title: Preradiation chemotherapy of children and young adults with malignant brain tumors: results of the German pilot trial HIT'88/'89.
abstract: BACKGROUND
  Preradiation chemotherapy could be beneficial in malignant brain tumors, because the blood-brain tumor-barrier is disrupted after surgery, bone marrow recovery--essential for intense chemotherapy--is still intact, and CNS toxicity and ototoxicity of active drugs are lower before irradiation of a child's brain.
  
  
  METHODS
  A neoadjuvant phase 2 and a single arm pilot trial were initiated to investigate the efficacy and toxicity of an intense multidrug regimen before radiotherapy in 147 patients aged between 3 and 29; 9 years with medulloblastoma (94), malignant glioma (22), ependymoma (21), and stPNET (10). They were treated with one or two cycles consisting of procarbazine, ifosfamide/mesna with etoposide, high dose methotrexate/CF, and cisplatin with cytarabine.
  
  
  RESULTS
  Radiation therapy was delayed for 17-30 weeks (median 23 weeks) in 112 patients who received two cycles. Chemotherapy was well tolerated. Serious infections were observed in 20 patients, with one fatal fungal septicemia. In 69 high risk patients with a residual tumor and/or solid CNS metastases an objective response (CR plus PR) was achieved in 67% medulloblastoma, 57% stPNET, 55% anaplastic ependymoma and 25% malignant glioma. Progression-free survival (PFS) at 5 years was 57% in 14 high risk patients with medulloblastoma, who achieved a complete response (CR). After a less than CR the PFS was 20% (p = 0.01). Overall survival at 5 years was 57% in medulloblastoma, 62% in ependymoma, 36% in malignant glioma and 30% in stPNET.
  
  
  CONCLUSIONS
  The HIT'88/'89 regimen was well tolerated and efficacious in regard to response rates and early PSF particularly in medulloblastoma and anaplastic ependymoma. Based on these results the prospectively randomized trial HIT'91 was designed to investigate the optimal timing of chemotherapy. Preradiation chemotherapy according to the HIT'88/'89 regimen was compared with the standard regimen using CCNU, cisplatin, and vincristine after radiation therapy. Additionally, strict quality control of the three treatment modalities was instituted to help improve the survival rates in both trial arms.
authors.affiliation: Department of Pediatric Oncology University of Würzburg.
authors.forename: J
authors.initials: J
authors.lastname: Kühl
authors.forename: H L
authors.initials: HL
authors.lastname: Müller
authors.forename: F
authors.initials: F
authors.lastname: Berthold
authors.forename: R D
authors.initials: RD
authors.lastname: Kortmann
authors.forename: F
authors.initials: F
authors.lastname: Deinlein
authors.forename: E
authors.initials: E
authors.lastname: Maass
authors.forename: N
authors.initials: N
authors.lastname: Graf
authors.forename: A
authors.initials: A
authors.lastname: Gnekow
authors.forename: W
authors.initials: W
authors.lastname: Scheurlen
authors.forename: U
authors.initials: U
authors.lastname: Göbel
authors.forename: J E
authors.initials: JE
authors.lastname: Wolff
authors.forename: M
authors.initials: M
authors.lastname: Bamberg
authors.forename: P
authors.initials: P
authors.lastname: Kaatsch
authors.forename: P
authors.initials: P
authors.lastname: Kleihues
authors.forename: D
authors.initials: D
authors.lastname: Rating
authors.forename: N
authors.initials: N
authors.lastname: Sörensen
authors.forename: O D
authors.initials: OD
authors.lastname: Wiestler
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020360:Neoadjuvant Therapy; D010865:Pilot Projects; D015996:Survival Rate