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Drug Insight: temozolomide as a treatment for malignant glioma—impact of a recent trial

Nature Clinical Practice Neurology volume 1, pages 88–95 (2005)Cite this article

Abstract

Glioblastoma multiforme is the most common primary brain tumor in adults. Until recently, the standard of care consisted of maximal surgical resection followed by external beam radiotherapy. The role of adjuvant chemotherapy for newly diagnosed glioblastoma has been controversial; most of the numerous randomized phase III trials conducted over the past 40 years have failed to show a statistically significant and clinically meaningful survival advantage for patients randomized to the chemotherapy arm. Consequently, the choices of chemotherapeutics for patients with glioblastoma have been limited, and cytotoxic treatment regimens have usually included a nitrosourea. Temozolomide, a relatively new orally administered methylating agent, has demonstrable activity in glioma. A recent trial conducted under the auspices of the European Organization for the Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) has defined a role for temozolomide in the initial management of glioblastoma. A companion correlative tumor-biology study has identified epigenetic silencing of the promoter of the gene that encodes MGMT (O6-methylguanine-DNA methyltransferase) in tumor specimens as a strong and independent prognostic factor for survival among patients with a newly diagnosed glioblastoma, as well as a predictor of survival benefit from chemoradiotherapy with temozolomide. This review briefly summarizes the development of temozolomide as a therapy for patients with malignant brain tumors, emphasizing recent trials that have established a new standard of care for patients with glioblastoma and speculating on how these advances might influence future therapeutic investigations for malignant primary brain tumors.

Key Points

  • Glioblastoma multiforme is the most common primary brain tumor in adults, but there are limited chemotherapeutic options for patients with this condition

  • The orally administered methylating agent temozolomide has demonstrable activity in glioma, and a recent trial has defined a role for this drug in the initial management of glioblastoma

  • Temozolomide resistance is mediated by two distinct repair mechanisms: the MGMT (O6-methylguanine-DNA methyltransferase) suicide protein and DNA mismatch repair

  • MGMT promoter methylation is associated with superior survival in patients who receive combined temozolomide and radiotherapy for glioblastoma

  • The addition of temozolomide concurrently with radiotherapy—and adjuvantly thereafter—for newly diagnosed glioblastoma will undoubtedly become the new standard of care for most patients with this illness

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Figure 1: Kaplan–Meier estimates of overall survival in patients with glioblastoma, according to treatment group.
Figure 2: Kaplan–Meier estimates of progression-free survival in patients with glioblastoma, according to treatment group.

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Author information

Authors and Affiliations

  1. neuro-oncologist at Princess Margaret Hospital, and an associate professor of medicine at the University of Toronto, Ontario, Canada

    Warren P Mason

  2. professor and head of the Department of Clinical Neurosciences at the University of Calgary, Alberta, Canada

    J Gregory Cairncross

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  1. Warren P Mason
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  2. J Gregory Cairncross
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Corresponding author

Correspondence to Warren P Mason.

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Competing interests

Warren Mason is a speaker and consultant for Schering-Plough—the manufacturers of temozolamide. J Gregory Cairncross has received honoraria from and has participated in advisory boards for Schering-Plough.

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Mason, W., Cairncross, J. Drug Insight: temozolomide as a treatment for malignant glioma—impact of a recent trial. Nat Rev Neurol 1, 88–95 (2005). https://doi.org/10.1038/ncpneuro0045

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