Glioma pp 26-40 | Cite as

Recent Medical Management of Glioblastoma

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 746)


This chapter contains an overview of standard of care and experimental chemotherapy treatments for glioblastoma multiforme (GBM). We discuss the role of alkylating agents, focusing primarily on temozolomide (TMZ) which, in combination with radiation therapy, is part of the standard of care treatment for newly diagnosed GBM. TMZ has proven both well tolerated and effective in prolonging patient survival, but tumor recurrence remains the rule. We review the development and use of molecularly targeted agents, low molecular weight kinase inhibitors and monoclonal antibodies that interrupt the signaling pathways exploited by tumors to grow, migrate and avoid apoptosis.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Lacroix M, Abi-Said D, Fourney DR et al. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection and survival. J Neurosurg 2001; 95:190–198.PubMedGoogle Scholar
  2. 2.
    Laperriere N, Zuraw L, Cairncross G. Cancer care ontario practice guidelines initiative neuro-oncology disease site group. Radiotherapy for newly diagnosed malignant glioma in adults: a systematic review. Radiother Oncol 2002; 64:259–273.PubMedCrossRefGoogle Scholar
  3. 3.
    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.PubMedCrossRefGoogle Scholar
  4. 4.
    Ostermann S, Csajka C, Buclin T et al. Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients. Clin Cancer Res 2004; 10:3728–3736.PubMedCrossRefGoogle Scholar
  5. 5.
    Roos WP, Batista LF, Naumann SC et al. Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine. Oncogene 2007; 26:186–197.PubMedCrossRefGoogle Scholar
  6. 6.
    Newlands ES, Stevens MF, Wedge SR et al. Temozolomide: a review of its discovery, chemical properties, preclinical development and clinical trials. Cancer Treat Rev 1997; 23:35–61.PubMedCrossRefGoogle Scholar
  7. 7.
    Bower M, Newlands ES, Bleehen NM et al. Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma. Cancer Chemother Pharmacol 1997; 40:484–488.PubMedCrossRefGoogle Scholar
  8. 8.
    Yung WK, Prados MD, Yaya-Tur R et al. Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group. J Clin Oncol 1999; 17:2762–2771.PubMedGoogle Scholar
  9. 9.
    Brada M, Hoang-Xuan K, Rampling R et al. Multicenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse. Ann Oncol 2001; 12:259–266.PubMedCrossRefGoogle Scholar
  10. 10.
    Brandes AA, Ermani M, Basso U et al. Temozolomide in patients with glioblastoma at second relapse after first line nitrosourea-procarbazine failure: a phase II study. Oncology 2002; 63:38–41.PubMedCrossRefGoogle Scholar
  11. 11.
    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.PubMedCrossRefGoogle Scholar
  12. 12.
    Stupp R, Dietrich PY, Ostermann 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.PubMedCrossRefGoogle Scholar
  13. 13.
    Lanzetta G, Campanella C, Rozzi A et al. Temozolomide in radio-chemotherapy combined treatment for newly-diagnosed glioblastoma multiforme: phase II clinical trial. Anticancer Res 2003; 23:5159–5164.PubMedGoogle Scholar
  14. 14.
    Athanassiou H, Synodinou M, Maragoudakis E et al. Randomized phase II study of temozolomide and radiotherapy compared with radiotherapy alone in newly diagnosed glioblastoma multiforme. J Clin Oncol 2005; 23:2372–2377.PubMedCrossRefGoogle Scholar
  15. 15.
    Stupp R, Hegi ME, Mason WP et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009; 10:459–466.PubMedCrossRefGoogle Scholar
  16. 16.
    Chakravarti A, Erkkinen MG, Nestler U et al. Temozolomide-mediated radiation enhancement in glioblastoma: a report on underlying mechanisms. Clin Cancer Res 2006; 12:4738–4746.PubMedCrossRefGoogle Scholar
  17. 17.
    Combs SE, Gutwein S, Schulz-Ertner D et al. Temozolomide combined with irradiation as postoperative treatment of primary glioblastoma multiforme. Phase I/II study. Strahlenther Onkol 2005; 181:372–377.PubMedCrossRefGoogle Scholar
  18. 18.
    Hegi ME, Liu L, Herman JG et al. Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J Clin Oncol 2008; 26:4189–4199.PubMedCrossRefGoogle Scholar
  19. 19.
    Belanich M, Randall T, Pastor MA et al. Intracellular Localization and intercellular heterogeneity of the human DNA repair protein O(6)-methylguanine-DNA methyltransferase. Cancer Chemother Pharmacol 1996; 37:547–555.PubMedCrossRefGoogle Scholar
  20. 20.
    Watts GS, Pieper RO, Costello JF et al. Methylation of discrete regions of the O6-methylguanine DNA methyltransferase (MGMT) CpG island is associated with heterochromatinization of the MGMT transcription start site and silencing of the gene. Mol Cell Biol 1997; 17:5612–5619.PubMedGoogle Scholar
  21. 21.
    Esteller M, Garcia-Foncillas J, Andion E et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 2000; 343:1350–1354.PubMedCrossRefGoogle Scholar
  22. 22.
    Jaeckle KA, Eyre HJ, Townsend JJ et al. Correlation of tumor O6 methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis-chloroethylnitrosourea: a Southwest Oncology Group study. J Clin Oncol 1998; 16:3310–3315.PubMedGoogle Scholar
  23. 23.
    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.PubMedCrossRefGoogle Scholar
  24. 24.
    Quinn JA, Desjardins A, Weingart J et al. Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma. J Clin Oncol 2005; 23:7178–7187.PubMedCrossRefGoogle Scholar
  25. 25.
    Quinn JA, Jiang SX, Reardon DA et al. Phase II trial of temozolomide plus o6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma. J Clin Oncol 2009; 27:1262–1267.PubMedCrossRefGoogle Scholar
  26. 26.
    Chalmers AJ. The potential role and application of PARP inhibitors in cancer treatment. Br Med Bull 2009; 89:23–40.PubMedCrossRefGoogle Scholar
  27. 27.
    Taphoorn MJ, Stupp R, Coens C et al. Health-related quality of life in patients with glioblastoma: a randomised controlled trial. Lancet Oncol 2005; 6:937–944.PubMedCrossRefGoogle Scholar
  28. 28.
    Mahindra AK, Grossman SA. Pneumocystis carinii pneumonia in HIV negative patients with primary brain tumors. J Neurooncol 2003; 63:263–270.PubMedCrossRefGoogle Scholar
  29. 29.
    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.PubMedCrossRefGoogle Scholar
  30. 30.
    Glas M, Happold C, Rieger J et al. Long-term survival of patients with glioblastoma treated with radiotherapy and lomustine plus temozolomide. J Clin Oncol 2009; 27:1257–1261.PubMedCrossRefGoogle Scholar
  31. 31.
    Yung WK, Mechtler L, Gleason MJ. Intravenous carboplatin for recurrent malignant glioma: a phase II study. J Clin Oncol 1991; 9:860–864.PubMedGoogle Scholar
  32. 32.
    Warnick RE, Prados MD, Mack EE et al. A phase II study of intravenous carboplatin for the treatment of recurrent gliomas. J Neurooncol 1994; 19:69–74.PubMedCrossRefGoogle Scholar
  33. 33.
    Peterson K, Harsh G 4th, Fisher PG et al. Daily low-dose carboplatin as a radiation sensitizer for newly diagnosed malignant glioma. J Neurooncol 2001; 53:27–32.PubMedCrossRefGoogle Scholar
  34. 34.
    Finn GP, Bozek T, Souhami RL et al. High-dose etoposide in the treatment of relapsed primary brain tumors. Cancer Treat Rep 1985; 69:603–605.PubMedGoogle Scholar
  35. 35.
    Fulton D, Urtasun R, Forsyth P. Phase II study of prolonged oral therapy with etoposide (VP16) for patients with recurrent malignant glioma. J Neurooncol 1996; 27:149–155.PubMedCrossRefGoogle Scholar
  36. 36.
    Hellman RM, Calogero JA, Kaplan BM. VP-16, vincristine and procarbazine with radiation therapy for treatment of malignant brain tumors. J Neurooncol 1990; 8:163–166.PubMedCrossRefGoogle Scholar
  37. 37.
    Lassen U, Kristjansen PE, Wagner A et al. Treatment of newly diagnosed glioblastoma multiforme with carmustine, cisplatin and etoposide followed by radiotherapy. A phase II study. J Neurooncol 1999; 43:161–166.PubMedCrossRefGoogle Scholar
  38. 38.
    Silvani A, Lamperti E, Gaviani P et al. Salvage chemotherapy with procarbazine and fotemustine combination in the treatment of temozolomide treated recurrent glioblastoma patients. J Neurooncol 2008; 87:143–151.PubMedCrossRefGoogle Scholar
  39. 39.
    Brandes AA, Tosoni A, Basso U et al. Second-line chemotherapy with irinotecan plus carmustine in glioblastoma recurrent or progressive after first-line temozolomide chemotherapy: a phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). J Clin Oncol 2004; 22:4779–4786.PubMedCrossRefGoogle Scholar
  40. 40.
    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. Neuro Oncol 2003; 5:79–88.PubMedGoogle Scholar
  41. 41.
    Westphal M, Ram Z, Riddle V et al. Executive Committee of the Gliadel Study Group. Gliadel wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial. Acta Neurochir (Wien) 2006; 148:269–75; discussion 275.CrossRefGoogle Scholar
  42. 42.
    Brem H, Piantadosi S, Burger PC et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet 1995; 345:1008–1012.PubMedCrossRefGoogle Scholar
  43. 43.
    Hart MG, Grant R, Garside R et al. Chemotherapeutic wafers for High Grade Glioma. Cochrane Database Syst Rev 2008; 3:CD007294.PubMedGoogle Scholar
  44. 44.
    McGirt MJ, Than KD, Weingart JD et al. Gliadel (BCNU) wafer plus concomitant temozolomide therapy after primary resection of glioblastoma multiforme. J Neurosurg 2009; 110:583–588.PubMedCrossRefGoogle Scholar
  45. 45.
    Cohen S. The epidermal growth factor (EGF). Cancer 1983; 51:1787–1791.PubMedCrossRefGoogle Scholar
  46. 46.
    Ekstrand AJ, James CD, Cavenee WK et al. Genes for epidermal growth factor receptor, transforming growth factor alpha and epidermal growth factor and their expression in human gliomas in vivo. Cancer Res 1991; 51:2164–2172.PubMedGoogle Scholar
  47. 47.
    Pelloski CE, Ballman KV, Furth AF et al. Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J Clin Oncol 2007; 25:2288–2294.PubMedCrossRefGoogle Scholar
  48. 48.
    Scaltriti M, Baselga J. The epidermal growth factor receptor pathway: a model for targeted therapy. Clin Cancer Res 2006; 12:5268–5272.PubMedCrossRefGoogle Scholar
  49. 50.
    van den Bent MJ, Brandes AA, Rampling R et al. Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin Oncol 2009; 27:1268–1274.PubMedCrossRefGoogle Scholar
  50. 51.
    Prados MD, Chang SM, Butowski N et al. Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. J Clin Oncol 2009; 27:579–584.PubMedCrossRefGoogle Scholar
  51. 52.
    Brown PD, Krishnan S, Sarkaria JN et al. Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme: North Central Cancer Treatment Group Study N0177. J Clin Oncol 2008; 26:5603–5609.PubMedCrossRefGoogle Scholar
  52. 53.
    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.PubMedCrossRefGoogle Scholar
  53. 54.
    Perez-Soler R. Can rash associated with HER1/EGFR inhibition be used as a marker of treatment outcome? Oncology (Williston Park) 2003; 17(11 Suppl 12):23–28.Google Scholar
  54. 55.
    Tsuboi M, Le Chevalier T. Interstitial lung disease in patients with nonsmall-cell lung cancer treated with epidermal growth factor receptor inhibitors. Med Oncol 2006; 23:161–170.PubMedCrossRefGoogle Scholar
  55. 56.
    Wen PY, Yung WK, Lamborn KR et al. Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08. Clin Cancer Res 2006; 12:4899–4907.PubMedCrossRefGoogle Scholar
  56. 57.
    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.PubMedCrossRefGoogle Scholar
  57. 58.
    Abounader R, Laterra J. Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis. Neuro Oncol 2005; 7:436–451.PubMedCrossRefGoogle Scholar
  58. 59.
    Reznik TE, Sang Y, Ma Y et al. Transcription-dependent epidermal growth factor receptor activation by hepatocyte growth factor. Mol Cancer Res 2008; 6:139–150.PubMedCrossRefGoogle Scholar
  59. 60.
    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971; 285:1182–1186.PubMedCrossRefGoogle Scholar
  60. 61.
    Kerbel RS. Tumor angiogenesis. N Engl J Med 2008; 358:2039–2049.PubMedCrossRefGoogle Scholar
  61. 62.
    Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350:2335–2342.PubMedCrossRefGoogle Scholar
  62. 63.
    Vredenburgh JJ, Desjardins A, Herndon JE 2nd et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 2007; 25:4722–4729.PubMedCrossRefGoogle Scholar
  63. 64.
    Cloughesy TF, Prados MD, Wen PY et al. A phase II, randomized, noncomparative clinical trial of the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT) on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM) [abstract]. J Clin Oncol 2008; 26(May 20 Supplement):Abstract 2010b.Google Scholar
  64. 65.
    Gomez-Manzano C, Holash J, Fueyo J et al. VEGF Trap induces antiglioma effect at different stages of disease. Neuro Oncol 2008; 10:940–945.PubMedCrossRefGoogle Scholar
  65. 66.
    Batchelor TT, Sorensen AG, di Tomaso E et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007; 11:83–95.PubMedCrossRefGoogle Scholar
  66. 67.
    Norden AD, Young GS, Setayesh K et al. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity and patterns of recurrence. Neurology 2008; 70:779–787.PubMedCrossRefGoogle Scholar
  67. 68.
    Xia P, Aiello LP, Ishii H et al. Characterization of vascular endothelial growth factor’s effect on the activation of protein kinase C, its isoforms and endothelial cell growth. J Clin Invest 1996; 98:2018–2026.PubMedCrossRefGoogle Scholar
  68. 69.
    Graff JR, McNulty AM, Hanna KR et al. The protein kinase Cbeta-selective inhibitor, Enzastaurin (LY317615. HCl), suppresses signaling through the AKT pathway, induces apoptosis and suppresses growth of human colon cancer and glioblastoma xenografts. Cancer Res 2005; 65:7462–7469.PubMedCrossRefGoogle Scholar
  69. 70.
    Fine HA, Kim L, Royce C et al. Results from phase II trial of Enzastaurin (LY317615) in patients with recurrent high grade gliomas [abstract]. J Clin Oncol 2005; 23(16S, June 1 Supplement.):Abstract 1504.Google Scholar
  70. 71.
    Fine HA, Puduvalli VK, Chamberlain MC et al. Enzastaurin (ENZ) versus lomustine (CCNU) in the treatment of recurrent, intracranial glioblastoma multiforme (GBM): A phase III study [abstact]. J Clin Oncol 2008; 26(No 15S (May 20 Supplement)):Abstract 2005.Google Scholar
  71. 72.
    Bauer KS, Dixon SC, Figg WD. Inhibition of angiogenesis by thalidomide requires metabolic activation, which is species-dependent. Biochem Pharmacol 1998; 55:1827–1834.PubMedCrossRefGoogle Scholar
  72. 73.
    Sampaio EP, Sarno EN, Galilly R et al. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 1991; 173:699–703.PubMedCrossRefGoogle Scholar
  73. 74.
    Fine HA, Figg WD, Jaeckle K et al. Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol 2000; 18:708–715.PubMedGoogle Scholar
  74. 75.
    Fine HA, Kim L, Albert PS et al. A phase I trial of lenalidomide in patients with recurrent primary central nervous system tumors. Clin Cancer Res 2007; 13:7101–7106.PubMedCrossRefGoogle Scholar
  75. 76.
    Parise LV, Lee J, Juliano RL. New aspects of integrin signaling in cancer. Semin Cancer Biol 2000; 10:407–414.PubMedCrossRefGoogle Scholar
  76. 77.
    Gingras MC, Roussel E, Bruner JM et al. Comparison of cell adhesion molecule expression between glioblastoma multiforme and autologous normal brain tissue. J Neuroimmunol 1995; 57:143–153.PubMedCrossRefGoogle Scholar
  77. 78.
    Gladson CL. Expression of integrin alpha v beta 3 in small blood vessels of glioblastoma tumors. J Neuropathol Exp Neurol 1996; 55:1143–1149.PubMedCrossRefGoogle Scholar
  78. 79.
    Nabors LB, Mikkelsen T, Rosenfeld SS et al. Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma. J Clin Oncol 2007; 25:1651–1657.PubMedCrossRefGoogle Scholar
  79. 80.
    Reardon DA, Fink KL, Mikkelsen T et al. Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol 2008; 26:5610–5617.PubMedCrossRefGoogle Scholar
  80. 81.
    Stupp R, Goldbrunner R, Neyns B et al. Phase I/IIa trial of cilengitide (EMD121974) and temozolomide with concomitant radiotherapy, followed by temozolomide and cilengitide maintenance therapy in patients (pts) with newly diagnosed glioblastoma (GBM) [abstract]. J Clin Oncol 2007; 25(18S, (June 20 Supplement)):Abstract 2000.Google Scholar
  81. 82.
    McLendon RE, Turner K, Perkinson K et al. Second messenger systems in human gliomas. Arch Pathol Lab Med 2007; 131:1585–1590.PubMedGoogle Scholar
  82. 83.
    Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am J Pathol 2007; 170:1445–1453.PubMedCrossRefGoogle Scholar
  83. 84.
    Galanis E, Buckner JC, Maurer MJ et al. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 2005; 23:5294–5304.PubMedCrossRefGoogle Scholar
  84. 85.
    Momota H, Nerio E, Holland EC. Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo. Cancer Res 2005; 65:7429–7435.PubMedCrossRefGoogle Scholar
  85. 86.
    Knobbe CB, Reifenberger J, Reifenberger G. Mutation analysis of the Ras pathway genes NRAS, HRAS, KRAS and BRAF in glioblastomas. Acta Neuropathol 2004; 108:467–470.PubMedCrossRefGoogle Scholar
  86. 87.
    Cloughesy TF, Wen PY, Robins HI et al. Phase II trial of tipifarnib in patients with recurrent malignant glioma either receiving or not receiving enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study. J Clin Oncol 2006; 24:3651–3656.PubMedCrossRefGoogle Scholar
  87. 88.
    Hahn O, Stadler W. Sorafenib. Curr Opin Oncol 2006; 18:615–621.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  1. 1.Department of Neurological SurgeryUniversity of California San FranciscoSan FranciscoUSA

Personalised recommendations