Medline ® Abstracts for References 80-82
of 'Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management'
A dose-escalating study of oral eniluracil/5-fluorouracil plus oxaliplatin in patients with advanced gastrointestinal malignancies.
Yip D, Karapetis C, Strickland AH, Steer C, Holford C, Knight S, Harper P
Ann Oncol. 2003 Jun;14(6):864-6.
BACKGROUND: Oral eniluracil/5-fluorouracil (5-FU) was shown in early clinical studies to have promising activity against gastrointestinal malignancies. Oxaliplatin in combination with 5-FU also has activity against these tumour types. The primary objective of this study was to determine a tolerable dose for oral eniluracil/5-FU in combination with oxaliplatin.
PATIENTS AND METHODS: Twenty-three patients with advanced gastrointestinal malignancies were recruited into this open-label study. Patients received a fixed dose of oxaliplatin (130 mg/m(2) on the first day of a 21-day cycle), and the dose intensity of oral eniluracil/5-FU was gradually increased by escalating the number of days of treatment per course.
RESULTS: The maximum tolerated dose intensity was eniluracil/5-FU 10.0/1.0 mg/m(2) twice daily for 16 days in combination with oxaliplatin 130 mg/m(2) on the first day of a 21-day cycle. Dose-limiting toxicities included vomiting and diarrhoea. The objective tumour response rate was 26% with a median duration of response of 15.3 weeks (95% confidence interval 8.5-22.1). Twenty-two patients (96%) experienced neurotoxicity (sensory neuropathy or cold-related dysaesthesia), although only two events were severe (grade 3).
CONCLUSIONS: The recommended dose for future study in patients with advanced gastrointestinal cancer is 10.0/1.0 mg/m(2) oral eniluracil/5-FU twice daily for 14 days in combination with oxaliplatin 130 mg/m(2) on the first day of each treatment cycle.
Department of Medical Oncology, Guys Hospital, London, UK.
Pharmacokinetic and pharmacodynamic effects of oral eniluracil, fluorouracil and leucovorin given on a weekly schedule.
Guo XD, Harold N, Saif MW, Schuler B, Szabo E, Hamilton JM, Monahan BP, Quinn MG, Cliatt J, Nguyen D, Grollman F, Thomas RR, McQuigan EA, Wilson R, Takimoto CH, Grem JL
Cancer Chemother Pharmacol. 2003 Jul;52(1):79-85. Epub 2003 Apr 18.
PURPOSE: To determine the toxicities and pharmacokinetic effects of eniluracil (EU) given on two weekly dosing schedules with 5-fluorouracil (5-FU) and leucovorin (LV).
METHODS: A group of 26 patients received a single 24-h i.v. infusion of 5-FU 2300 mg/m(2) to provide a pharmacokinetic reference. After 2 weeks, patients received oral EU 20 mg plus LV 30 mg on days 1-3 with a single dose of 5-FU 15-29 mg/m(2) on day 2, or LV 30 mg on days 1-2 with a single dose of EU at least 1 h prior to 5-FU 29 mg/m(2) on day 2 weekly for 3 of 4 weeks.
RESULTS: Diarrhea was the most common dose-limiting toxicity. The recommended dose of 5-FU is 29 mg/m(2) per day. EU on either schedule decreased 5-FU plasma clearance by 48 to 52-fold, prolonged the half-life to>5 h, and increased the percentage of 5-FU excreted in the urine from 2% to 64-66%. With EU, plasma fluoro-beta-alanine was not detectedwhile urinary excretion was reduced to<1% of that seen with i.v. 5-FU alone. Marked increases in both plasma and urinary uracil were seen. Thymidylate synthase ternary complex formation was demonstrated in bone marrow mononuclear cells isolated 24 h after the first oral 5-FU dose; the average was 66.5% bound.
CONCLUSIONS: Either a single 20-mg dose of EU given prior to or for 3 days around the oral 5-FU dose led to comparable effects on 5-FU pharmacokinetic parameters, and inhibition of dihydropyrimidine dehydrogenase and thymidylate synthase.
National Cancer Institute-Navy Medical Oncology, Cancer Therapeutics Branch, Center for Cancer Research, National Naval Medical Center, Bethesda, MD 20889-5105, USA.
Eastern Cooperative Oncology Group phase II trial (E4296) of oral 5-fluorouracil and eniluracil as a 28-day regimen in metastatic colorectal cancer.
Marsh JC, Catalano P, Huang J, Graham DL, Cornfeld MJ, O'Dwyer PJ, Benson AB 3rd
Clin Colorectal Cancer. 2002 May;2(1):43-50.
Coadministration of eniluracil with 5-fluorouracil (5-FU) allows the oral absorption of small doses of 5-FU, resulting in therapeutic plasma levels. A phase II clinical trial of this combination using a continuous dosing schedule was carried out in patients with metastatic colorectal cancer. Fifty-three previously untreated patients and 46 patients who had received one prior regimen for metastatic disease were enrolled. Patients received 10 mg/m2 of eniluracil and 1 mg/m2 of 5-FU twice daily for 28 days, with cycles repeated after a 7-day rest until progression of disease or prohibitive toxicity. Seven of 53 previously untreated patients had an objective tumor response (13.2%): 1 complete response and 6 partial responses. The mean duration of response was 6.3 months. Only 1 of the 45 evaluable patients in the previously treated group had a partial response, with no complete responses. The duration of response was 3 months. The median progression-free survival was 3.4 months for the previously untreated group and 2.5 months for the previously treated group. Median overall survival was 11.1 months for the previously untreated group and 9.0 months for the previously treated group. Hematologic toxicity was infrequent, with 3 patients experiencing grade 3 toxicity. Incidence of grade 3/4 toxicity included 11 patients with diarrhea, 5 with nausea, and 4 with vomiting. Other common toxicities included anemia and stomatitis, but they were generally mild. This regimen is well tolerated and shows activity in previously untreated patients with metastatic colorectal cancer that is similar to that observed with other 5-FU-based regimens. This regimen has not shown to be effective in patients who have had prior chemotherapy.
Yale University School of Medicine, New Haven, CT, USA. firstname.lastname@example.org