Advertisement

Radiation Therapy in High-Grade Gliomas

  • Frank Saran
  • Liam Welsh
  • Delali Adjogatse
Living reference work entry
First Online:
Received:
Accepted:

Abstract

High grade gliomas (HGG) account for the majority of primary malignant brain tumors in adults with increasing incidence in age, peaking in the 75–84 age group. Glioblastoma (GB) is the most frequently occurring subtype, followed by anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), and mixed anaplastic oligoastrocytoma (AOA). Since 2016 a new WHO classification has radically changed our understanding of gliomas and introduced a molecular classification system allowing for future, more personalized, treatment approaches.

As the incidence of HGG increases with advancing age, selection of optimal treatment is complicated by preexisting comorbidities and deteriorating performance status. HGG are aggressive tumors which are best managed with a combined modality approach. Maximal surgical resection is associated with improved survival and favorable neurological improved outcome. However, due to the infiltrative nature of HGG, a complete microscopic clearance is rarely possible.

Radiotherapy post surgery  has been the mainstay of treatment for HGG for several decades. Involved field radiotherapy is now the standard approach used to maximize coverage of infiltrative tumor cells, while limiting the volume of normal brain tissue irradiated. Dose escalation above 60Gy, hypo- or hyper-fractionation has not shown any additional benefit. The introduction of concomitant and adjuvant temozolomide to radical radiotherapy has provided a modest but significant improvement in overall survival for patients with GB.

Despite optimal treatment, the prognosis for HGG remains poor with limited treatment options at recurrence. Additional molecular pathways identified in the development of HGG are now the target for novel therapies, which may potentially improve the prognosis of what remains to be a challenging and highly fatal disease.

Keywords

Radiotherapy High grade glioma Malignant glioma Personalised medicine Target volume definition 
This is a preview of subscription content, log in to check access.

References

  1. Armstrong GT, Jain N, Liu W, Merchant TE, Stovall M, Srivastava DK, Gurney JG, Packer RJ, Robison LL, Krull KR. Region-specific radiotherapy and neuropsychological outcomes in adult survivors of childhood CNS malignancies. Neuro-Oncology. 2010;12(11):1173–86.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Avril T, Saikali S, Vauléon E, Jary A, Hamlat A, De Tayrac M, Mosser J, Quillien V. Distinct effects of human glioblastoma immunoregulatory molecules programmed cell death ligand-1 (PDL-1) and indoleamine 2, 3-dioxygenase (IDO) on tumour-specific T cell functions. J Neuroimmunol. 2010;225(1):22–33.CrossRefPubMedGoogle Scholar
  3. Belozerov VE, Van Meir EG. Inhibitors of hypoxia-inducible factor-1 signaling. Curr Opin Investig Drugs. 2006;7:1067–76.PubMedGoogle Scholar
  4. Bhandare N, Jackson A, Eisbruch A, et al. Radiation therapy and hearing loss. Int J Radiat Oncol Biol Phys. 2010;76:S50–7.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bokstein F, Shpigel S, Blumenthal DT. Treatment with bevacizumab and irinotecan for recurrent high-grade glial tumors. Cancer. 2008;112(10):2267–73.CrossRefPubMedGoogle Scholar
  6. Brandes AA, Franceschi E, Tosoni A, Hegi ME, Stupp R. Epidermal growth factor receptor inhibitors in neuro-oncology: hopes and disappointments. Clin Cancer Res. 2008;14(4):957–60.CrossRefPubMedGoogle Scholar
  7. Brandsma D, Stalpers L, Taal W, et al. Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol. 2008;9:453–61.CrossRefPubMedGoogle Scholar
  8. Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA, Black K, Sisti M, Brem S, Mohr G, Muller P. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet. 1995;345(8956):1008–12.CrossRefPubMedGoogle Scholar
  9. Cairncross G, Wang M, Shaw E, Jenkins R, Brachman D, Buckner J, Fink K, Souhami L, Laperriere N, Curran W, Mehta M. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2013;31(3):337.CrossRefPubMedGoogle Scholar
  10. Chamberlain MC. Bevacizumab for the treatment of recurrent glioblastoma. Clin Med Insights Oncol. 2011;5:117.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Chemaitilly W, Li Z, Huang S, Ness KK, Clark KL, Green DM, Barnes N, Armstrong GT, Krasin MJ, Srivastava DK, Pui CH. Anterior hypopituitarism in adult survivors of childhood cancers treated with cranial radiotherapy: a report from the St Jude lifetime cohort study. J Clin Oncol. 2015;33(5):492–500.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Desjardins A, Reardon DA, Herndon JE, Marcello J, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, Bailey L, Bigner DD. Bevacizumab plus irinotecan in recurrent WHO grade 3 malignant gliomas. Clin Cancer Res. 2008;14(21):7068–73.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Dixit S, Hingorani M, Achawal S, Scott I. Retrospective comparison of chemoradiotherapy followed by adjuvant chemotherapy, with or without previous gliadel implantation (carmustine) after initial surgery in patients with newly diagnosed high-grade gliomas: in regard to noel et al. Int J Radiat Oncol Biol Phys. 2011;81(5):1593.CrossRefPubMedGoogle Scholar
  14. Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro-Oncology. 2012;14(5):v1–49.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Farrell CJ, Plotkin SR. Genetic causes of brain tumors: neurofibromatosis, tuberous sclerosis, von Hippel-Lindau, and other syndromes. Neurol Clin. 2007;25(4):925–46.CrossRefPubMedGoogle Scholar
  16. Fisher JL, Schwartzbaum JA, Wrensch M, Wiemels JL. Epidemiology of brain tumors. Neurol Clin. 2007;25:8678–90.CrossRefGoogle Scholar
  17. Furnari FB, Fenton T, Bachoo RM, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev. 2007;21:2683–710.CrossRefPubMedGoogle Scholar
  18. 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;31:4085.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Gondi V, Tolakanahalli R, Mehta MP, Tewatia D, Rowley H, Kuo JS, Khuntia D, Tomé WA. Hippocampal-sparing whole-brain radiotherapy: a “how-to” technique using helical tomotherapy and linear accelerator–based intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys. 2010;78(4):1244–52.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Gorlia T, Stupp R, Brandes AA, et al. New prognostic factors and calculators for outcome prediction in patients with recurrent glioblastoma: a pooled analysis of EORTC brain tumour group phase I and II clinical trials. Eur J Cancer. 2012;48:1176–84.CrossRefPubMedGoogle Scholar
  21. Grabowski MM, Recinos PF, Nowacki AS, Schroeder JL, Angelov L, Barnett GH, Vogelbaum MA. Residual tumor volume versus extent of resection: predictors of survival after surgery for glioblastoma. J Neurosurg. 2014;121(5):1115–23.CrossRefPubMedGoogle Scholar
  22. Hardesty DA, Sanai N. The value of glioma extent of resection in the modern neurosurgical era. Front Neurol. 2012;3:140.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Hartmann C, Meyer J, Balss J, Capper D, Mueller W, Christians A, Felsberg J, Wolter M, Mawrin C, Wick W, Weller M. 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. 2009;118(4):469–74.CrossRefPubMedGoogle Scholar
  24. Helseth R, Helseth E, Johannesen TB, Langberg CW, Lote K, Ronning P, Scheie D, Vik A, Meling TR. Overall survival, prognostic factors, and repeated surgery in a consecutive series of 516 patients with glioblastoma multiforme. Acta Neurol Scand. 2010;122:159–67.CrossRefPubMedGoogle Scholar
  25. Herrlinger U, Felsberg J, Küker W, et al. Gliomatosis cerebri: molecular pathology and clinical course. Ann Neurol. 2002;52:390–9.CrossRefPubMedGoogle Scholar
  26. Hochberg FH, Pruitt A. Assumptions in the radiotherapy of glioblastoma. Neurology. 1980;30(9):907.CrossRefPubMedGoogle Scholar
  27. Horbinski C, Kofler J, Kelly LM, Murdoch GH, Nikiforova MN. Diagnostic use of IDH1/2 mutation analysis in routine clinical testing of formalin-fixed, paraffin-embedded glioma tissues. J Neuropathol Exp Neurol. 2009;68(12):1319–25.CrossRefPubMedGoogle Scholar
  28. Hottinger AF, Levivier M, Negretti L, et al. PET imaging in glioma. The neurooncologist’s expectations. PET Clin. 2013;8:117–28.CrossRefPubMedGoogle Scholar
  29. Jenkins RB, Blair H, Ballman KV, Giannini C, Arusell RM, Law M, Flynn H, Passe S, Felten S, Brown PD, Shaw EG. 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(20):9852–61.CrossRefPubMedGoogle Scholar
  30. Kleinschmidt-DeMasters BK, Aisner DL, Birks DK, Foreman NK. Epithelioid GBMs show a high percentage of BRAF V600E mutation. Am J Surg Pathol. 2013;37(5):685.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, Lang FF, McCutcheon IE, Hassenbusch SJ, Holland E, Hess K. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg. 2001;95(2):190–8.CrossRefPubMedGoogle Scholar
  32. Lahkola A, Auvinen A, Raitanen J, et al. Mobile phone use and risk of glioma in 5 north European countries. Int J Cancer. 2007;120:1769–75.CrossRefPubMedGoogle Scholar
  33. Laperriere N, Zuraw L, Cairncross G, the 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;64:259–73.CrossRefPubMedGoogle Scholar
  34. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803–20.CrossRefGoogle Scholar
  35. Malmer B, Adatto P, Armstrong G, Barnholtz-Sloan J, Bernstein JL, Claus E, Davis F, Houlston R, Il'yasova D, Jenkins R, Johansen C. GLIOGENE—an international consortium to understand familial glioma. Cancer Epidemiol Prev Biomarkers. 2007;16(9):1730–4.CrossRefGoogle Scholar
  36. Malmström A, Grønberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, Abacioglu U, Tavelin B, Lhermitte B, Hegi ME, Rosell J. 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(9):916–26.CrossRefPubMedGoogle Scholar
  37. Mayer R, Sminia P. Reirradiation tolerance of the human brain. Int J Radiat Oncol Biol Phys. 2008;70(5):1350–60.CrossRefPubMedGoogle Scholar
  38. Mayo C, Martel MK, Marks LB, et al. Radiation dose-volume effects of optic nerves and chiasm. Int J Radiat Oncol Biol Phys. 2010a;76:S28–35.CrossRefPubMedGoogle Scholar
  39. Mayo C, Yorke E, Merchant TE. Radiation associated brainstem injury. Int J Radiat Oncol Biol Phys. 2010b;76:S36–41.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 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.CrossRefGoogle Scholar
  41. Nieder C, Astner ST, Mehta MP, Grosu AL, Molls M. Improvement, clinical course, and quality of life after palliative radiotherapy for recurrent glioblastoma. Am J Clin Oncol. 2008;31:300–5.CrossRefPubMedGoogle Scholar
  42. Niyazi M, Brada M, Chalmers AJ, Combs SE, Erridge SC, Fiorentino A, Grosu AL, Lagerwaard FJ, Minniti G, Mirimanoff RO, Ricardi U. ESTRO-ACROP guideline “target delineation of glioblastomas”. Radiother Oncol. 2016;118(1):35–42.CrossRefPubMedGoogle Scholar
  43. Noorbakhsh A, Tang JA, Marcus LP, McCutcheon B, Gonda DD, Schallhorn CS, Talamini MA, Chang DC, Carter BS, Chen CC. Gross-total resection outcomes in an elderly population with glioblastoma: a SEER-based analysis. J Neurosurg. 2014;120(1):31–9.CrossRefPubMedGoogle Scholar
  44. Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP, Pan F, Pelloski CE, Sulman EP, Bhat KP, Verhaak RG. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010;17(5):510–22.CrossRefPubMedPubMedCentralGoogle Scholar
  45. Okada H, Weller M, Huang R, et al. Immunotherapy response assessment in neuro-oncology (iRANO): a report of the RANO working group. Lancet Oncol. 2015;16(15):e534–42.CrossRefPubMedPubMedCentralGoogle Scholar
  46. Paleologos TS, Dorward NL, Wadley JP, Thomas DG. Clinical validation of true frameless stereotactic biopsy: analysis of the first 125 consecutive cases. Neurosurgery. 2001;49(4):830–7.PubMedGoogle Scholar
  47. Paulsson AK, McMullen KP, Peiffer AM, Hinson WH, Kearns WT, Johnson AJ, Lesser GJ, Ellis TL, Tatter SB, Debinski W, Shaw EG. Limited margins using modern radiotherapy techniques does not increase marginal failure rate of glioblastoma. Am J Clin Oncol. 2014;37(2):177.CrossRefPubMedPubMedCentralGoogle Scholar
  48. Perry JR. Thromboembolic disease in patients with high-grade glioma. Neuro-Oncology. 2012;14(4):iv73–80.PubMedPubMedCentralGoogle Scholar
  49. Perry JR, Rizek P, Cashman R, Morrison M, Morrison T. Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule. Cancer. 2008;113(8):2152–7.CrossRefPubMedGoogle Scholar
  50. Perry JR, Laperriere N, O’Callaghan CJ, Brandes AA, Menten J, Phillips C, Fay M, Nishikawa R, Cairncross JG, Roa W, Osoba D. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med. 2017;376(11):1027–37.CrossRefPubMedGoogle Scholar
  51. Reardon DA, Schuster J, Tran DD, Fink KL, Nabors LB, Li G, Bota DA, Lukas RV, Desjardins A, Ashby LS, Duic JP. ReACT: overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma. Neuro Oncol. 2014;16(Suppl 5):v116Google Scholar
  52. Ringel F. SN1 study group, Pape H, SN1 study group, Sabel M, SN1 study group, Krex D, SN1 study group, bock HC, SN1 study group, Misch M. Clinical benefit from resection of recurrent glioblastomas: results of a multicenter study including 503 patients with recurrent glioblastomas undergoing surgical resection. Neuro-Oncology. 2015;18(1):96–104.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 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;22:1583e1588.CrossRefGoogle Scholar
  54. Romanelli P, Conti A, Pontoriero A, Ricciardi GK, Tomasello F, De Renzis C, Innocenzi G, Esposito V, Cantore G. Role of stereotactic radiosurgery and fractionated stereotactic radiotherapy for the treatment of recurrent glioblastoma multiforme. Neurosurg Focus. 2009;27(6):E8.CrossRefPubMedGoogle Scholar
  55. Sanai N, Polley MY, McDermott MW, Parsa AT, Berger MS. An extent of resection threshold for newly diagnosed glioblastomas. J Neurosurg. 2011;115(1):3–8.CrossRefPubMedGoogle Scholar
  56. Sanson M, Cartalat-Carel S, Taillibert S, the ANOCEF Group, et al. Initial chemotherapy in gliomatosis cerebri. Neurology. 2004;63:270–5.CrossRefPubMedGoogle Scholar
  57. Sanson M, Marie Y, Paris S, Idbaih A, Laffaire J, Ducray F, El Hallani S, Boisselier B, Mokhtari K, Hoang-Xuan K, Delattre JY. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol. 2009;27(25):4150–4.CrossRefPubMedGoogle Scholar
  58. Sathornsumetee S, Rich JN, Reardon DA. Diagnosis and treatment of high grade astrocytoma. Neurol Clin. 2007;25:1111–39.CrossRefPubMedGoogle Scholar
  59. Senft C, Bink A, Franz K, Vatter H, Gasser T, Seifert V. Intraoperative MRI guidance and extent of resection in glioma surgery: a randomised, controlled trial. Lancet Oncol. 2011;12(11):997–1003.CrossRefPubMedGoogle Scholar
  60. Stewart LA, Group GM. Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet. 2002;359(9311):1011–8.CrossRefPubMedGoogle Scholar
  61. Stummer W, Pichlmeier U, Meinel T, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7:392–401.CrossRefPubMedGoogle Scholar
  62. Stupp R, Mason WP, Van Den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96.CrossRefPubMedGoogle Scholar
  63. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P. 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(5):459–66.CrossRefGoogle Scholar
  64. Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, Aldape KD, Lhermitte B, Pietsch T, Grujicic D, Steinbach JP. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(10):1100–8.CrossRefPubMedGoogle Scholar
  65. Subbiah V, Bang YJ, Lassen UN, Wainberg ZA, Soria JC, Wen PY, Zenz T, Moreau P, Brunsvig P, De Braud FG, De Greve J. ROAR: a phase 2, open-label study in patients (pts) with BRAF V600E–mutated rare cancers to investigate the efficacy and safety of dabrafenib (D) and trametinib (T) combination therapy. J Clin Oncol. 2016;34(15).Google Scholar
  66. Theeler BJ, Gilbert MR. Advances in the treatment of newly diagnosed glioblastoma. BMC Med. 2015;13(1):293.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 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.CrossRefPubMedGoogle Scholar
  68. Van Den Bent MJ, Erridge S, Vogelbaum MA, Nowak AK, Sanson M, Brandes AA, Wick W, Clement PM, Baurain JF, Mason WP, Wheeler H. Results of the interim analysis of the EORTC randomized phase III CATNON trial on concurrent and adjuvant temozolomide in anaplastic glioma without 1p/19q co-deletion: an Intergroup trial. Lancet. 2017;390:1645–1653Google Scholar
  69. 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;49:333–43.CrossRefPubMedGoogle Scholar
  70. Wallner KE, Galicich JH, Krol G, Arbit E, Malkin MG. Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys. 1989;16(6):1405–9.CrossRefPubMedGoogle Scholar
  71. Weller M, Stupp R, Wick W. Epilepsy meets cancer: when, why, and what to do about it? Lancet Oncol. 2012;13(9):e375–82.CrossRefPubMedGoogle Scholar
  72. Weller M, van den Bent M, Hopkins K, Tonn JC, Stupp R, Falini A, Cohen-Jonathan-Moyal E, Frappaz D, Henriksson R, Balana C, Chinot O. EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma. Lancet Oncol. 2014;15(9):e395–403.CrossRefPubMedGoogle Scholar
  73. Weller M, Butowski N, Tran DD, Recht LD, Lim M, Hirte H, Ashby L, Mechtler L, Goldlust SA, Iwamoto F, Drappatz J. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol. 2017;18(10):1373–85.CrossRefPubMedGoogle Scholar
  74. Wen PY, Schiff D, Kesari S, Drappatz J, Gigas D, Doherty L. Medical management of patients with brain tumors. J Neuro-Oncol. 2006;80:313–32.CrossRefGoogle Scholar
  75. 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.CrossRefPubMedGoogle Scholar
  76. 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-Oncology. 2003;5:79–88.CrossRefPubMedPubMedCentralGoogle Scholar
  77. Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009;27(35):5874–80.CrossRefPubMedGoogle Scholar
  78. Wick W, Meisner C, Hentschel B, Platten M, Schilling A, Wiestler B, Sabel MC, Koeppen S, Ketter R, Weiler M, Tabatabai G. Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation. Neurology. 2013;81(17):1515–22.CrossRefPubMedGoogle Scholar
  79. Yin A-a, Zhang L-h, Cheng J-x, Dong Y, Liu B-l, et al. Radiotherapy plus concurrent or sequential temozolomide for glioblastoma in the elderly: a meta-analysis. PLoS One. 2013;8(9):e74242.CrossRefPubMedPubMedCentralGoogle Scholar
  80. You G, Sha Z, Jiang T. The pathogenesis of tumor-related epilepsy and its implications for clinical treatment. Seizure. 2012;21:153–9.CrossRefPubMedGoogle Scholar
  81. Zach L, Guez D, Last D, Daniels D, Grober Y, Nissim O, Hoffmann C, Nass D, Talianski A, Spiegelmann R, Tsarfaty G. Delayed contrast extravasation MRI: a new paradigm in neuro-oncology. Neuro-Oncology. 2014;17(3):457–65.CrossRefPubMedPubMedCentralGoogle Scholar
  82. Zhao F, Li M, Kong L, Zhang G, Yu J. Delineation of radiation therapy target volumes for patients with postoperative glioblastoma: a review. OncoTargets Ther. 2016;9:3197–204.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Radiotherapy and Neuro-oncologyRoyal Marsden Hospital NHS Foundation TrustSuttonUK

Personalised recommendations

Cite entry