title: A multicenter phase I trial of combination therapy with interferon-β and temozolomide for high-grade gliomas (INTEGRA study): the final report.
abstract: Our previous study demonstrated that interferon-β markedly enhanced chemosensitivity to temozolomide; one of the major mechanisms is downregulation of O(6)-methylguanine DNA-methyltransferase transcription via p53 induction. This effect was also observed in an experimental animal model. The results of these studies suggest that compared to temozolomide-based chemotherapy performed concomitantly with radiotherapy, chemotherapy with interferon-β and temozolomide and concomitant radiotherapy might further improve the clinical outcomes of patients with malignant gliomas. A multicenter phase I clinical trial-the Integrated Japanese Multicenter Clinical Trial: a Phase I Study of Interferon-β and Temozolomide for Glioma in Combination with Radiotherapy (INTEGRA Study)-was conducted in patients with high-grade gliomas in order to evaluate the safety, feasibility, and preliminary clinical effectiveness of combination therapy with interferon-β and temozolomide. The primary endpoint was the incidence of adverse events. The exploratory endpoints were progression-free survival time and overall survival time. The study population comprised 16 patients with newly diagnosed and 7 patients with recurrent high-grade gliomas. Grades 3-4 leukocytopenia and neutropenia were observed in 6.7 and 13.3% of patients, respectively. Overall, 40% of patients showed an objective response to therapy. In patients with newly diagnosed glioblastoma, the median overall survival time was 17.1 months and the rate of 1-year progression-free survival was 50%. We conclude that this regimen is safe and well tolerated and may prolong survival of patients with glioblastoma. A phase II clinical study is essential to corroborate our findings.
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Wakabayashi
authors.forename: Takamasa
authors.initials: T
authors.lastname: Kayama
authors.forename: Ryo
authors.initials: R
authors.lastname: Nishikawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Naoya
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Jun
authors.initials: J
authors.lastname: Takahashi
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Aoki
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Sugiyama
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Ogura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Natsume
authors.forename: Jun
authors.initials: J
authors.lastname: Yoshida
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D016899:Interferon-beta / Q000008:administration & dosage / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D000077204:Temozolomide
chemical_list: D016899:Interferon-beta; D003606:Dacarbazine; D000077204:Temozolomide