title: Recombinant mutant human tumor necrosis factor-alpha (TNF-SAM2) immunotherapy with ranimustine chemotherapy and concurrent radiation therapy for malignant astrocytomas.
abstract: BACKGROUND
  This study assessed the safety, tolerance and preliminary efficacy of a combination chemotherapy regimen consisting of ranimustine (MCNU) and recombinant human mutant tumor necrosis factor-alpha (TNF-SAM2) for patients with newly diagnosed supratentorial malignant astrocytomas.
  
  
  METHODS
  The initial regimens were prescribed as adjuvant therapy in conjunction with radiotherapy following standard surgical treatment. Ranimustine (MCNU) was administered intravenously at 100 mg/m2 on Day 1, i.e., at the onset of radiation therapy, and was followed by 80 x 10(4) U/m2 TNF-SAM2 intravenously from Day 3. TNF-SAM2 was prescribed weekly for up to 5 injections during the postoperative period concurrent with radiation therapy. TNF-SAM2 and MCNU were given each 8- to 12-week cycle until tumor progression was evident, or for a total of four cycles over a 1-year period. The primary end-points were safety and tolerability and the secondary end-point was overall survival.
  
  
  RESULTS
  Twenty-six consecutive eligible patients, including 5 with anaplastic astrocytoma (3 men and 2 women) and 21 with glioblastoma (13 men and 8 women), were treated. All of the 3 evaluable patients with anaplastic astrocytoma partially responded to treatment (PR), with a time to tumor progression (TTP) of 107 weeks and an estimated median survival time of 330 weeks. Of the 15 evaluable patients with glioblastoma, 8 (53.3%) showed no change in response to the treatment (NC), while 7 (46.7%) had progressive disease (PD), with a time to tumor progression (TTP) of 36 weeks and an estimated median survival time of 69 weeks. Although this regimen appeared to be safe, there was no improvement in response or survival time compared with a historical control of patients who received chemotherapy with MCNU alone in conjunction with radiotherapy for glioblastoma. Neither neurological toxicity, severe or life-threatening hematological toxicity, nor fatal toxicity (WHO Grade 4) was experienced.
  
  
  CONCLUSIONS
  These results suggest that combined chemotherapy with mutant TNF-alpha (TNF-SAM2) in this patient population seems to be safe and tolerable and may benefit those with anaplastic astrocytoma. These intriguing clinical observations warrant further evaluation to determine whether this approach can provide therapeutic benefits and improve survival.
authors.affiliation: Department of Neurosurgery, Fukuoka University School of Medicine, 45-1, 7-chome, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Fukushima
authors.forename: Masaaki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Shinya
authors.initials: S
authors.lastname: Oshiro
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tsugu
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Hirakawa
authors.forename: Gen-Ichiro
authors.initials: G
authors.lastname: Soma
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001254:Astrocytoma / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged; D009607:Nitrosourea Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; C109083:TNF-SAM2; D014409:Tumor Necrosis Factor-alpha; C020766:ranimustine