title: Phase II study of high-dose chemotherapy before radiation in children with newly diagnosed high-grade astrocytoma: final analysis of Children's Cancer Group Study 9933.
abstract: BACKGROUND
  High-grade astrocytomas (HGA) carry a dismal prognosis and compose nearly 20% of all childhood brain tumors. The role of high-dose chemotherapy (HDCT) in the treatment of HGA remains unclear.
  
  
  METHODS
  In a nationwide study, The Children's Cancer Group (CCG) prospectively evaluated 102 children with HGA and postoperative residual disease for efficacy and toxicity of four courses of HDCT before radiotherapy (RT). Patients were randomly assigned to one of three couplets of drugs: carboplatin/etoposide (Regimen A), ifosfamide/etoposide (Regimen B), or cyclophosphamide/etoposide (Regimen C). After HDCT, all patients were to receive local RT followed by lomustine and vincristine. Twenty-six patients were excluded after central neuroradiographic review (n = 8) or pathology review (n = 18).
  
  
  RESULTS
  Of 76 evaluable patients (median age, 11.95 yrs; range, 3-20 yrs), 30 patients relapsed during HDCT, and 11 others did not complete HDCT because of toxicity. Nonhematologic serious toxicities were common (29%), and 21% of patients did not receive RT. Objective response rates were not associated with amount of residual disease and did not statistically differ between regimens: 27% (Regimen A), 8% (Regimen B), and 29% (Regimen C). Overall survival (OS) was 24% +/- 5% at 5 years and did not differ between groups. Median time to an event was longest for Regimen A (283 days compared with 83 and 91 days for Regimens B and C, respectively). The five-year, event-free survival (EFS) rate for all patients was 8% +/- 3% and 14% +/- 7% for Regimen A (P = 0.07).
  
  
  CONCLUSIONS
  OS and EFS were not affected by histologic grade. Patients who responded to HDCT had a nominally higher survival rate (P = 0.03 for trend). The authors conclude that these commonly used HDCT regimens provide no additional clinical benefit to conventional treatment in HGA, regardless of the amount of measurable residual tumor.
authors.affiliation: Department of Hematology-Oncology, Children's National Medical Center, Washington, DC 20010, USA. tmacdona@cnmc.org
authors.forename: Tobey J
authors.initials: TJ
authors.lastname: MacDonald
authors.forename: Edward B
authors.initials: EB
authors.lastname: Arenson
authors.forename: Joann
authors.initials: J
authors.lastname: Ater
authors.forename: Richard
authors.initials: R
authors.lastname: Sposto
authors.forename: Herbert E
authors.initials: HE
authors.lastname: Bevan
authors.forename: Janet
authors.initials: J
authors.lastname: Bruner
authors.forename: Melvin
authors.initials: M
authors.lastname: Deutsch
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kurczynski
authors.forename: Thomas
authors.initials: T
authors.lastname: Luerssen
authors.forename: Patricia
authors.initials: P
authors.lastname: McGuire-Cullen
authors.forename: Richard
authors.initials: R
authors.lastname: O'Brien
authors.forename: Narayan
authors.initials: N
authors.lastname: Shah
authors.forename: Paul
authors.initials: P
authors.lastname: Steinbok
authors.forename: John
authors.initials: J
authors.lastname: Strain
authors.forename: John
authors.initials: J
authors.lastname: Thomson
authors.forename: Emi
authors.initials: E
authors.lastname: Holmes
authors.forename: Gilbert
authors.initials: G
authors.lastname: Vezina
authors.forename: Allan
authors.initials: A
authors.lastname: Yates
authors.forename: Peter
authors.initials: P
authors.lastname: Phillips
authors.forename: Roger
authors.initials: R
authors.lastname: Packer
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D020295:Brain Stem Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D020360:Neoadjuvant Therapy / Q000379:methods; D009367:Neoplasm Staging; D011336:Probability; D011379:Prognosis; D011446:Prospective Studies; D011882:Radiotherapy, High-Energy; D012016:Reference Values; D018570:Risk Assessment; D013120:Spinal Cord Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome