Multicentre phase II and pharmacokinetic study of RFS2000 (9-nitro-camptothecin) administered orally 5 days a week in patients with glioblastoma multiforme

A phase II trial was instigated to investigate the antitumour activity, the safety and the pharmacokinetic parameters of RFS2000, a recently identified oral topoisomerase I inhibitor, given once daily (1.5 mg/m(2)/day) as first-line chemotherapy treatment for patients with advanced glioblastoma multiforme (GBM). Between 9 March and 15 September 2000, 17 patients were entered onto the trial. 15 patients were considered eligible. A total of 49 cycles (range 1-8) were administered. Grade 3-4 toxicity was observed in 5 patients. Neutropenia and thrombocytopenia were common toxicities. Pharmacokinetic analysis showed that 9-nitro camptothecin (9-NC) could be detected in the plasma and is progressively converted into 9-amino-camptothecin (9-AC). The response rate was poor, with 5 patients experiencing tumour stabilisation and 10 progressing. Thus, the results do not support the further evaluation of RFS2000 as a single agent in patients with recurrent GBM

Relationship between 5-fluorouracil exposure and outcome in patients receiving continuous venous infusion with or without concomitant radiotherapy

What is already known about this subjectDihydropyrimidine dehydrogenase (DPD) deficiency is currently evaluated as a means of identifying patients with a risk of toxicity during 5-fluorouracil (5-FU) treatment.Therapeutic drug monitoring (TDM) is a complementary tool already shown to be useful for doses of 1000 mg m−2 day−1.We carried out the first analysis of the concentration – effect relationships of 5-FU administered at a dose of 600 mg m−2 day−1 with concomitant radiotherapy.What this study addsNo relationship was found between exposure and toxicity for 5-FU administered at a dose of 600 mg m−2 day−1 with concomitant radiotherapy.The use of TDM to improve tolerance to this treatment protocol is not supported by our data.This study confirms the existence of an exposure – toxicity relationship for a dose of 1000 mg m−2 day−1 and has developed a simplified sampling strategy to make TDM easier to implement with this dose schedule

Evaluation of predictive tests for screening for dihydropyrimidine dehydrogenase deficiency

5-Fluorouracil (5-FU) is rapidly degraded by dihyropyrimidine dehydrogenase (DPD). Therefore, DPD deficiency can lead to severe toxicity or even death following treatment with 5-FU or capecitabine. Different tests based on assessing DPD enzyme activity, genetic variants in DPYD and mRNA variants have been studied for screening for DPD deficiency, but none of these are implemented broadly into clinical practice. We give an overview of the tests that can be used to detect DPD deficiency and discuss the advantages and disadvantages of these test