A POPULATION STUDY OF DIHYDROPYRIMIDINE D EHYDROGENASE IN CANCER-PATIENTS

Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme of 5-fluor ouracil (5-FU) catabolism. The clinical importance of DPD has recently been demonstrated with the identification of severe and/or lethal 5-F U-related toxicity in patients with suspected or proven DPD deficiency revealed in lymphocytes. We conducted a prospective study on 185 canc er patients in order to evaluate the incidence of complete or partial DPD deficiency. The population comprised 152 men (mean age 62.1) and 3 3 women (mean age 59.2). Sixty eight were head and neck patients treat ed by a 5-day continuous infusion of 5-FU (starting dose 1 g/m(2)/day, with dose adaptation at mid-cycle) for which DPD activity was measure d 2-3 days before 5-FU administration (94 cycles analyzed). DPD activi ty was measured by a radioenzymatic assay using C-14-5-FU. DPD activit y showed a unimodal distribution, which globally fits a Gaussian distr ibution. Mean and median DPD activity were 0.222 and 0.211 nmol/min/mg prot respectively (range 0.065-559). No total DPD deficiency was foun d. Neither liver function nor age influenced DPD activity, but DPD act ivity was on average 15% lower in women than in men (0.194 and 0.228 n mol/min/mg prot respectively, p = 0.03). In patients treated with 5-FU , the risk of developing side effects was not linked to pretreatment D PD activity. 5FU-related toxicity was linked to FU systemic exposure. The correlation between DPD activity and FU clearance was weak (n = 90 , r = 0.31, p = 0.002). As a corollary, DPD activity in patients requi ring a dose reduction was not significantly different from DPD activit y in patients who did not require dose modification. From the present study it appears that total DPD deficiency is a very rare event. Altho ugh pre-treatment DPD activity cannot be a useful indicator for improv ing 5-FU dose adaptation strategy, the identification of partial DPD d eficiency (< 0.100 nmol/min/mg prot, 3% of the population) could lead to starting the treatment with a markedly reduce 5-FU dose.