Phase I study of 5-fluorouracil in children and young adults with recurrent ependymoma

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We report a phase I study to examine the pharmacokinetics, safety, and recommended dosage of weekly intravenous bolus 5-fluorouracil (5-FU) in children and young adults with recurrent ependymoma.


Patients 22 years of age or less with recurrent ependymoma were treated with bolus dosage 5-FU weekly for 4 weeks followed by a 2-week rest period, defining one cycle. Patients could continue on therapy for 16 cycles. The starting 5-FU dosage was 500 mg/m2. Dose-limiting toxicity was determined after one cycle. Patients were initially enrolled according to a rolling-6 design; subsequent dose re-escalation phase was based on a 3 + 3 design.


We treated patients at 400 (n = 6), 500 (n = 15), and 650 (n = 5) mg/m2, with de-escalation due to toxicity. Twenty-three of twenty-six patients enrolled were evaluable. Five patients experienced grade 4 neutropenia (n = 2: 650 mg/m2; n = 3: 500 mg/m2). One patient experienced grade 3 diarrhea. At 500 mg/m2, the median 5-FU maximal concentration, AUC0–∞, and alpha half-life were 825 µM, 205 µM × h, and 9.9 min, respectively. Interim analysis revealed an association between hematologic toxicity and prior number of chemotherapeutic regimens (P = .03). The study was amended to re-escalate the dosage in a less heavily pretreated cohort of patients.


These phase I clinical data provide initial pharmacokinetic parameters to describe i.v. bolus 5-FU disposition in children with recurrent ependymoma. Tumor exposures effective in preclinical testing can be achieved with tolerable bolus dosages in patients. Bolus 5-FU is well tolerated and possesses antitumor activity.

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