title: Phase I study of 5-fluorouracil in children and young adults with recurrent ependymoma.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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/m(2). 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.
  
  
  RESULTS
  We treated patients at 400 (n = 6), 500 (n = 15), and 650 (n = 5) mg/m(2), 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/m(2); n = 3: 500 mg/m(2)). One patient experienced grade 3 diarrhea. At 500 mg/m(2), 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.D.W., R.J.G., A.G.); Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (V.M.D., D.C.T., C.F.S); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (A.O.-T.); Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee (N.B., R.J.G.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (B.A.O.).
authors.forename: Karen D
authors.initials: KD
authors.lastname: Wright
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.D.W., R.J.G., A.G.); Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (V.M.D., D.C.T., C.F.S); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (A.O.-T.); Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee (N.B., R.J.G.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (B.A.O.).
authors.forename: Vinay M
authors.initials: VM
authors.lastname: Daryani
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.D.W., R.J.G., A.G.); Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (V.M.D., D.C.T., C.F.S); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (A.O.-T.); Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee (N.B., R.J.G.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (B.A.O.).
authors.forename: David C
authors.initials: DC
authors.lastname: Turner
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.D.W., R.J.G., A.G.); Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (V.M.D., D.C.T., C.F.S); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (A.O.-T.); Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee (N.B., R.J.G.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (B.A.O.).
authors.forename: Arzu
authors.initials: A
authors.lastname: Onar-Thomas
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.D.W., R.J.G., A.G.); Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (V.M.D., D.C.T., C.F.S); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (A.O.-T.); Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee (N.B., R.J.G.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (B.A.O.).
authors.forename: Nidal
authors.initials: N
authors.lastname: Boulos
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.D.W., R.J.G., A.G.); Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (V.M.D., D.C.T., C.F.S); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (A.O.-T.); Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee (N.B., R.J.G.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (B.A.O.).
authors.forename: Brent A
authors.initials: BA
authors.lastname: Orr
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.D.W., R.J.G., A.G.); Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (V.M.D., D.C.T., C.F.S); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (A.O.-T.); Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee (N.B., R.J.G.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (B.A.O.).
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.D.W., R.J.G., A.G.); Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (V.M.D., D.C.T., C.F.S); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (A.O.-T.); Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee (N.B., R.J.G.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (B.A.O.).
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.D.W., R.J.G., A.G.); Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (V.M.D., D.C.T., C.F.S); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (A.O.-T.); Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee (N.B., R.J.G.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (B.A.O.).
authors.forename: Amar
authors.initials: A
authors.lastname: Gajjar
mesh_terms: D000293:Adolescent; D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004806:Ependymoma / Q000188:drug therapy*; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil
keywords: 5-fluorouracil; pharmacokinetics; phase I; toxicity