title: Phase I/IIa trial of fractionated radiotherapy, temozolomide, and autologous formalin-fixed tumor vaccine for newly diagnosed glioblastoma.
abstract: OBJECTIVE
  Temozolomide (TMZ) may enhance antitumor immunity in patients with glioblastoma multiforme (GBM). In this paper the authors report on a prospective Phase I/IIa clinical trial of fractionated radiotherapy (FRT) concomitant with TMZ therapy, followed by treatment with autologous formalin-fixed tumor vaccine (AFTV) and TMZ maintenance in patients with newly diagnosed GBM.
  
  
  METHODS
  Twenty-four patients (age 16-75 years, Karnofsky Performance Scale score ≥ 60% before initiation of FRT) with newly diagnosed GBM received a total dose of 60 Gy of FRT with daily concurrent TMZ. After a 4-week interval, the patients received 3 AFTV injections and the first course of TMZ maintenance chemotherapy for 5 days, followed by multiple courses of TMZ for 5 days in each 28-day cycle.
  
  
  RESULTS
  This treatment regimen was well tolerated by all patients. The percentage of patients with progression-free survival (PFS) ≥ 24 months was 33%. The median PFS, median overall survival (OS), and the actuarial 2- and 3-year survival rates of the 24 patients were 8.2 months, 22.2 months, 47%, and 38%, respectively. The median PFS in patients with a delayed-type hypersensitivity (DTH) response after the third AFTV injection (DTH-2) of 10 mm or larger surpassed the median length of follow-up for progression-free patients (29.5 months), which was significantly greater than the median PFS in patients with a smaller DTH-2 response.
  
  
  CONCLUSIONS
  The treatment regimen was well tolerated and resulted in favorable PFS and OS for newly diagnosed GBM patients. Clinical trial registration no.: UMIN000001426 (UMIN clinical trials registry, Japan).
authors.affiliation: Department of Neurosurgery, Faculty of Medicine.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Ishikawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Muragaki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Maruyama
authors.forename: Koji
authors.initials: K
authors.lastname: Tsuboi
authors.forename: Soko
authors.initials: S
authors.lastname: Ikuta
authors.forename: Koichi
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Youji
authors.initials: Y
authors.lastname: Uemae
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ishihara
authors.forename: Masahide
authors.initials: M
authors.lastname: Matsuda
authors.forename: Masao
authors.initials: M
authors.lastname: Matsutani
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Karasawa
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakazato
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Abe
authors.forename: Tadao
authors.initials: T
authors.lastname: Ohno
authors.forename: Akira
authors.initials: A
authors.lastname: Matsumura
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000401:mortality / Q000628:therapy*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018572:Disease-Free Survival; D019583:Dose Fractionation, Radiation; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000401:mortality / Q000628:therapy*; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011878:Radiotherapy / Q000379:methods*; D015996:Survival Rate; D000077204:Temozolomide; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D019496:Cancer Vaccines; D003606:Dacarbazine; D000077204:Temozolomide
keywords: AFTV = autologous formalin-fixed tumor vaccine; CREIL Center = Critical Path Research and Education Integrated Leading; CTCAE = Common Terminology Criteria for Adverse Events; DTH = delayed-type hypersensitivity; FRT = fractionated radiotherapy; GBM = glioblastoma multiforme; IDH1 = isocitrate dehydrogenase-1; JBTRC = Japan Brain Tumor Reference Center; KPS = Karnofsky Performance Scale; MGMT = O6-methylguanine-DNA methyltransferase; MHC = major histocompatibility complex; MRC = Medical Research Council; OS = overall survival; PFS = progression-free survival; RPA = recursive partitioning analysis; TMZ = temozolomide; autologous formalin-fixed tumor vaccine; brain tumor immunotherapy; clinical trial; glioblastoma; oncology; temozolomide