Dose-Dense Temozolomide for Newly Diagnosed Glioblastoma: A Randomized Phase III Clinical Trial
Open accessAbstract
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.
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- Authors
- Gilbert, M. R., Wang, M., Aldape, K. D., Stupp, R., Hegi, M. E., Jaeckle, K. A., Armstrong, T. S., Wefel, J. S., Won, M., Blumenthal, D. T., Mahajan, A., Schultz, C. J., Erridge, S., Baumert, B., Hopkins, K. I., Tzuk-Shina, T., Brown, P. D., Chakravarti, A., Curran, W. J., & Mehta, M. P.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2013-11-10
- Volume
- 31
- Issue
- 32
- Pages
- 4085-4091
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC3816958
- OpenAlex
- W2135947790
- Cited by
- 1,063
- References
- 25
- Citations by year
- 2026: 35 · 2025: 70 · 2024: 93 · 2023: 88 · 2022: 99 · 2021: 114 · 2020: 92 · 2019: 73 · 2018: 79 · 2017: 97 · 2016: 65 · 2015: 77 · 2014: 73 · 2013: 5 · 2012: 2
- FWCI
- 36.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- GlaxoSmithKline
- American Society of Clinical Oncology
- Novocure
- Accuray
- Genentech
- EMD Serono
- Pharmacyclics
- National Cancer Institute (P30CA016672, P30CA016058)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
- Keywords
- glioblastoma, MGMT promoter methylation, adjuvant chemotherapy, overall survival, progression-free survival, prognostic factors, chemotherapy toxicity, lymphopenia, newly diagnosed brain tumors
- MeSH terms
- Temozolomide, Aged, Brain Neoplasms, Dacarbazine, Female, Glioblastoma, Humans, Male, Middle Aged, DNA Modification Methylases, Proportional Hazards Models, Disease-Free Survival, Antineoplastic Agents, Alkylating, DNA Methylation, Tumor Suppressor Proteins, DNA Repair Enzymes, Kaplan-Meier Estimate, Chemoradiotherapy
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