Abstract
Glioblastoma multiforme (GBM) is the most common central nervous system malignancy. It is rapidly progressive with rare opportunity for cure. After three decades of laboratory and clinical research, a newly evolved chemoradiotherapy approach using the alkylating agent temozolomide during and after radiotherapy has resulted in the first significant impact on this disease. Here we discuss the basis for this positive interaction as well as potential mechanisms of resistance to it. Additionally, in the context of current and planned research, we explore approaches to take advantage of this combination and the use of targeted therapies to exploit cell signaling alterations found in GBM. We anticipate that a multimodality approach directed at tumor-specific biology will result in more meaningful advancements in the treatment of this fatal disease.
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References and Recommended Reading
Grossman SA, Batara JF:Current management of glioblastoma multiforme.Semin Oncol 2004,31:635–644.
Stupp R, Mason WP, van den Bent MJ, et al.:Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.N Engl J Med 2005,352:987–996.
Walker MD, Alexander E, Hunt WE, et al.:Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial.J Neurosurg 1978,49:333–343.
Fine HA, Dear KB, Loeffler JS, et al.:Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults.Cancer 1993,71:2585–2597.
Stewart LA:Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials.Lancet 2002,359:1011–1018.
Gilbert MR, Friedman HS, Kuttesch JF, et al.:A phase II study of temozolomide in patients with newly diagnosed supratentorial malignant glioma before radiation therapy.Neurooncology 2002,4:261–267.
Westphal M, Hilt DC, Bortey E, et al.:A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma.Neurooncology 2003,5:79–88.
Stupp R, Dietrich PY, Ostermann Kraljevic S, et al.:Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide.J Clin Oncol 2002,20:1375–1382.
Tolcher AW, Gerson SL, Denis L, et al.:Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules.Br J Cancer 2003,88:1004–1011.
Hegi ME, Diserens AC, Gorlia T, et al.:MGMT gene silencing and benefit from temozolomide in glioblastoma.N Engl J Med 2005,352:997–1003.
Tentori L, Graziani G:Chemopotentiation by PARP inhibitors in cancer therapy.Pharmacol Res 2005,52:25–33.
Tentori L, Leonetti C, Scarsella M, et al.:Brain distribution and efficacy as chemosensitizer of an oral formulation of PARP-1 inhibitor GPI 15427 in experimental models of CNS tumors.Int J Oncol 2005,26:415–422.
Wen PY, Yung WKA, Lamborn K, et al.:Phase I/II study of imatinib mesylate (Gleevec) for patients with recurrent malignant gliomas (North American Brain Tumor Consortium Study 99-08). Clin Cancer Res, in press.
Lassman AB, Rossi MR, Raizer JJ, et al.:Molecular study of malignant gliomas treated with epidermal growth factor receptor inhibitors: tissue analysis from North American Brain Tumor Consortium Trials 01-03 and 00-01.Clin Cancer Res 2005,11:7841–7850.
Chang SM, Wen P, Cloughesy T, et al.:Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme.Invest New Drugs 2005,23:357–361.
Mellinghoff IK, Wang MY, Vivanco I, et al.:Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors.N Engl J Med 2005,353:2012–2024.
Haas-Kogan DA, Prados MD, Tihan T, et al.:Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib.J Natl Cancer Inst 2005,97:880–887.
Stupp R, Hegi ME, van den Bent MJ, et al.:Changing paradigms—an update on the multidisciplinary management of malignant glioma.Oncologist 2006,11:165–180.
Vredenburgh JJ, Desjardins A, Herndon JE, et al.:Bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), and irinotecan for treatment of malignant gliomas [abstract].Proc ASCO 2006,24:1506.
Guha A, Dashner K, Black PM, et al.:Expression of PDGF and PDGF receptors in human astrocytoma operation specimens supports the existence of an autocrine loop.Int J Cancer 1995,60:168–173.
George D:Platelet-derived growth factor receptors: a therapeutic target in solid tumors.Semin Oncol 2001,28:27–33.
Reardon DA, Egorin MJ, Quinn JA, et al.:Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme.J Clin Oncol 2005,23:9359–9368.
Dresemann G:Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series.Ann Oncol 2005,16:1702–1708.
Nagane M, Narita Y, Mishima K, et al.:Human glioblastoma xenografts overexpressing a tumor-specific mutant epidermal growth factor receptor sensitized to cisplatin by the AG1478 tyrosine kinase inhibitor.J Neurosurg 2001,95:472–479.
Chakravarti A, Chakladar A, Delaney MA, et al.:The epidermal growth factor receptor pathway mediates resistance to sequential administration of radiation and chemotherapy in primary human glioblastoma cells in a RAS-dependent manner.Cancer Res 2002,62:4307–4315.
Geng L, Donnelly E, McMahon G, et al.:Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy.Cancer Res 2001,61:2413–2419.
Fan QW, Specht KM, Zhang C, et al.:Combinatorial efficacy achieved through two-point blockade within a signaling pathway-a chemical genetic approach.Cancer Res 2003,63:8930–8938.
Goudar RK, Shi Q, Hjelmeland MD, et al.:Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition.Mol Cancer Ther 2005,4:101–112.
Yung WK, Albright RE, Olson J, et al.:A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse.Br J Cancer 2000,83:588–593.
Wong ET, Hess KR, Gleason MJ, et al.:Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials.J Clin Oncol 1999,17:2572–2578.
Byar DP, Piantadosi S:Factorial designs for randomized clinical trials.Cancer Treat Rep 1985,69:1055–1063.
Green S, Liu PY, O’Sullivan J:Factorial design considerations.J Clin Oncol 2002,20:3424–3430.
Vray M, Girault D, Hoog-Labouret N, et al.:Methodology for small clinical trials.Therapie 2004,59:273–279, 281–276.
Gilbert MR:Molecularly targeted therapy for malignant gliomas: an introduction. InAmerican Society of Clinical Oncology Educational Book. Alexandria, VA.: ASCO; 2005: 155–160.
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Robins, H.I., Chang, S., Butowski, N. et al. Therapeutic advances for glioblastoma multiforme: Current status and future prospects. Curr Oncol Rep 9, 66–70 (2007). https://doi.org/10.1007/BF02951428
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DOI: https://doi.org/10.1007/BF02951428