title: Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma.
abstract: OBJECTIVE
  This open-label, prospective, single-arm, phase II study combined erlotinib with radiation therapy (XRT) and temozolomide to treat glioblastoma multiforme (GBM) and gliosarcoma. The objectives were to determine efficacy of this treatment as measured by survival and to explore the relationship between molecular markers and treatment response.
  
  
  METHODS
  Sixty-five eligible adults with newly diagnosed GBM or gliosarcoma were enrolled. We intended to treat patients not currently treated with enzyme-inducing antiepileptic drugs (EIAEDs) with 100 mg/d of erlotinib during XRT and 150 mg/d after XRT. Patients receiving EIAEDs were to receive 200 mg/d of erlotinib during XRT and 300 mg/d after XRT. After XRT, the erlotinib dose was escalated until patients developed tolerable grade 2 rash or until the maximum allowed dose was reached. All patients received temozolomide during and after XRT. Molecular markers of epidermal growth factor receptor (EGFR), EGFRvIII, phosphatase and tensin homolog (PTEN), and methylation status of the promotor region of the MGMT gene were analyzed from tumor tissue. Survival was compared with outcomes from two historical phase II trials.
  
  
  RESULTS
  Median survival was 19.3 months in the current study and 14.1 months in the combined historical control studies, with a hazard ratio for survival (treated/control) of 0.64 (95% CI, 0.45 to 0.91). Treatment was well tolerated. There was a strong positive correlation between MGMT promotor methylation and survival, as well as an association between MGMT promotor-methylated tumors and PTEN positivity shown by immunohistochemistry with improved survival.
  
  
  CONCLUSIONS
  Patients treated with the combination of erlotinib and temozolomide during and following radiotherapy had better survival than historical controls. Additional studies are warranted.
authors.affiliation: University of California, San Francisco, CA 94143, USA. pradosm@neurosurg.ucsf.edu
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
authors.forename: Susan M
authors.initials: SM
authors.lastname: Chang
authors.forename: Nicholas
authors.initials: N
authors.lastname: Butowski
authors.forename: Rebecca
authors.initials: R
authors.lastname: DeBoer
authors.forename: Rupa
authors.initials: R
authors.lastname: Parvataneni
authors.forename: Hannah
authors.initials: H
authors.lastname: Carliner
authors.forename: Paul
authors.initials: P
authors.lastname: Kabuubi
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ayers-Ringler
authors.forename: Jane
authors.initials: J
authors.lastname: Rabbitt
authors.forename: Margaretta
authors.initials: M
authors.lastname: Page
authors.forename: Anne
authors.initials: A
authors.lastname: Fedoroff
authors.forename: Penny K
authors.initials: PK
authors.lastname: Sneed
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.forename: Michael W
authors.initials: MW
authors.lastname: McDermott
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Parsa
authors.forename: Scott
authors.initials: S
authors.lastname: Vandenberg
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Lamborn
authors.forename: David
authors.initials: D
authors.lastname: Stokoe
authors.forename: Daphne A
authors.initials: DA
authors.lastname: Haas-Kogan
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000069347:Erlotinib Hydrochloride; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy; D018316:Gliosarcoma / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy; D006801:Humans; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D003606:Dacarbazine; D000069347:Erlotinib Hydrochloride; D000077204:Temozolomide