Dose-Dense Temozolomide for Newly Diagnosed Glioblastoma: A Randomized Phase III Clinical Trial

• Type of Material: Article
• Authors: Mark R. Gilbert, University of Texas MD Anderson Cancer Center; Meihua Wang, Radiation Therapy Oncology Group Statistical Center, Philadelphia, PA; Kenneth D. Aldape, University of Texas MD Anderson Cancer Center; Roger Stupp, Lausanne University Hospital; Monika E. Hegi, Lausanne University Hospital; Kurt A. Jaeckle, Mayo Clinic Florida; Terri S. Armstrong, University of Texas MD Anderson Cancer Center; Jeffrey S. Wefel, University of Texas MD Anderson Cancer Center; Minhee Won, Radiation Therapy Oncology Group Statistical Center, Philadelphia, PA; Deborah T. Blumenthal, Tel Aviv Medical Centre; Anita Mahajan, University of Texas MD Anderson Cancer Center; Christopher J. Schultz, Medical College of Wisconsin; Sara Erridge, University of Edinburgh; Brigitta Baumert, Maastricht University; Kristin I. Hopkins, University Hospital Bristol; Tzahala Tzuk-Shina, Rambam Medical Center, Haifa, Israel; Paul D. Brown, University of Texas MD Anderson Cancer Center; Arnab Chakravarti, Ohio State University; Walter Curran Jr, Emory University; Minesh Mehta, University of Maryland
• Language: English
• Date: 2013-11-10
• Publisher: American Society of Clinical Oncology
• Publication Version: Final Published Version
• Copyright Statement: © 2013 by American Society of Clinical Oncology.
• Final Published Version (URL): http://dx.doi.org/10.1200/JCO.2013.49.6968
• Title of Journal or Parent Work: Journal of Clinical Oncology
• Volume: 31
• Issue: 32
• Start Page: 4085
• End Page: +
• Grant/Funding Information: None declared
• Keywords: Therapy; Combination; Malignant glioma; MGMT; Oncology; Science & Technology; Recurrent; Cancer; Life Sciences & Biomedicine; Inactivation; Validation
• Research Categories: Health Sciences, Rehabilitation and Therapy; Biology, Cell; Health Sciences, Oncology; Health Sciences, Immunology

Abstract

Purpose: Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O6-methylguanine-DNA methyltransferase (MGMT) methylation status may be an important determinant of treatment response. Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM. Patients and Methods: This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of ≥ 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status. Results: A total of 833 patients were randomly assigned to either arm 1 or arm 2 (1,173 registered). No statistically significant difference was observed between arms for median OS (16.6 v 14.9 months, respectively; hazard ratio [HR], 1.03; P = .63) or median PFS (5.5 v 6.7 months; HR, 0.87; P = .06). Efficacy did not differ by methylation status. MGMT methylation was associated with improved OS (21.2 v 14 months; HR, 1.74; P < .001), PFS (8.7 v 5.7 months; HR, 1.63; P < .001), and response (P = .012). There was increased grade ≥ 3 toxicity in arm 2 (34% v 53%; P < .001), mostly lymphopenia and fatigue. Conclusion: This study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status. However, it did confirm the prognostic significance of MGMT methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated.