title: A phase I trial of etanidazole and hyperfractionated radiotherapy in children with diffuse brainstem glioma.
abstract: OBJECTIVE
  To determine the toxicity and maximum tolerated dose of etanidazole administered concurrently with hyperfractionated radiation therapy (HRT) for children with brainstem glioma.
  
  
  METHODS
  Eighteen patients with brainstem glioma were treated with etanidazole and HRT on a dose escalation protocol (Phase I trial) between 1990 and 1996. All patients had MRI confirmation of diffuse pontine glioma and signs/symptoms of cranial nerve deficit, ataxia, or long tract signs of <6 months' duration. Cervicomedullary tumors were excluded. Patients (median age: 8.5 years; 11 males, 7 females) received HRT to the tumor volume plus a 2-cm margin with parallel-opposed 6-15-MV photons. The total dose was 66 Gy in 44 fractions (1.5 Gy b.i.d., with at least 6 h between fractions) for the first 3 patients and 63 Gy in 42 fractions for the subsequent 15 patients. Etanidazole was administered as a rapid i.v. infusion 30 min before the morning fraction of HRT. Planned doses of etanidazole were 1.8 g/m(2) x 17 doses (30.6 g/m(2)) at Step 1 to a maximum of 2.4 g/m(2) x 21 doses (50.4 g/m(2)) at Step 8. Dose escalation was planned with 3 patients at each of the 8 levels.
  
  
  RESULTS
  Three patients were treated at each dose level except Level 2, on which only 1 patient was treated. The highest dose level achieved was Level 7, which delivered a total etanidazole dose of 46.2 g/m(2). Two patients were treated at this level, and both patients experienced Grade 3 toxicity in the form of a diffuse cutaneous rash. Three patients received a lower dose of 42 g/m(2) (dose Level 6) without significant toxicity, and this represents the maximum tolerated dose (MTD). There were 23 cases of Grade 1 toxicity (10 vomiting, 5 peripheral neuropathy, 2 rash, 2 constipation, 1 weight loss, 3 others), 11 cases of Grade 2 toxicity (4 vomiting, 2 skin erythema, 2 constipation, 1 arthralgia, 1 urinary retention, 1 hematologic), and 4 Grade 3 toxicities (2 rash, 1 vomiting, 1 skin desquamation). Grade 2 or 3 peripheral neuropathy was not seen at any dose level. The median survival from the start of treatment was 8.5 months (range: 3-58 months).
  
  
  CONCLUSIONS
  The MTD of etanidazole in children receiving HRT for brainstem glioma is 42 g/m(2), with cutaneous rash as the dose-limiting toxicity. This is in contrast to the adult experience, which demonstrates a 24% lower MTD of 34 g/m(2) limited by peripheral neuropathy.
authors.affiliation: Department of Medicine, Division of Radiation Oncology, Children's Hospital, Boston, MA 02115, USA. KMARCUS@LROC.Harvard.edu
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Marcus
authors.forename: Sharon C
authors.initials: SC
authors.lastname: Dutton
authors.forename: Patrick
authors.initials: P
authors.lastname: Barnes
authors.forename: C Norman
authors.initials: CN
authors.lastname: Coleman
authors.forename: Scott L
authors.initials: SL
authors.lastname: Pomeroy
authors.forename: Liliana
authors.initials: L
authors.lastname: Goumnerova
authors.forename: Amy L
authors.initials: AL
authors.lastname: Billett
authors.forename: Mark
authors.initials: M
authors.lastname: Kieran
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Tarbell
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001254:Astrocytoma / Q000188:drug therapy / Q000532:radiotherapy; D020295:Brain Stem Neoplasms / Q000188:drug therapy / Q000532:radiotherapy*; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D016371:Cranial Irradiation; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D004334:Drug Administration Schedule; D017341:Etanidazole / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000532:radiotherapy; D005910:Glioma / Q000188:drug therapy / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D011882:Radiotherapy, High-Energy; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D017341:Etanidazole