Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial

Mark R Gilbert, Meihua Wang, Kenneth D Aldape, Roger Stupp, Monika E Hegi, Kurt A Jaeckle, Terri S Armstrong, Jeffrey S Wefel, Minhee Won, Deborah T Blumenthal, Anita Mahajan, Christopher J Schultz, Sara Erridge, Brigitta Baumert, Kristen I Hopkins, Tzahala Tzuk-Shina, Paul D Brown, Arnab Chakravarti, Walter J Curran Jr, Minesh P Mehta, Mark R Gilbert, Meihua Wang, Kenneth D Aldape, Roger Stupp, Monika E Hegi, Kurt A Jaeckle, Terri S Armstrong, Jeffrey S Wefel, Minhee Won, Deborah T Blumenthal, Anita Mahajan, Christopher J Schultz, Sara Erridge, Brigitta Baumert, Kristen I Hopkins, Tzahala Tzuk-Shina, Paul D Brown, Arnab Chakravarti, Walter J Curran Jr, Minesh P Mehta

Abstract

Purpose: Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O(6)-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.

Trial registration: ClinicalTrials.gov NCT00304031.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
CONSORT diagram outlining accrual and eligibility. GBM, glioblastoma; IMRT, intensity-modulated radiotherapy.
Fig 2.
Fig 2.
Protocol schema. MGMT, O6-methylguanine-DNA methyltransferase; RPA, recursive partitioning analysis; RT, radiotherapy; TMZ, temozolomide.
Fig 3.
Fig 3.
Outcomes comparing standard and dose-dense temozolomide therapy. (A, B) Overall and progression-free survival for all randomly assigned patients. (C, D) Overall and progression-free survival for patients with O6-methylguanine-DNA methyltransferase (MGMT) unmethylated tumors. (E, F) Overall and progression-free survival for patients with MGMT methylated tumors. HR, hazard ratio.
Fig 4.
Fig 4.
Outcomes based on tumor O6-methylguanine-DNA methyltransferase (MGMT) methylation status. (A) Overall survival. (B) Progression-free survival. HR, hazard ratio.

Source: PubMed

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