title: Phase 2 study of dose-intense temozolomide in recurrent glioblastoma.
abstract: BACKGROUND
  Among patients with glioblastoma (GBM) who progress on standard temozolomide, the optimal therapy is unknown. Resistance to temozolomide is partially mediated by O(6)-methylguanine-DNA methyltransferase (MGMT). Because MGMT may be depleted by prolonged temozolomide administration, dose-intense schedules may overcome resistance.
  
  
  METHODS
  This was a multicenter, phase 2, single-arm study of temozolomide (75-100 mg/m(2)/day) for 21 days of each 28-day cycle. Patients had GBM in first recurrence after standard therapy. The primary end point was 6-month progression-free survival (PFS6).
  
  
  RESULTS
  Fifty-eight participants were accrued, 3 of whom were ineligible for analysis; one withdrew before response assessment. There were 33 men (61%), with a median age of 57 years (range, 25-79 years) and a median Karnofsky performance score of 90 (range, 60-100). Of 47 patients with MGMT methylation results, 36 (65%) had methylated tumors. There were 7 (13%) partial responses, and PFS6 was only 11%. Response and PFS did not depend on MGMT status; MSH2, MLH1, or ERCC1 expression; the number of prior temozolomide cycles; or the time off temozolomide. Treatment was well tolerated, with limited grade 3 neutropenia (n = 2) or thrombocytopenia (n = 2).
  
  
  CONCLUSIONS
  Dose-intense temozolomide on this schedule is safe in recurrent GBM. However, efficacy is marginal and predictive biomarkers are needed.
authors.affiliation: Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, 450 Brookline Ave., Boston, MA 02215, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Norden
authors.forename: Glenn J
authors.initials: GJ
authors.lastname: Lesser
authors.forename: Jan
authors.initials: J
authors.lastname: Drappatz
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.forename: Samantha N
authors.initials: SN
authors.lastname: Hammond
authors.forename: Eudocia Q
authors.initials: EQ
authors.lastname: Lee
authors.forename: David R
authors.initials: DR
authors.lastname: Reardon
authors.forename: Camilo E
authors.initials: CE
authors.lastname: Fadul
authors.forename: Scott R
authors.initials: SR
authors.lastname: Plotkin
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
authors.forename: Jay-Jiguang
authors.initials: JJ
authors.lastname: Zhu
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.forename: Alona
authors.initials: A
authors.lastname: Muzikansky
authors.forename: Lisa
authors.initials: L
authors.lastname: Doherty
authors.forename: Debra
authors.initials: D
authors.lastname: Lafrankie
authors.forename: Katrina
authors.initials: K
authors.lastname: Smith
authors.forename: Vida
authors.initials: V
authors.lastname: Tafoya
authors.forename: Rosina
authors.initials: R
authors.lastname: Lis
authors.forename: Edward C
authors.initials: EC
authors.lastname: Stack
authors.forename: Myrna R
authors.initials: MR
authors.lastname: Rosenfeld
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D019175:DNA Methylation / Q000187:drug effects*; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015996:Survival Rate; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes; D000077204:Temozolomide
keywords: MGMT promoter methylation; dose-intense temozolomide; recurrent glioblastoma
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