Malignant Glioma: Viewpoint—Chemotherapy

  • Roger Stupp
  • Krisztian Homicsko
  • J. Gregory Cairncross


Malignant gliomas are diffusely infiltrating and thus any local treatment has its inherent limitations. Alkylating agent chemotherapy has repeatedly demonstrated improvement in disease-free and overall survival. Concomitant chemoradiotherapy with temozolomide is the standard of care in glioblastoma, neoadjuvant or adjuvant chemotherapy with PCV improves survival in anaplastic oligodendroglial tumors with a 1p/19q co-deletion, however the benefit is only seen with long follow-up of > 6 years. Randomized trials in anaplastic glioma have shown that the treatment sequence, radiotherapy first and chemotherapy at recurrence or the reverse, does not matter in terms of progression-free or overall survival.

MGMT gene promoter methylation is the single strongest predictive factor for benefit from chemotherapy in grade IV tumors, and is an important prognostic marker in grade III tumors. In elderly patients, treatment with TMZ was beneficial for tumors with a methylated MGMT, and superior to radiotherapy alone, while patients with an unmethylated MGMT should not be treated with TMZ but rather with RT.

Novel agents are under investigation for patients with recurrent disease. Although VEGF pathway inhibition failed to prolong overall survival, treatment with the monoclonal antibody bevacizumab may improve quality of life of selected patients with recurrent glioma.


Malignant Glioma Anaplastic Astrocytoma Radiation Therapy Oncology Group Stereotactic Radiosurgery MGMT Promoter Methylation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Stupp R, Hegi ME, Gilbert MR, Chakravarti A. Chemoradiotherapy in malignant glioma: standard of care and future directions. J Clin Oncol. 2007;25:4127–36.PubMedCrossRefGoogle Scholar
  2. 2.
    Balis FM, Blaney SM, McCully CL, et al. Methotrexate distribution within the subarachnoid space after intraventricular and intravenous administration. Cancer Chemother Pharmacol. 2000;45: 259–64.PubMedCrossRefGoogle Scholar
  3. 3.
    Noushmehr H, Weisenberger DJ, Diefes K, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010;17:510–22.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Verhaak RG, Hoadley KA, Purdom E, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17:98–110.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Sturm D, Witt H, Hovestadt V, et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell. 2012;22:425–37.PubMedCrossRefGoogle Scholar
  6. 6.
    Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366:883–92.PubMedCrossRefGoogle Scholar
  7. 7.
    Fisher R, Pusztai L, Swanton C. Cancer heterogeneity: implications for targeted therapeutics. Br J Cancer. 2013;108(3):479–85.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Sampson JH, Heimberger AB, Archer GE, et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010;28: 4722–9.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Huse JT, Holland EC. Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma. Nat Rev Cancer. 2010;10:319–31.PubMedCrossRefGoogle Scholar
  10. 10.
    Roesch A, Fukunaga-Kalabis M, Schmidt EC, et al. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell. 2010;141:583–94.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Gupta PB, Onder TT, Jiang G, et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138:645–59.PubMedCrossRefGoogle Scholar
  12. 12.
    Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21:309–22.PubMedCrossRefGoogle Scholar
  13. 13.
    Straussman R, Morikawa T, Shee K, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012;487:500–4.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Dichter MA, Brodie MJ. New antiepileptic drugs. N Engl J Med. 1996;334:1583–90.PubMedCrossRefGoogle Scholar
  15. 15.
    Kanner AM, Balabanov AJ. The use of monotherapy in patients with epilepsy: an appraisal of the new antiepileptic drugs. Curr Neurol Neurosci Rep. 2005;5:322–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Vecht CJ, Wagner GL, Wilms EB. Interactions between antiepileptic and chemotherapeutic drugs. Lancet Neurol. 2003;2: 404–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Weller M, Gorlia T, Cairncross JG, et al. Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. Neurology. 2011;77:1156–64.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Weller M, Stupp R, Wick W. Epilepsy meets cancer: when, why, and what to do about it? Lancet Oncol. 2012;13:e375–82.PubMedCrossRefGoogle Scholar
  19. 19.
    Macdonald DR, Cascino TL, Schold Jr SC, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990;8:1277–80.PubMedGoogle Scholar
  20. 20.
    Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–16.PubMedCrossRefGoogle Scholar
  21. 21.
    Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010;28: 1963–72.PubMedCrossRefGoogle Scholar
  22. 22.
    Leimgruber A, Ostermann S, Yeon E, et al. Perfusion and diffusion MRI of glioblastoma progression in a 4 years prospective temozolomide clinical trial. Int J Radiat Oncol Biol Phys. 2006;64:869–75.PubMedCrossRefGoogle Scholar
  23. 23.
    Moffat BA, Chenevert TL, Lawrence TS, et al. Functional diffusion map: a noninvasive MRI biomarker for early stratification of clinical brain tumor response. Proc Natl Acad Sci U S A. 2005;102:5524–9.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    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.PubMedGoogle Scholar
  25. 25.
    Irish WD, Macdonald DR, Cairncross JG. Measuring bias in uncontrolled brain tumor trials–to randomize or not to randomize? Can J Neurol Sci. 1997;24:307–12.PubMedCrossRefGoogle Scholar
  26. 26.
    Wick W, Puduvalli VK, Chamberlain MC, et al. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol. 2010;28:1168–74.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Batchelor TT, Mulholland P, Neyns B, et al. Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol. 2013;31:3212–8.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Frenay M, Giroux B, Khoury S, et al. Phase II study of fotemustine in recurrent supratentorial malignant gliomas. Eur J Cancer. 1991;27:852–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Takakura K, Abe H, Tanaka R, et al. Effects of ACNU and radiotherapy on malignant glioma. J Neurosurg. 1986;64:53–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Yoshida J, Kajita Y, Wakabayashi T, Sugita K. Long-term follow-up results of 175 patients with malignant glioma: importance of radical tumour resection and postoperative adjuvant therapy with interferon, ACNU and radiation. Acta Neurochir. 1994;127:55–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Kochii M, Kitamura I, Goto T, et al. Randomized comparison of intra-arterial versus intravenous infusion of ACNU for newly diagnosed patients with glioblastoma. J Neuro Oncol. 2000;49: 63–70.CrossRefGoogle Scholar
  32. 32.
    Weller M, Müller B, Koch R, et al. Neuro-Oncology Working Group 01 trial of nimustine plus teniposide versus nimustine plus cytarabine chemotherapy in addition to involved-field radiotherapy in the first-line treatment of malignant glioma. J Clin Oncol. 2003;21:3276–84.PubMedCrossRefGoogle Scholar
  33. 33.
    Green SB, Byar DP, Walker MD, et al. Comparisons of carmustine, procarbazine, and high-dose methylprednisolone as additions to surgery and radiotherapy for the treatment of malignant glioma. Cancer Treat Rep. 1983;67:121–32.PubMedGoogle Scholar
  34. 34.
    Rodriguez LA, Prados M, Silver P, Levin VA. Reevaluation of procarbazine for the treatment of recurrent malignant central nervous system tumors. Cancer. 1989;64:2420–3.PubMedCrossRefGoogle Scholar
  35. 35.
    Newton HB, Junck L, Bromberg J, et al. Procarbazine chemotherapy in the treatment of recurrent malignant astrocytomas after radiation and nitrosourea failure. Neurology. 1990;40:1743–6.PubMedCrossRefGoogle Scholar
  36. 36.
    Levin VA, Silver P, Hannigan J, et al. Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys. 1990;18:321–4.PubMedCrossRefGoogle Scholar
  37. 37.
    Prados MD, Scott C, Curran Jr WJ, et al. Procarbazine, lomustine, and vincristine (PCV) chemotherapy for anaplastic astrocytoma: A retrospective review of radiation therapy oncology group protocols comparing survival with carmustine or PCV adjuvant chemotherapy. J Clin Oncol. 1999;17:3389–95.PubMedGoogle Scholar
  38. 38.
    Medical Research Council Brain Tumor Working Party. Randomized trial of procarbazine, lomustine and vincristine in the adjuvant treatment of high-grade astrocytoma: a Medical Research Council trial. J Clin Oncol. 2001;19:509–18.Google Scholar
  39. 39.
    Stupp R, Gander M, Leyvraz S, Newlands E. Current and future developments in the use of temozolomide in the treatment of brain tumors. Lancet Oncol. 2001;2:552–60.PubMedCrossRefGoogle Scholar
  40. 40.
    Brada M, Judson I, Beale P, et al. Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies. Br J Cancer. 1999;81:1022–30.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Ostermann S, Csajka C, Buclin T, et al. Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients. Clin Cancer Res. 2004;10:3728–36.PubMedCrossRefGoogle Scholar
  42. 42.
    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;17:2762–71.PubMedGoogle Scholar
  43. 43.
    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;83:588–93.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Brada M, Hoang-Xuang K, Rampling R, et al. Multicenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse. Ann Oncol. 2001;12:259–66.PubMedCrossRefGoogle Scholar
  45. 45.
    Brada M, Stenning S, Gabe R, et al. Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma. J Clin Oncol. 2010;28:4601–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Wick W, Hartmann C, Engel C, et al. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009;27:5874–80.PubMedCrossRefGoogle Scholar
  47. 47.
    Gilbert MR, Wang M, Aldape KD, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013;10:4085–91.CrossRefGoogle Scholar
  48. 48.
    Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.PubMedCrossRefGoogle Scholar
  49. 49.
    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: 459–66.PubMedCrossRefGoogle Scholar
  50. 50.
    Stupp R, van den Bent MJ, Hegi ME. Optimal role of temozolomide in the treatment of malignant gliomas. Curr Neurol Neurosci Rep. 2005;5:198–206.PubMedCrossRefGoogle Scholar
  51. 51.
    van den Bent M, Brandes A, Rampling R, et al. Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma. Report from EORTC Brain Tumor Group study 26034. J Clin Oncol. 2009;27:1268–74.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    van den Bent MJ, Chinot O, Boogerd W, et al. Second-line chemotherapy with temozolomide in recurrent oligodendroglioma after PCV (procarbazine, lomustine and vincristine) chemotherapy: EORTC Brain Tumor Group phase II study 26972. Ann Oncol. 2003;14:599–602.PubMedCrossRefGoogle Scholar
  53. 53.
    van den Bent MJ, Taphoorn MJ, Brandes AA, et al. Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. J Clin Oncol. 2003;21:2525–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27:4733–40.PubMedCrossRefGoogle Scholar
  55. 55.
    Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27:740–5.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Wick W, Weller M, van den Bent M, Stupp R. Bevacizumab and recurrent malignant gliomas: a European perspective. J Clin Oncol. 2010; 28: e188–189; author reply e190–182Google Scholar
  57. 57.
    Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370:709–22.PubMedCrossRefGoogle Scholar
  58. 58.
    Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370:699–708.PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    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;26:5610–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Stupp R, Hegi ME, Neyns B, et al. Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010;28: 2712–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Stupp R, Hegi ME, Gorlia T et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma and methylated O6-methylguanine-DNA methyltransferase (MGMT) gene promoter: Key results of the multicenter, randomized, open-label, controlled, phase III CENTRIC study. Lancet Oncol 2014, in pressGoogle Scholar
  62. 62.
    Dresemann G, Weller M, Rosenthal MA, et al. Imatinib in combination with hydroxyurea versus hydroxyurea alone as oral therapy in patients with progressive pretreated glioblastoma resistant to standard dose temozolomide. J Neurooncol. 2010;96:393–402.PubMedCrossRefGoogle Scholar
  63. 63.
    Friedman HS, Petros WP, Friedman AH, et al. Irinotecan therapy in adults with recurrent or progressive malignant glioma. J Clin Oncol. 1999;17:1516–25.PubMedGoogle Scholar
  64. 64.
    Raymond E, Fabbro M, Boige V, et al. Multicentre phase II study and pharmacokinetic analysis of irinotecan in chemotherapy-naive patients with glioblastoma. Ann Oncol. 2003;14:603–14.PubMedCrossRefGoogle Scholar
  65. 65.
    Grossman SA, O’Neill A, Grunnet M, et al. Phase III study comparing three cycles of infusional carmustine and cisplatin followed by radiation therapy with radiation therapy and concurrent carmustine in patients with newly diagnosed supratentorial glioblastoma multiforme: Eastern Cooperative Oncology Group Trial 2394. J Clin Oncol. 2003;21:1485–91.PubMedCrossRefGoogle Scholar
  66. 66.
    Brandes AA, Basso U, Reni M, et al. First-line chemotherapy with cisplatin plus fractionated temozolomide in recurrent glioblastoma multiforme: a phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia. J Clin Oncol. 2004;22:1598–604.PubMedCrossRefGoogle Scholar
  67. 67.
    Bafaloukos D, Tsoutsos D, Kalofonos H, et al. Temozolomide and cisplatin versus temozolomide in patients with advanced melanoma: a randomized phase II study of the Hellenic Cooperative Oncology Group. Ann Oncol. 2005;16:950–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Walker MD, Alexander Jr E, Hunt WE, et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg. 1978;49:333–43.PubMedCrossRefGoogle Scholar
  69. 69.
    Walker MD, Green SB, Byar DP, et al. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med. 1980;303:1323–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Kristiansen K, Hagen S, Kollevold T, et al. Combined modality therapy of operated astrocytomas grade III and IV. Confirmation of the value of postoperative irradiation and lack of potentiation of bleomycin on survival time: a prospective multicenter trial of the Scandinavian Glioblastoma Study Group. Cancer. 1981;47:649–52.PubMedCrossRefGoogle Scholar
  71. 71.
    Walker MD, Strike TA, Sheline GE. An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys. 1979;5:1725–31.PubMedCrossRefGoogle Scholar
  72. 72.
    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;71:2585–97.PubMedCrossRefGoogle Scholar
  73. 73.
    Stewart LA. Chemotherapy in adult high-grade glioma: a systematic review and meta- analysis of individual patient data from 12 randomised trials. Lancet. 2002;359:1011–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Weller M, Stupp R, Hegi ME, et al. Personalized care in neuro-oncology coming of age: why we need MGMT and 1p/19q testing for malignant glioma patients in clinical practice. Neuro Oncol. 2012;14 Suppl 4:iv100–8.PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Weller M, Stupp R, Reifenberger G, et al. MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol. 2010;6:39–51.PubMedCrossRefGoogle Scholar
  76. 76.
    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
  77. 77.
    Hildebrand J, Sahmoud T, Mignolet F, et al. Adjuvant therapy with dibromodulcitol and BCNU increases survival of adults with malignant gliomas. EORTC Brain Tumor Group. Neurology. 1994;44:1479–83.PubMedCrossRefGoogle Scholar
  78. 78.
    Hildebrand J, Gorlia T, Kros JM, et al. Adjuvant dibromodulcitol and BCNU chemotherapy in anaplastic astrocytoma: results of a randomised European Organisation for Research and Treatment of Cancer phase III study (EORTC study 26882). Eur J Cancer. 2008;44:1210–6.PubMedCrossRefGoogle Scholar
  79. 79.
    Levin VA, Hess KR, Choucair A, et al. Phase III Randomized Study of Postradiotherapy Chemotherapy with Combination alpha-Difluoromethylornithine-PCV versus PCV for Anaplastic Gliomas. Clin Cancer Res. 2003;9:981–90.PubMedGoogle Scholar
  80. 80.
    Kleihues P, Cavenee WK. Pathology and Genetics of tumours of the nervous system. Lyon: IARC Press; 2000.Google Scholar
  81. 81.
    Cairncross JG, Ueki K, Zlatescu MC, et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst. 1998;90: 1473–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Cairncross G, Berkey B, Shaw E, et al. Phase III Trial of Chemotherapy Plus Radiotherapy Compared With Radiotherapy Alone for Pure and Mixed Anaplastic Oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol. 2006;24:2707–14.PubMedCrossRefGoogle Scholar
  83. 83.
    van den Bent MJ, Carpentier AF, Brandes AA, et al. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but Not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European organisation for research and treatment of cancer phase III trial. J Clin Oncol. 2006;24:2715–22.PubMedCrossRefGoogle Scholar
  84. 84.
    van den Bent MJ, Brandes AA, Taphoorn MJ, et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-Up of EORTC brain tumor group study 26951. J Clin Oncol. 2013;31: 344–50.PubMedCrossRefGoogle Scholar
  85. 85.
    Cairncross G, Wang M, Shaw E, et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2013;31:337–43.PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    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;95:190–8.PubMedCrossRefGoogle Scholar
  87. 87.
    Gallego Perez-Larraya J, Ducray F, Chinot O, et al. Temozolomide in elderly patients with newly diagnosed glioblastoma and poor performance status: an ANOCEF phase II trial. J Clin Oncol. 2011;29:3050–5.PubMedCrossRefGoogle Scholar
  88. 88.
    Keime-Guibert F, Chinot O, Taillandier L, et al. Radiotherapy for glioblastoma in the elderly. N Engl J Med. 2007;356:1527–35.PubMedCrossRefGoogle Scholar
  89. 89.
    Roa W, Brasher PM, Bauman G, et al. Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol. 2004;22:1583–8.PubMedCrossRefGoogle Scholar
  90. 90.
    Malmstrom A, Gronberg BH, Marosi C, et al. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 2012;13: 916–26.PubMedCrossRefGoogle Scholar
  91. 91.
    Wick W, Platten M, Meisner C, et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012;13:707–15.PubMedCrossRefGoogle Scholar
  92. 92.
    Curran Jr WJ, Scott CB, Horton J, et al. Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst. 1993;85: 704–10.PubMedCrossRefGoogle Scholar
  93. 93.
    Scott CB, Scarantino C, Urtasun R, et al. Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: a report using RTOG 90-06. Int J Radiat Oncol Biol Phys. 1998;40:51–5.PubMedCrossRefGoogle Scholar
  94. 94.
    Mirimanoff RO, Gorlia T, Mason W, et al. Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol. 2006;24:2563–9.PubMedCrossRefGoogle Scholar
  95. 95.
    Weller M, Pfister SM, Wick W, et al. Molecular neuro-oncology in clinical practice: a new horizon. Lancet Oncol. 2013;14:e370–9.PubMedCrossRefGoogle Scholar
  96. 96.
    Jenkins RB, Blair H, Ballman KV, et al. A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res. 2006;66:9852–61.PubMedCrossRefGoogle Scholar
  97. 97.
    Brandes AA, Franceschi E, Tosoni A, et al. Epidermal growth factor receptor inhibitors in neuro-oncology: hopes and disappointments. Clin Cancer Res. 2008;14:957–60.PubMedCrossRefGoogle Scholar
  98. 98.
    Hegi ME, Rajakannu P, Weller M. Epidermal growth factor receptor: a re-emerging target in glioblastoma. Curr Opin Neurol. 2012;25(6):774–9.PubMedCrossRefGoogle Scholar
  99. 99.
    Murat A, Migliavacca E, Gorlia T, et al. Stem cell-related “self-renewal” signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J Clin Oncol. 2008;26:3015–24.PubMedCrossRefGoogle Scholar
  100. 100.
    Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360:765–73.PubMedCentralPubMedCrossRefGoogle Scholar
  101. 101.
    Phillips HS, Kharbanda S, Chen R, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006;9:157–73.PubMedCrossRefGoogle Scholar
  102. 102.
    Hegi ME, Diserens AC, Godard S, et al. Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res. 2004;10:1871–4.PubMedCrossRefGoogle Scholar
  103. 103.
    Godard S, Getz G, Delorenzi M, et al. Classification of human astrocytic gliomas on the basis of gene expression: a correlated group of genes with angiogenic activity emerges as a strong predictor of subtypes. Cancer Res. 2003;63:6613–25.PubMedGoogle Scholar
  104. 104.
    O’Driscoll BR, Hasleton PS, Taylor PM, et al. Active lung fibrosis up to 17 years after chemotherapy with carmustine (BCNU) in childhood. N Engl J Med. 1990;323:378–82.PubMedCrossRefGoogle Scholar
  105. 105.
    Kreisman H, Wolkove N. Pulmonary toxicity of antineoplastic therapy. Semin Oncol. 1992;19:508–20.PubMedGoogle Scholar
  106. 106.
    Schmitz N, Diehl V. Carmustine and the lungs. Lancet. 1997;349:1712–3.PubMedCrossRefGoogle Scholar
  107. 107.
    Brock CS, Newlands ES, Wedge SR, et al. Phase I trial of temozolomide using an extended continuous oral schedule. Cancer Res. 1998;58:4363–7.PubMedGoogle Scholar
  108. 108.
    Su YB, Sohn S, Krown SE, et al. Selective CD4+ lymphopenia in melanoma patients treated with temozolomide: a toxicity with therapeutic implications. J Clin Oncol. 2004;22:610–6.PubMedCrossRefGoogle Scholar
  109. 109.
    Stupp R, Dietrich P, 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;20:1375–82.PubMedCrossRefGoogle Scholar
  110. 110.
    Kovacs JA, Masur H. Prophylaxis against opportunistic infections in patients with human immunodeficiency virus infection. N Engl J Med. 2000;342:1416–29.PubMedCrossRefGoogle Scholar
  111. 111.
    Osoba D, Brada M, Yung W, Prados M. Health-related quality of life in patients treated with temozolomide versus procarbazine for recurrent glioblastoma multiforme. J Clin Oncol. 2000;18: 1481–91.PubMedGoogle Scholar
  112. 112.
    Osoba D, Brada M, Yung WK, Prados MD. Health-related quality of life in patients with anaplastic astrocytoma during treatment with temozolomide. Eur J Cancer. 2000;36:1788–95.PubMedCrossRefGoogle Scholar
  113. 113.
    Taphoorn MJ, Stupp R, Coens C, et al. Health-related quality of life in patients with glioblastoma: a randomised controlled trial. Lancet Oncol. 2005;6:937–44.PubMedCrossRefGoogle Scholar
  114. 114.
    Tsao MN, Mehta MP, Whelan TJ, et al. The American Societey for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for malignant glioma. Int J Radiat Oncol Biol Phys. 2005;63:47–55.PubMedCrossRefGoogle Scholar
  115. 115.
    Souhami L, Seiferheld W, Brachman D, et al. Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol. Int J Radiat Oncol Biol Phys. 2004;60:853–60.PubMedCrossRefGoogle Scholar
  116. 116.
    Brada M, Baumert B. Focal fractionated conformal stereotactic boost following conventional radiotherapy of high-grade gliomas: a randomized phase III study. A joint study of the EORTC (22972) and the MRC (BR10). Front Radiat Ther Oncol. 1999;33: 241–3.PubMedCrossRefGoogle Scholar
  117. 117.
    Stupp R, Weber DC. The role of radio- and chemotherapy in glioblastoma. Onkologie. 2005;28:315–7.PubMedCrossRefGoogle Scholar
  118. 118.
    Hochberg FH, Pruitt A. Assumptions in the radiotherapy of glioblastoma. Neurology. 1980;30:907–11.PubMedCrossRefGoogle Scholar
  119. 119.
    Romanelli P, Conti A, Pontoriero A, et al. Role of stereotactic radiosurgery and fractionated stereotactic radiotherapy for the treatment of recurrent glioblastoma multiforme. Neurosurg Focus. 2009;27:E8.PubMedCrossRefGoogle Scholar
  120. 120.
    Einstein DB, Wessels B, Bangert B, et al. Phase II trial of radiosurgery to magnetic resonance spectroscopy-defined high-risk tumor volumes in patients with glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 2012;84:668–74.PubMedCentralPubMedCrossRefGoogle Scholar
  121. 121.
    Stupp R, Hegi ME. Treatment of brain tumors (author reply). N Engl J Med. 2005;352:2350–3.CrossRefGoogle Scholar
  122. 122.
    Fogh SE, Andrews DW, Glass J, et al. Hypofractionated stereotactic radiation therapy: an effective therapy for recurrent high-grade gliomas. J Clin Oncol. 2010;28:3048–53.PubMedCentralPubMedCrossRefGoogle Scholar
  123. 123.
    Koga T, Maruyama K, Tanaka M, et al. Extended field stereotactic radiosurgery for recurrent glioblastoma. Cancer. 2012;118: 4193–200.PubMedCrossRefGoogle Scholar
  124. 124.
    Shapiro LQ, Beal K, Goenka A, et al. Patterns of failure after concurrent bevacizumab and hypofractionated stereotactic radiation therapy for recurrent high-grade glioma. Int J Radiat Oncol Biol Phys. 2012;85(3):636–42.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Roger Stupp
    • 1
  • Krisztian Homicsko
    • 2
  • J. Gregory Cairncross
    • 3
  1. 1.Department of Oncology and Cancer CenterUniversity Hospital ZurichZurichSwitzerland
  2. 2.Department of OncologyCentre Hospitalier Universitaire VaudoisLausanneSwitzerland
  3. 3.Southern Alberta Cancer Research InstituteUniversity of CalgaryCalgaryCanada

Personalised recommendations