title: Phase I and pharmacokinetic study of preirradiation chemotherapy with BCNU, cisplatin, etoposide, and accelerated radiation therapy in patients with high-grade glioma.
abstract: OBJECTIVE
  We conducted a Phase I study of bischloroethylnitrosourea (BCNU), cisplatin, and oral etoposide administered prior to and during accelerated hyperfractionated radiation therapy in newly diagnosed high-grade glioma. Pharmacokinetic studies of oral etoposide were also done.
  
  
  METHODS
  Patients started chemotherapy after surgery but prior to definitive radiation therapy (160 cGy twice daily x 15 days; 4800 cGy total). Initial chemotherapy consisted of BCNU 40 mg/m2 days 1-3, cisplatin 30 mg/m2 days 1-3 and 29-31, and etoposide 50 mg orally days 1-14 and 29-42, repeated in 8 weeks concurrent with radiation therapy. BCNU 200 mg/m2 every 8 weeks x 4 cycles was given after radiation therapy.
  
  
  RESULTS
  Sixteen patients, 5 with grade 3 anaplastic astrocytoma and 11 with glioblastoma were studied. Grade 3-4 leukopenia (38%) and thrombocytopenia (31%) were dose-limiting. Other toxicities were anorexia (81%), nausea (94%), emesis (56%), alopecia (88%), and ototoxicity (38%). The maximum tolerated dose was BCNU 40 mg/m2 days 1-3, cisplatin 20 mg/m2 days 1-3 and 29-31, and oral etoposide 50 mg days 1-21 and 29-49 prior to radiation therapy and repeated in 8 weeks with the start of radiation therapy followed by BCNU 200 mg/m2 every 8 weeks for 4 cycles. Median time to progression and survival were 13 and 14 months respectively. Responses occurred in 2 of 9 (22%) patients with evaluable disease. In pharmacokinetic studies, all patients achieved plasma concentrations of >0.1 microg/ml etoposide (the in vitro radiosensitizing threshold), following a 50 mg oral dose. The mean +/- SD 2 hr and 6 hr plasma concentrations were 0.92 +/- 0.43 microg/ml and 0.36 +/- 0.12 microg/ml, respectively. Estimated duration of exposure to >0.1 microg/ml etoposide was 10-17 hr.
  
  
  CONCLUSIONS
  Preirradiation chemotherapy with BCNU, cisplatin, and oral etoposide with accelerated hyperfractionated radiation therapy in high-grade gliomas is feasible and merits further investigation. Sustained radiosensitizing concentrations can be achieved with low oral doses of etoposide.
authors.affiliation: Division of Medical Oncology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
authors.forename: S V
authors.initials: SV
authors.lastname: Rajkumar
authors.forename: J C
authors.initials: JC
authors.lastname: Buckner
authors.forename: P J
authors.initials: PJ
authors.lastname: Schomberg
authors.forename: J M
authors.initials: JM
authors.lastname: Reid
authors.forename: P J
authors.initials: PJ
authors.lastname: Bagniewski
authors.forename: M M
authors.initials: MM
authors.lastname: Ames
authors.forename: T L
authors.initials: TL
authors.lastname: Cascino
authors.forename: R S
authors.initials: RS
authors.lastname: Marks
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001853:Bone Marrow / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D002330:Carmustine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D016019:Survival Analysis
chemical_list: D005047:Etoposide; D002945:Cisplatin; D002330:Carmustine