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, Minesh P. Mehta

Research output: Contribution to journalArticle

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Abstract

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. 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. 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. 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.

Original languageEnglish (US)
Pages (from-to)4085-4091
Number of pages7
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology
Volume31
Issue number32
StatePublished - Nov 10 2013

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temozolomide
Phase III Clinical Trials
Glioblastoma
Methyltransferases
Randomized Controlled Trials
DNA Methylation
Disease-Free Survival
Survival
Methylation
O(6)-Methylguanine-DNA Methyltransferase
Neoplasms
Lymphopenia
DNA
Standard of Care
Fatigue
Blood Cells
Radiotherapy

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Gilbert, M. R., Wang, M., Aldape, K. D., Stupp, R., Hegi, M. E., Jaeckle, K. A., ... Mehta, M. P. (2013). Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 31(32), 4085-4091.

Dose-dense temozolomide for newly diagnosed glioblastoma : a randomized phase III clinical trial. / Gilbert, Mark R.; Wang, Meihua; Aldape, Kenneth D.; Stupp, Roger; Hegi, Monika E.; Jaeckle, Kurt A.; Armstrong, Terri S.; Wefel, Jeffrey S.; Won, Minhee; Blumenthal, Deborah T.; Mahajan, Anita; Schultz, Christopher J.; Erridge, Sara; Baumert, Brigitta; Hopkins, Kristen I.; Tzuk-Shina, Tzahala; Brown, Paul D.; Chakravarti, Arnab; Curran, Walter J.; Mehta, Minesh P.

In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Vol. 31, No. 32, 10.11.2013, p. 4085-4091.

Research output: Contribution to journalArticle

Gilbert, MR, Wang, M, Aldape, KD, Stupp, R, Hegi, ME, Jaeckle, KA, Armstrong, TS, Wefel, JS, Won, M, Blumenthal, DT, Mahajan, A, Schultz, CJ, Erridge, S, Baumert, B, Hopkins, KI, Tzuk-Shina, T, Brown, PD, Chakravarti, A, Curran, WJ & Mehta, MP 2013, 'Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial.', Journal of clinical oncology : official journal of the American Society of Clinical Oncology, vol. 31, no. 32, pp. 4085-4091.
Gilbert, Mark R. ; Wang, Meihua ; Aldape, Kenneth D. ; Stupp, Roger ; Hegi, Monika E. ; Jaeckle, Kurt A. ; Armstrong, Terri S. ; Wefel, Jeffrey S. ; Won, Minhee ; Blumenthal, Deborah T. ; Mahajan, Anita ; Schultz, Christopher J. ; Erridge, Sara ; Baumert, Brigitta ; Hopkins, Kristen I. ; Tzuk-Shina, Tzahala ; Brown, Paul D. ; Chakravarti, Arnab ; Curran, Walter J. ; Mehta, Minesh P. / Dose-dense temozolomide for newly diagnosed glioblastoma : a randomized phase III clinical trial. In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013 ; Vol. 31, No. 32. pp. 4085-4091.
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AU - Gilbert, Mark R.

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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

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N2 - 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. 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. 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. 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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