Brain Tumors

Part of the Medical Radiology book series (MEDRAD)


Glial tumors represent a class of primary brain tumor that includes neoplasms of astrocytic, oligodendritic and ependymal origin. The majority of adult gliomas are grade II–IV astrocytomas and oligodendrogliomas or are mixed with components of both (oligoastrocytoma) (CBTRUS 2010; Robertson et al. 2011; Brat et al. 2008) (Table 1). Histo-pathology and grading have been the historical cornerstones of diagnosis and therapeutic recommendation in the treatment of glioma (Weller et al. 2012). Nevertheless, prognosis and response to treatment is widely variable even among patients diagnosed with the same histo-pathologic disease entity and grade (Robertson et al. 2011). Modern techniques in gene and enzyme analysis have led to the recent proliferation of predictive and prognostic markers available for study. Some of these play a role in explaining the variable outcomes for glioma patients while others provide tantalizing prospects for potential future therapies. This chapter will provide a current review of the treatment of adult primary glioma including high and low grade astrocytoma, oligodendroglioma and oligoastrocytoma. There is an emphasis on predictive and prognostic models that have been published in recent years as applies to radiation oncologists. An evaluation of confidence levels in the literature will be provided.


Overall Survival Anaplastic Astrocytoma Pilocytic Astrocytoma MGMT Promoter Methylation MGMT Methylation 


  1. Aldape K, Burger PC, Perry A (2007) Clinicopathologic aspects of 1p/19q loss and the diagnosis of oligodendroglioma. Arch Pathol Lab Med 131(2):242–251PubMedGoogle Scholar
  2. Alexander BM, Mehta MP (2011) Role of isocitrate dehydrogenase in glioma. Expert Rev Neurother 11(10):1399–1409PubMedCrossRefGoogle Scholar
  3. Armstrong TS et al (2013) Comparative impact of treatment on patient reported outcomes (PROs) in patients with glioblastoma (GBM) enrolled in RTOG 0825. ASCO Meet Abst 31(15):2003Google Scholar
  4. Barbashina V et al (2005) Allelic losses at 1p36 and 19q13 in gliomas: correlation with histologic classification, definition of a 150-kb minimal deleted region on 1p36, and evaluation of CAMTA1 as a candidate tumor suppressor gene. Clin Cancer Res: Off J Am Assoc Cancer Res 11(3):1119–1128Google Scholar
  5. Bauman G et al (1999) Pretreatment factors predict overall survival for patients with low-grade glioma: a recursive partitioning analysis. Radiat Oncol Biol 45(4):923–929CrossRefGoogle Scholar
  6. Bauman GS et al (2000) Allelic loss of chromosome 1p and radiotherapy plus chemotherapy in patients with oligodendrogliomas. Radiat Oncol Biol 48(3):825–830CrossRefGoogle Scholar
  7. Baumert BG et al (2013) Temozolomide chemotherapy versus radiotherapy in molecularly characterized (1p loss) low-grade glioma: a randomized phase III intergroup study by the EORTC/NCIC-CTG/TROG/MRC-CTU (EORTC 22033–26033). ASCO Meet Abs 31(15):2007Google Scholar
  8. Brada M et al (2010) Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma. J Clin Oncol: Offi J Am Soc Clin Oncol 28(30):4601–4608CrossRefGoogle Scholar
  9. Brandes AA et al (2008) MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol : Off J Am Soc Clin Oncol 26(13):2192–2197CrossRefGoogle Scholar
  10. Brat DJ et al (2008) Diagnosis of malignantglioma: role of neuropathology. J Neurooncol 89(3):287–311PubMedCrossRefGoogle Scholar
  11. Cairncross G et al (1994) Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol: Off J Am Soc Clin Oncol 12(10):2013–2021Google Scholar
  12. Cairncross G et al (2013) Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol: Off J Am Soc Clin Oncol 31(3):337–343CrossRefGoogle Scholar
  13. Cairncross JG et al (1998) Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 90(19):1473–1479PubMedCrossRefGoogle Scholar
  14. Combs SE et al (2011) Prognostic significance of IDH-1 and MGMT inpatients with glioblastoma: one step forward, and one step back? Radiat Oncol 6(1):115PubMedCentralPubMedCrossRefGoogle Scholar
  15. Capper D, Reuss D, Schittenhelm J, Hartmann C, Bremer J, Sahm F, Harter PN, Jeibmann A, von Deimling A (2011) Mutation-specific IDH1 antibody differentiates oligodendrogliomas and oligoastrocytomas from other brain tumors with oligodendroglioma-like morphology. Acta Neuropathol 121(2):241–252Google Scholar
  16. Ellingson BM et al (2011) Quantitative volumetric analysis of conventional MRI response in recurrent glioblastoma treated with bevacizumab. Neuro-Oncol 13(4):401–409PubMedCentralPubMedCrossRefGoogle Scholar
  17. Fisher BJ et al (2013) A phase II study of a temozolomide-based chemoradiotherapy regimen for high-risk low-grade gliomas: preliminary results of RTOG 0424. ASCO Meet Abs 31(15):2008Google Scholar
  18. Goldberg P Accessed 14 June 2013
  19. Gilbert MR et al (2011) RTOG 0525: a randomized phase III trial comparing standard adjuvant temozolomide (TMZ) with a dose-dense (dd) schedule in newly diagnosed glioblastoma (GBM). ASCO Meet Abs 29(15):2006Google Scholar
  20. Gilbert MR et al (2013) RTOG 0825: phase III double-blind placebo-controlled trial evaluating bevacizumab (Bev) in patients (Pts) with newly diagnosed glioblastoma (GBM). ASCO Meet Abs 31(15):1Google Scholar
  21. Gorlia T, van den Bent MJ, Hegi ME, Mirimanoff RO, Weller M, Cairncross JG, Eisenhauer E, Belanger K, Brandes AA, Allgeier A, Lacombe D, Stupp R (2008) Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981–22981/CE.3. Lancet Oncol 9(1):29–38PubMedCrossRefGoogle Scholar
  22. Groenendijk FH, Taal W, Dubbink HJ, Haarloo CR, Kouwenhoven MC, van den Bent MJ, Kros JM, Dinjens WN (2011) MGMT promoter hypermethylation is a frequent, early, and consistent event in astrocytoma progression, and not correlated with TP53 mutation. J Neurooncol 101(3):405–417Google Scholar
  23. Gupta K, Salunke P (2012) Molecular markers of glioma: an update on recent progress and perspectives. J Cancer Res Clin Oncol 138(12):1971–1981PubMedCrossRefGoogle Scholar
  24. Gupta R et al (2011) Isocitrate dehydrogenase mutations in diffuse gliomas: clinical and aetiological implications. J Clin Pathol 64(10):835–844PubMedCrossRefGoogle Scholar
  25. Hartmann C et al (2009) Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol 4:469–474CrossRefGoogle Scholar
  26. Hartmann C et al (2010) Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. Acta Neuropathol 120(6):707–718PubMedCrossRefGoogle Scholar
  27. Hartmann C et al (2011) Molecular markers in low-grade gliomas: predictive or prognostic? Clin Cancer Res 17(13):4588–4599PubMedCrossRefGoogle Scholar
  28. Hegi ME et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352(10):997–1003PubMedCrossRefGoogle Scholar
  29. Henriksson R et al (2013) Progression-free survival (PFS) and health-related quality of life (HRQoL) in AVAglio, a phase III study of bevacizumab (Bv), temozolomide (T), and radiotherapy (RT) in newly diagnosed glioblastoma (GBM). ASCO Meet Abs 31(15):2005Google Scholar
  30. Hofer S, Lassman AB (2010) Molecular markers in gliomas: impact for the clinician. Targeted Oncol 5(3):201–210CrossRefGoogle Scholar
  31. Houillier C et al (2010) IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology 75(17):1560–1566PubMedCrossRefGoogle Scholar
  32. Intergroup Radiation Therapy Oncology Group Trial 9402 et al (2006) 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: Off J Am Soc Clin Oncol 24(18):2707–2714CrossRefGoogle Scholar
  33. Karim AB et al (1996) A randomized trial on dose-response in radiation therapy oflow-gradecerebralglioma: European Organization for Research and Treatment of Cancer (EORTC) Study 22844. Int J Radiat Oncol Biol Phys 36(3):549–556PubMedCrossRefGoogle Scholar
  34. Keime-Guibert F et al (2007) Radiotherapy for glioblastoma in the elderly. N Engl J Med 356(15):1527–1535PubMedCrossRefGoogle Scholar
  35. Keles GE, Lamborn KR, Berger MS (2001) Low-grade hemispheric gliomas in adults: a critical review of extent of resection as a factor influencing outcome. J Neurosurg 95(5):735–745PubMedCrossRefGoogle Scholar
  36. Kesari S et al (2009) Phase II study of protracted daily temozolomide for low-grade gliomas in adults. Clin Cancer Res 15(1):330–337PubMedCrossRefGoogle Scholar
  37. Lassman AB et al (2011) International retrospective study of over 1000 adults with anaplastic oligodendroglial tumors. Neuro-Oncol 13(6):649–659PubMedCentralPubMedCrossRefGoogle Scholar
  38. Lee YY et al (1989) Juvenile pilocytic astrocytomas: CT and MR characteristics. AJR Am J Roentgenol 152(6):1263–1270Google Scholar
  39. Lee YY, Van Tassel P (1989) Intracranial oligodendrogliomas: imaging findings in 35 untreated cases. AJR Am J Roentgenol 152(2):361–369PubMedCrossRefGoogle Scholar
  40. Leu S, von Felten S, Frank S, Vassella E, Vajtai I, Taylor E, Schulz M, Hutter G, Hench J, Schucht P, Boulay JL, Mariani L (2013) IDH/MGMT-driven molecular classification of low-grade glioma is a strong predictor for long-term survival. Neuro Oncol 15(4):469–479Google Scholar
  41. Lote K et al (1998) Prevalence and prognostic significance of epilepsy in patients with gliomas. Eur J Cancer 34(1):98–102PubMedCrossRefGoogle Scholar
  42. Malmstrom A et al (2012) 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 13(9):916–926PubMedCrossRefGoogle Scholar
  43. Mason WP, Krol GS, DeAngelis LM (1996) Low-grade oligodendroglioma responds to chemotherapy. Neurology 46(1):203–207PubMedCrossRefGoogle Scholar
  44. McKnight TR et al (2002) Histopathological validation of a three-dimensional magnetic resonance spectroscopy index as a predictor of tumor presence. J Neurosurg 97(4):794–802PubMedCrossRefGoogle Scholar
  45. Metellus P, Coulibaly B, Colin C, de Paula AM, Vasiljevic A, Taieb D, Barlier A, Boisselier B, Mokhtari K, Wang XW, Loundou A, Chapon F, Pineau S, Ouafik L, Chinot O, Figarella-Branger D (2010) Absence of IDH mutation identifies a novel radiologic and molecular subtype of WHO grade II gliomas with dismal prognosis. Acta Neuropathol 120(6):719–729Google Scholar
  46. Minetti D et al (2012) Phase II study of short-course radiotherapy plus concomitant and adjuvant temozolomide in elderly patients with glioblastoma. Radiat Oncol Biol 83(1):93–99CrossRefGoogle Scholar
  47. Narayana A et al (2008) Bevacizumab therapy in recurrent high grade glioma: impact on local control and survival. ASCO Meet Abs 26(15):13000Google Scholar
  48. Norden AD, Drappatz J, Wen PY (2008) Rapid review. Lancet Neurol 7(12):1152–1160PubMedCrossRefGoogle Scholar
  49. Noushmehr H et al (2010) Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17(5):510–522PubMedCentralPubMedCrossRefGoogle Scholar
  50. Parks C, Heald J, Hall G, Kamaly-Asl I (2013) Can the prognosis of individual patients with glioblastoma be predicted using an online calculator? Neuro Oncol 15(8):1074–1078Google Scholar
  51. Parsons DW et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321(5897):1807–1812PubMedCentralPubMedCrossRefGoogle Scholar
  52. Peyre M et al (2010) Prolonged response without prolonged chemotherapy: a lesson from PCV chemotherapy in low-grade gliomas. Neuro Oncol 12(10):1078–1082PubMedCentralPubMedCrossRefGoogle Scholar
  53. Pignatti F (2002) Prognostic factors for survival in adult patients with cerebral low-grade glioma. J Clin Oncol 20(8):2076–2084PubMedCrossRefGoogle Scholar
  54. Pirotte B et al (2004) Combined use of 18F-fluorodeoxyglucose and 11C-methionine in 45 positron emission tomography-guided stereotactic brain biopsies. J Neurosurg 3:476–483CrossRefGoogle Scholar
  55. Reardon DA et al (2011) A review of VEGF/VEGFR-targeted therapeutics for recurrent glioblastoma. J Natl Compr Canc Netw 9(4):414–427PubMedCentralPubMedGoogle Scholar
  56. Ricard D et al (2007) Dynamic history of low-grade gliomas before and after temozolomide treatment. Ann Neurol 61(5):484–490PubMedCrossRefGoogle Scholar
  57. Roa W (2004) Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol: Off J Am Soc Clin Oncol 22(9):1583–1588CrossRefGoogle Scholar
  58. Robertson T, Koszyca B, Gonzales M (2011) Overview and recent advances in neuropathology. Part 1: central nervous system tumours. Pathology 43(2):88–92PubMedCrossRefGoogle Scholar
  59. Sanson M et al (2009) Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol: Off J Am Soc Clin Oncol 27(25):4150–4154CrossRefGoogle Scholar
  60. Schatzkin A, Gail M (2002) The promise and peril of surrogate endpoints in cancer research. Nat Rev Cancer 2:19–27PubMedCrossRefGoogle Scholar
  61. Scott CB et al (1998) Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: a report using RTOG 90–06. Radiat Oncol Biol 40(1):51–55CrossRefGoogle Scholar
  62. Shaw E (2002) Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a north central cancer treatment group/radiation therapy oncology group/eastern cooperative oncology group study. J Clin Oncol 20(9):2267–2276PubMedCrossRefGoogle Scholar
  63. Shaw EG et al (2012) Randomized trial of radiation therapy plus procarbazine, lomustine, and vincristine chemotherapy for supratentorial adult low-grade glioma: initial results of RTOG 9802. J Clin Oncol: Off J Am Soc Clin Oncol 30(25):3065–3070CrossRefGoogle Scholar
  64. Smith JS et al (2000) Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas. J Clin Oncol 18(3):636–645PubMedGoogle Scholar
  65. Smith JS et al (2008) Role of extent of resection in the long-term outcome of low-grade hemispheric gliomas. J Clin Oncol: Off J Am Soc Clin Oncol 26(8):1338–1345CrossRefGoogle Scholar
  66. Stege EM et al (2005) Successful treatment of low-grade oligodendroglial tumors with a chemotherapy regimen of procarbazine, lomustine, and vincristine. Cancer 103(4):802–809PubMedCrossRefGoogle Scholar
  67. Stupp R et al (2009) 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 10(5):459–466PubMedCrossRefGoogle Scholar
  68. Stupp R et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996PubMedCrossRefGoogle Scholar
  69. Tosoni A, Franceschi E, Ermani M, Bertorelle R, Bonaldi L, Blatt V, Brandes AA (2008) Temozolomide three weeks on and one week off as first line therapy for patients with recurrent or progressive low grade gliomas. J Neurooncol 89(2):179–85Google Scholar
  70. Van den Bent M et al (2005) Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. The Lancet 366(9490):985–990CrossRefGoogle Scholar
  71. van den Bent MJ (2006) 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: Off J Am Soc Clin Oncol 24(18):2715–2722CrossRefGoogle Scholar
  72. van den Bent MJ et al (2013) 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: Off J Am Soc Clin Oncol 31(3):344–350CrossRefGoogle Scholar
  73. van den Bent MJ et al (2010) IDH1 and IDH2 mutations are prognostic but not predictive for outcome in anaplastic oligodendroglial tumors: a report of the European organization for research and treatment of cancer brain tumor group. Clin Cancer Res: Off J Am Assoc Cancer Res 16(5):1597–1604CrossRefGoogle Scholar
  74. Vogelbaum MA et al (2009) Phase II trial of preirradiation and concurrent temozolomide in patients with newly diagnosed anaplastic oligodendrogliomas and mixed anaplastic oligoastrocytomas: RTOG BR0131. Neuro-Oncol 11(2):167–175PubMedCentralPubMedGoogle Scholar
  75. Watling CJ et al (1994) Corticosteroid-induced magnetic resonance imaging changes in patients with recurrent malignant glioma. J Clin Oncol: Off J Am Soc Clin Oncol 12(9):1886–1889Google Scholar
  76. Wefel JS et al (2013) Neurocognitive function (NCF) outcomes in patients with glioblastoma (GBM) enrolled in RTOG 0825. ASCO Meet Abs 31(15):2004Google Scholar
  77. Weiss SE, Cheung A, Drappatz J (2010) Hypofractionated radiotherapy with temozolomide for elderly patients with glioblastoma. Int J Radiat Oncol, Biol, Phys 78(3):S271 EPGoogle Scholar
  78. Weller M (2010) Chemotherapy for low-grade gliomas: when? How? how long? Neuro-Oncol 12(10):1013PubMedCentralPubMedCrossRefGoogle Scholar
  79. Weller M et al (2009) Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German glioma network. J Clin Oncol: Off J Am Soc Clin Oncol 27(34):5743–5750CrossRefGoogle Scholar
  80. Weller M, Stupp R, Hegi ME, van den Bent M, Tonn JC, Sanson M, Wick W, Reifenberger G (2012) 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 14:4Google Scholar
  81. Wen PY et al (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol: Off J Am Soc Clin Oncol 28(11):1963–1972CrossRefGoogle Scholar
  82. Wick W et al (2012) Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol 13(7):707–715PubMedCrossRefGoogle Scholar
  83. Wick W et al (2013) Tumor response based on adapted Macdonald criteria and assessment of pseudoprogression (PsPD) in the phase III AVAglio trial of bevacizumab (Bv) plus temozolomide (T) plus radiotherapy (RT) in newly diagnosed glioblastoma (GBM). ASCO Meet Abs 31(15):2002Google Scholar
  84. Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, Deimling von A, Weller M (2009a) NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol: Off J Am Soc Clin Oncol 27(35):5874–5880Google Scholar
  85. Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, Deimling von A, Weller M (2009b) NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol: OffJ Am Soc Clin Oncol 27(35):5874–5880Google Scholar
  86. Yan H et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360(8):765–773PubMedCentralPubMedCrossRefGoogle Scholar
  87. Zhao S et al (2009) Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science 324(5924):261–265PubMedCentralPubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of Radiation Oncology Fox Chase Cancer CenterChief of Adult Brain Tumors Radiotherapy and RadiosurgeryPhiladelphiaUSA
  2. 2.Department of Radiation OncologyFox Chase Cancer CenterPhiladelphiaUSA

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