TY - JOUR
T1 - Dose-dense temozolomide for newly diagnosed glioblastoma
T2 - A randomized phase III clinical trial
AU - Gilbert, Mark R.
AU - Wang, Meihua
AU - Aldape, Kenneth D.
AU - Stupp, Roger
AU - Hegi, Monika E.
AU - Jaeckle, Kurt A.
AU - Armstrong, Terri S.
AU - Wefel, Jeffrey S.
AU - Won, Minhee
AU - Blumenthal, Deborah T.
AU - Mahajan, Anita
AU - Schultz, Christopher J.
AU - Erridge, Sara
AU - Baumert, Brigitta
AU - Hopkins, Kristen I.
AU - Tzuk-Shina, Tzahala
AU - Brown, Paul D.
AU - Chakravarti, Arnab
AU - Curran, Walter J.
AU - Mehta, Minesh P.
N1 - Funding Information:
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. The recent phase III randomized clinical trial performed by the European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) established the current standard of care for newly diagnosed GBM, which involves surgery or regional radiotherapy with concomitant temozolomide daily during the radiation therapy.1 Following completion of radiotherapy, patients undergo six cycles of single-agent temozolomide (5 days of a 28-day cycle). However, even with this treatment, the outcome for most patients with GBM remains grim, with a 2-year survival rate of only 27%.
Funding Information:
Mark R. Gilbert, GlaxoSmithKline, Genentech; Monika E. Hegi, MDxHealth; Terri S. Armstrong, Merck, Genentech.
Publisher Copyright:
© 2013 by American Society of Clinical Oncology.
PY - 2013/11/10
Y1 - 2013/11/10
N2 - 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.
AB - 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.
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U2 - 10.1200/JCO.2013.49.6968
DO - 10.1200/JCO.2013.49.6968
M3 - Article
C2 - 24101040
AN - SCOPUS:84891785971
SN - 0732-183X
VL - 31
SP - 4085
EP - 4091
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 32
ER -
