Dihydropyrimidine dehydrogenase deficiency and fluorouracil-related toxicity

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of 5-fluorouracil (5-FU) catabolism. We report lymphocytic DPD data concerning a group of 53 patients (23 men, 30 women, mean age 58, range 36–73), treated by 5-FU-based chemotherapy in different French institutions and who developed unanticipated 5-FU-related toxicity. Lymphocyte samples (standard collection procedure) were sent to us for DPD determination (biochemical method). Among the whole group of 53 patients, 19 had a significant DPD deficiency (DD; below 150 fmol min−1 mg−1 protein, i.e. less than 70% of the mean value observed from previous population study). There was a greater majority of women in the DD group (15 out of 19, 79%) compared with the remaining 34 patients (15 out of 34, 44%, P<0.014). Toxicity was often severe, leading to patient death in two cases (both women). The toxicity score (sum of WHO grading, theoritical range 0–20) was twice as high in patients with marked DD (below 100 pmol min−1 mg−1 protein, n = 11, mean score = 13.2) compared with patients with moderate DD (between 150 and 100 pmol min−1 mg−1 protein, n = 8, mean score = 6.8), P = 0.008. In the DD group, there was a high frequency of neurotoxic syndromes (7 out of 19, 37%). The two deceased patients both had severe neurotoxicity. The occurrence of cardiac toxicity was relatively rare (1 out of 19, 5%). These data suggest that women are particularly prone to DPD deficiency and allow a more precise definition of the DD toxicity profile. © 1999 Cancer Research Campaig

Profound variation in dihydropyrimidine dehydrogenase activity in human blood cells: major implications for the detection of partly deficient patients

Dihydropyrimidine dehydrogenase (DPD) is responsible for the breakdown of the widely used antineoplastic agent 5-fluorouracil (5FU), thereby limiting the efficacy of the therapy. To identify patients suffering from a complete or partial DPD deficiency, the activity of DPD is usually determined in peripheral blood mononuclear cells (PBM cells). In this study, we demonstrated that the highest activity of DPD was found in monocytes followed by that of lymphocytes, granulocytes and platelets, whereas no significant activity of DPD could be detected in erythrocytes. The activity of DPD in PBM cells proved to be intermediate compared with the DPD activity observed in monocytes and lymphocytes. The mean percentage of monocytes in the PBM cells obtained from cancer patients proved to be significantly higher than that observed in PBM cells obtained from healthy volunteers. Moreover, a profound positive correlation was observed between the DPD activity of PBM cells and the percentage of monocytes, thus introducing a large inter- and intrapatient variability in the activity of DPD and hindering the detection of patients with a partial DPD deficiency. © 1999 Cancer Research Campaig

Phase II study of vinorelbine in patients with androgen-independent prostate cancer.

PURPOSE: To evaluate the efficacy and toxicity of vinorelbine in a phase II study in patients with progressive metastatic androgen-independent prostate cancer. PATIENTS AND METHODS: Forty-seven men with progressive metastatic prostate cancer refractory to first-line or second-line hormonal therapy were treated with vinorelbine, a semisynthetic vinca-alkaloid. Vinorelbine was given, on an outpatient schedule, at 25 mg/m2 weekly for at least eight weeks or until progression or excessive toxicity. RESULTS: Forty-seven patients were included in the study, 33 being evaluable for tumour response, 36 for response to PSA, 21 for clinical benefit and 45 for toxicity. Median actual weekly dose was 19 mg/m2 (range 12.0-26.2 mg/m2). Six of thirty-six patients (17%) demonstrated a biologic response with a 50% or more decline in serum PSA on two consecutive measurements taken at least two weeks apart. The median duration of biologic response was 2.7 months. Two of three patients with measurable disease obtained an objective response but remained unconfirmed. No change disease was reported in 23 patients (49%). On entry into the study, 30 patients had symptomatic bone pain and required narcotic or non-narcotic analgesics. Clinical benefit from vinorelbine was achieved in 15 patients out of 21 (32% of the intent to treat analysis population and 71% of the assessable patients). Due to the low number of questionnaires (QLQ-C30) filled in, it was insufficient to allow any statistical analysis. The median survival was 10.2 months. Toxicity was mainly haematologic with 51% of patients experiencing grade 3 or 4 granulocytopenia. Three patients developed deep vein thrombosis. Non-haematologic toxicity, mainly nausea and neurotoxicity, was mild. CONCLUSION: The administration of weekly vinorelbine appears to be a safe treatment for those patients with androgen-independent prostate cancer and poor prognosis features who require chemotherapy. These results provide data for future investigation of vinorelbine in combination regimens.Clinical TrialClinical Trial, Phase IIComparative StudyJournal ArticleMulticenter StudyRandomized Controlled TrialResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe