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Continuous low-dose chemotherapy plus inhibition of cyclooxygenase-2 as an antiangiogenic therapy of glioblastoma multiforme

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Abstract

Purpose

Glioblastoma multiforme (GBM) represents the prototype of an angiogenic tumor. Recently, the continuous low-dose scheduling of chemotherapeutic drugs in combination with an inhibition of cyclooxygenase-2 (COX-2) has been suggested as a novel anti-angiogenic approach. The aim of this study was to evaluate the safety and activity of continuous low-dose temozolomide (TMZ) plus the COX-2 inhibitor rofecoxib in patients with newly diagnosed GBM.

Methods

In vitro, endothelial cells were characterized by a tenfold higher sensitivity to TMZ than glioma cells. Consequently, a subgroup of patients with incompletely resected GBM (n=13) was divided into three groups aiming at a dose escalation to 1/10 of the daily MTD for TMZ: (A) TMZ 10 mg/m2 every third day and rofecoxib 25 mg/d; (B) TMZ 10 mg/m2/d and rofecoxib 25 mg/d; (C) TMZ 5 mg/m2 twice a day and rofecoxib 12.5 mg twice a day. COX-2, VEGF, VEGF Receptor-2, and CD34 were assessed immunohistochemically, in the clinical setting.

Results

The mean follow-up period was 15 months. We observed no severe toxicity attributable to the therapy. Quality of life was not impaired. For the whole study population, median time to progression and overall survival were 8 months and 16 months, respectively. Immunohistochemistry suggested that tumors with higher vessel densities were characterized by a significantly better control than those with lower vessel densities.

Conclusions

Continuous low-dose TMZ plus rofecoxib is feasible, safe, and maintains good quality of life. This study is indicative of an anti-angiogenic efficacy of continuous low-dose TMZ plus rofecoxib in GBMs, especially in those tumors that are characterized by a high angiogenic activity.

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Acknowledgements

We thank Violetta Powajbo and Alexandra Kappeler for excellent technical assistance. We are grateful to Ralf Weigel and Michael Diepers for their help with the volumetric analysis of MRI images. This study was supported by grants from the German Research Foundation (DFG VA151/4–2 and UL 60/4–2) and the 5th framework of the European Union (BMH4-CT95–0875).

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Authors and Affiliations

  1. Department of Neurosurgery, Klinikum Mannheim, Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1–3, 68167 Mannheim, Germany

    Jochen Tuettenberg, Tobias Korn, Ralf Erber & Peter Vajkoczy

  2. Department of Pathology, Medical Faculty of the University of Heidelberg, Mannheim, Germany

    Rainer Grobholz

  3. Department of Radiation Oncology, Medical Faculty of the University of Heidelberg, Mannheim, Germany

    Frederik Wenz

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  1. Jochen Tuettenberg
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  2. Rainer Grobholz
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  3. Tobias Korn
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  4. Frederik Wenz
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  5. Ralf Erber
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  6. Peter Vajkoczy
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Correspondence to Peter Vajkoczy.

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Tuettenberg, J., Grobholz, R., Korn, T. et al. Continuous low-dose chemotherapy plus inhibition of cyclooxygenase-2 as an antiangiogenic therapy of glioblastoma multiforme. J Cancer Res Clin Oncol 131, 31–40 (2005). https://doi.org/10.1007/s00432-004-0620-5

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  • DOI: https://doi.org/10.1007/s00432-004-0620-5

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