +/- 2.3 mu g ml(-1) h) and lo w AUC(FdUrd) values (3.1 +/- 1.0 mu g ml(-1) h), respectively. A stati stically significant difference in AUC(FdUrd) values was also observed between cycles with and those without mucositis (P = 0.0027), with AU C(FdUrd) values being 22.6 +/- 5.6 and 7.8 +/- 1.9 mu g ml(-1) h, resp ectively. Whereas hematotoxicity could be correlated with both AUC(FUr d) and AUC(FdUrd) values, mucositis was associated with high AUC(FdUrd ) levels. Moreover, a negative correlation was found between the AUCs determined for FUrd and FdUrd (P = 0.002), indicating that activation of FUra via FUrd or via FdUrd may involve competitive processes. There fore, to follow the development of the major FUra-derived toxicities, measurement of FUrd and FdUrd plasma levels appeared very attractive.