WHO II and III Gliomas

  • Shawn L. Hervey-Jumper
  • M. J. van de Bent
  • Minesh P. Mehta
  • Mitchel S. BergerEmail author


Over 70,000 patients are diagnosed each year with a glioma. Prognosis and response to chemoradiation are determined by balanced translocations between chromosomes 1p and 19q in addition to the presence of mutations within isocitrate dehydrogenase 1 or 2 genes. WHO II and III gliomas are therefore subclassified according to both histopathology and molecular characterization. Regardless of tumor type, the first step in management remains surgical resection. It has been well established that greater extent of tumor resection impacts both overall and progression-free survival. Maximal resection can be difficult to achieve due to tumor proximity to eloquent structures and uncertainty as to tumor margins. Direct stimulation mapping, functional neuronavigation, and intraoperative MRI are all useful tools to improve extent of tumor resection while minimizing morbidity. Alkylating chemotherapy in addition to radiation therapy is used to improve survival for high-risk patient populations. This chapter is focused on the management of WHO II and III gliomas including strategies such as cytoreduction surgery, radiotherapy, and chemotherapy.


Low-grade glioma Oligodendroglioma Astrocytoma Extent of resection radiotherapy Chemotherapy Temozolomide PCV 


  1. 1.
    Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, Langer CE et al (2014) The epidemiology of glioma in adults: a “state of the science” review. Neuro Oncol 16(7):896–913. Scholar
  2. 2.
    Osorio JA, Hervey-Jumper SL, Walsh KM, Clarke JL, Butowski NA, Prados MD et al (2015) Familial gliomas: cases in two pairs of brothers. J Neurooncol 121(1):135–140. Scholar
  3. 3.
    Shete S, Hosking FJ, Robertson LB, Dobbins SE, Sanson M, Malmer B et al (2009) Genome-wide association study identifies five susceptibility loci for glioma. Nat Genet 41(8):899–904. Scholar
  4. 4.
    Wrensch M, Jenkins RB, Chang JS, Yeh RF, Xiao Y, Decker PA et al (2009) Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility. Nat Genet 41(8):905–908. Scholar
  5. 5.
    Sanson M, Hosking FJ, Shete S, Zelenika D, Dobbins SE, Ma Y et al (2011) Chromosome 7p11.2 (EGFR) variation influences glioma risk. Hum Mol Genet 20(14):2897–2904. Scholar
  6. 6.
    Stacey SN, Sulem P, Jonasdottir A, Masson G, Gudmundsson J, Gudbjartsson DF et al (2011) A germline variant in the TP53 polyadenylation signal confers cancer susceptibility. Nat Genet 43(11):1098–1103. Scholar
  7. 7.
    Rajaraman P, Melin BS, Wang Z, McKean-Cowdin R, Michaud DS, Wang SS et al (2012) Genome-wide association study of glioma and meta-analysis. Hum Genet 131(12):1877–1888. Scholar
  8. 8.
    Preston DL, Ron E, Yonehara S, Kobuke T, Fujii H, Kishikawa M et al (2002) Tumors of the nervous system and pituitary gland associated with atomic bomb radiation exposure. J Natl Cancer Inst 94(20):1555–1563CrossRefGoogle Scholar
  9. 9.
    Schwartzbaum JA, Fisher JL, Aldape KD, Wrensch M (2006) Epidemiology and molecular pathology of glioma. Nat Clin Pract Neurol 2:494. Scholar
  10. 10.
    Bondy ML, Scheurer ME, Malmer B, Barnholtz-Sloan JS, Davis FG, Il’yasova D et al (2008) Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium. Cancer 113(7 Suppl):1953–1968. Scholar
  11. 11.
    Sadetzki S, Chetrit A, Freedman L, Stovall M, Modan B, Novikov I (2005) Long-term follow-up for brain tumor development after childhood exposure to ionizing radiation for tinea capitis. Radiat Res 163(4):424–432. Scholar
  12. 12.
    Turner MC, Krewski D, Armstrong BK, Chetrit A, Giles GG, Hours M et al (2013) Allergy and brain tumors in the INTERPHONE study: pooled results from Australia, Canada, France, Israel, and New Zealand. Cancer Causes Control 24(5):949–960. Scholar
  13. 13.
    Chen C, Xu T, Chen J, Zhou J, Yan Y, Lu Y et al (2011) Allergy and risk of glioma: a meta-analysis. Eur J Neurol 18(3):387–395. Scholar
  14. 14.
    Baan R, Grosse Y, Lauby-Secretan B, El Ghissassi F, Bouvard V, Benbrahim-Tallaa L et al (2011) Carcinogenicity of radiofrequency electromagnetic fields. Lancet Oncol 12(7):624–626. Scholar
  15. 15.
    Chang EF, Potts MB, Keles GE, Lamborn KR, Chang SM, Barbaro NM et al (2008) Seizure characteristics and control following resection in 332 patients with low-grade gliomas. J Neurosurg 108(2):227–235. Scholar
  16. 16.
    Smith JS, Chang EF, Lamborn KR, Chang SM, Prados MD, Cha S et al (2008) Role of extent of resection in the long-term outcome of low-grade hemispheric gliomas. J Clin Oncol 26(8):1338–1345. Scholar
  17. 17.
    Pallud J, Fontaine D, Duffau H, Mandonnet E, Sanai N, Taillandier L et al (2010) Natural history of incidental World Health Organization grade II gliomas. Ann Neurol 68(5):727–733. Scholar
  18. 18.
    Cancer Genome Atlas Research Network, Brat DJ, Verhaak RG, Aldape KD, Yung WK, Salama SR et al (2015) Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 372(26):2481–2498. Scholar
  19. 19.
    Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA et al (2016) Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 164(3):550–563. Scholar
  20. 20.
    Buckner JC, Shaw EG, Pugh SL, Chakravarti A, Gilbert MR, Barger GR et al (2016) Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med 374(14):1344–1355. Scholar
  21. 21.
    Lote K, Egeland T, Hager B, Skullerud K, Hirschberg H (1998) Prognostic significance of CT contrast enhancement within histological subgroups of intracranial glioma. J Neurooncol 40(2):161–170CrossRefGoogle Scholar
  22. 22.
    Roberts HC, Roberts TP, Brasch RC, Dillon WP (2000) Quantitative measurement of microvascular permeability in human brain tumors achieved using dynamic contrast-enhanced MR imaging: correlation with histologic grade. AJNR Am J Neuroradiol 21(5):891–899PubMedGoogle Scholar
  23. 23.
    Smits M (2016) Imaging of oligodendroglioma. Br J Radiol 89(1060):20150857. Scholar
  24. 24.
    Pekmezci M, Rice T, Molinaro AM, Walsh KM, Decker PA, Hansen H et al (2017) Adult infiltrating gliomas with WHO 2016 integrated diagnosis: additional prognostic roles of ATRX and TERT. Acta Neuropathol 133(6):1001–1016. Scholar
  25. 25.
    Wijnenga MMJ, Dubbink HJ, French PJ, Synhaeve NE, Dinjens WNM, Atmodimedjo PN et al (2017) Molecular and clinical heterogeneity of adult diffuse low-grade IDH wild-type gliomas: assessment of TERT promoter mutation and chromosome 7 and 10 copy number status allows superior prognostic stratification. Acta Neuropathol 134(6):957–959. Scholar
  26. 26.
    Aoki K, Nakamura H, Suzuki H, Matsuo K, Kataoka K, Shimamura T et al (2018) Prognostic relevance of genetic alterations in diffuse lower-grade gliomas. Neuro Oncol 20(1):66–77. Scholar
  27. 27.
    Aibaidula A, Chan AK, Shi Z, Li Y, Zhang R, Yang R et al (2017) Adult IDH wild-type lower-grade gliomas should be further stratified. Neuro Oncol 19(10):1327–1337. Scholar
  28. 28.
    Wijnenga MMJ, French PJ, Dubbink HJ, Dinjens WNM, Atmodimedjo PN, Kros JM et al (2018) The impact of surgery in molecularly defined low-grade glioma: an integrated clinical, radiological, and molecular analysis. Neuro Oncol 20(1):103–112. Scholar
  29. 29.
    Kawaguchi T, Sonoda Y, Shibahara I, Saito R, Kanamori M, Kumabe T et al (2016) Impact of gross total resection in patients with WHO grade III glioma harboring the IDH 1/2 mutation without the 1p/19q co-deletion. J Neurooncol 129(3):505–514. Scholar
  30. 30.
    Reuss DE, Mamatjan Y, Schrimpf D, Capper D, Hovestadt V, Kratz A et al (2015) IDH mutant diffuse and anaplastic astrocytomas have similar age at presentation and little difference in survival: a grading problem for WHO. Acta Neuropathol 129(6):867–873. Scholar
  31. 31.
    Olar A, Wani KM, Alfaro-Munoz KD, Heathcock LE, van Thuijl HF, Gilbert MR et al (2015) IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II-III diffuse gliomas. Acta Neuropathol 129(4):585–596. Scholar
  32. 32.
    Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP et al (2010) Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17(5):510–522. Scholar
  33. 33.
    de Souza CF, Sabedot TS, Malta TM, Stetson L, Morozova O, Sokolov A et al (2018) A distinct DNA methylation shift in a subset of glioma CpG island methylator phenotypes during tumor recurrence. Cell Rep 23(2):637–651. Scholar
  34. 34.
    Shirahata M, Ono T, Stichel D, Schrimpf D, Reuss DE, Sahm F et al (2018) Novel, improved grading system(s) for IDH-mutant astrocytic gliomas. Acta Neuropathol 136(1):153–166. Scholar
  35. 35.
    Alentorn A, Dehais C, Ducray F, Carpentier C, Mokhtari K, Figarella-Branger D et al (2015) Allelic loss of 9p21.3 is a prognostic factor in 1p/19q codeleted anaplastic gliomas. Neurology 85(15):1325–1331. Scholar
  36. 36.
    Wijnenga MMJ, French PJ, Dubbink HJ, Dinjens WNM, Atmodimedjo PN, Kros JM et al (2018) Prognostic relevance of mutations and copy number alterations assessed with targeted next generation sequencing in IDH mutant grade II glioma. J Neurooncol 139(2):349–357. Scholar
  37. 37.
    Gleize V, Alentorn A, Connen de Kerillis L, Labussiere M, Nadaradjane AA, Mundwiller E et al (2015) CIC inactivating mutations identify aggressive subset of 1p19q codeleted gliomas. Ann Neurol 78(3):355–374. Scholar
  38. 38.
    Dubbink HJ, Atmodimedjo PN, Kros JM, French PJ, Sanson M, Idbaih A et al (2016) Molecular classification of anaplastic oligodendroglioma using next-generation sequencing: a report of the prospective randomized EORTC Brain Tumor Group 26951 phase III trial. Neuro Oncol 18(3):388–400. Scholar
  39. 39.
    Kamoun A, Idbaih A, Dehais C, Elarouci N, Carpentier C, Letouze E et al (2016) Integrated multi-omics analysis of oligodendroglial tumours identifies three subgroups of 1p/19q co-deleted gliomas. Nat Commun 7:11263. Scholar
  40. 40.
    Draaisma K, Wijnenga MM, Weenink B, Gao Y, Smid M, Robe P et al (2015) PI3 kinase mutations and mutational load as poor prognostic markers in diffuse glioma patients. Acta Neuropathol Commun 3:88. Scholar
  41. 41.
    Claus EB, Walsh KM, Wiencke JK, Molinaro AM, Wiemels JL, Schildkraut JM et al (2015) Survival and low-grade glioma: the emergence of genetic information. Neurosurg Focus 38(1):E6. Scholar
  42. 42.
    Eckel-Passow JE, Lachance DH, Molinaro AM, Walsh KM, Decker PA, Sicotte H et al (2015) Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med 372(26):2499–2508. Scholar
  43. 43.
    Walsh KM, Wiencke JK, Lachance DH, Wiemels JL, Molinaro AM, Eckel-Passow JE et al (2015) Telomere maintenance and the etiology of adult glioma. Neuro Oncol 17(11):1445–1452. Scholar
  44. 44.
    Snyder LA, Wolf AB, Oppenlander ME, Bina R, Wilson JR, Ashby L et al (2014) The impact of extent of resection on malignant transformation of pure oligodendrogliomas. J Neurosurg 120(2):309–314. Scholar
  45. 45.
    Hervey-Jumper SL, Berger MS (2014) Role of surgical resection in low- and high-grade gliomas. Curr Treat Options Neurol 16(4):284CrossRefGoogle Scholar
  46. 46.
    Frazier JL, Johnson MW, Burger PC, Weingart JD, Quinones-Hinojosa A (2010) Rapid malignant transformation of low-grade astrocytomas: report of 2 cases and review of the literature. World Neurosurg 73(1):53–62; discussion e5. Scholar
  47. 47.
    North CA, North RB, Epstein JA, Piantadosi S, Wharam MD (1990) Low-grade cerebral astrocytomas. Survival and quality of life after radiation therapy. Cancer 66(1):6–14CrossRefGoogle Scholar
  48. 48.
    Whitton AC, Bloom HJ (1990) Low grade glioma of the cerebral hemispheres in adults: a retrospective analysis of 88 cases. Int J Radiat Oncol Biol Phys 18(4):783–786CrossRefGoogle Scholar
  49. 49.
    Rajan B, Pickuth D, Ashley S, Traish D, Monro P, Elyan S et al (1994) The management of histologically unverified presumed cerebral gliomas with radiotherapy. Int J Radiat Oncol Biol Phys 28(2):405–413CrossRefGoogle Scholar
  50. 50.
    Nicolato A, Gerosa MA, Fina P, Iuzzolino P, Giorgiutti F, Bricolo A (1995) Prognostic factors in low-grade supratentorial astrocytomas: a uni-multivariate statistical analysis in 76 surgically treated adult patients. Surg Neurol 44(3):208–221; discussion 21–3CrossRefGoogle Scholar
  51. 51.
    Karim AB, Maat B, Hatlevoll R, Menten J, Rutten EH, Thomas DG et al (1996) A randomized trial on dose-response in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) Study 22844. Int J Radiat Oncol Biol Phys 36(3):549–556CrossRefGoogle Scholar
  52. 52.
    Leighton C, Fisher B, Bauman G, Depiero S, Stitt L, MacDonald D et al (1997) Supratentorial low-grade glioma in adults: an analysis of prognostic factors and timing of radiation. J Clin Oncol 15(4):1294–1301. Scholar
  53. 53.
    Lote K, Egeland T, Hager B, Stenwig B, Skullerud K, Berg-Johnsen J et al (1997) Survival, prognostic factors, and therapeutic efficacy in low-grade glioma: a retrospective study in 379 patients. J Clin Oncol 15(9):3129–3140. Scholar
  54. 54.
    Peraud A, Ansari H, Bise K, Reulen H (1998) Clinical outcome of supratentorial astrocytoma WHO grade II. Acta Neurochir 140(12):1213–1222CrossRefGoogle Scholar
  55. 55.
    van Veelen ML, Avezaat CJ, Kros JM, van Putten W, Vecht C (1998) Supratentorial low grade astrocytoma: prognostic factors, dedifferentiation, and the issue of early versus late surgery. J Neurol Neurosurg Psychiatry 64(5):581–587CrossRefGoogle Scholar
  56. 56.
    Nakamura M, Konishi N, Tsunoda S, Nakase H, Tsuzuki T, Aoki H et al (2000) Analysis of prognostic and survival factors related to treatment of low-grade astrocytomas in adults. Oncology 58(2):108–116. Scholar
  57. 57.
    Shaw E, Arusell R, Scheithauer B, O’Fallon J, O’Neill B, Dinapoli R et al (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):2267–2276. Scholar
  58. 58.
    Johannesen TB, Langmark F, Lote K (2003) Progress in long-term survival in adult patients with supratentorial low-grade gliomas: a population-based study of 993 patients in whom tumors were diagnosed between 1970 and 1993. J Neurosurg 99(5):854–862. Scholar
  59. 59.
    Scerrati M, Roselli R, Iacoangeli M, Pompucci A, Rossi GF (1996) Prognostic factors in low grade (WHO grade II) gliomas of the cerebral hemispheres: the role of surgery. J Neurol Neurosurg Psychiatry 61(3):291–296CrossRefGoogle Scholar
  60. 60.
    Ito S, Chandler KL, Prados MD, Lamborn K, Wynne J, Malec MK et al (1994) Proliferative potential and prognostic evaluation of low-grade astrocytomas. J Neurooncol 19(1):1–9CrossRefGoogle Scholar
  61. 61.
    Claus EB, Horlacher A, Hsu L, Schwartz RB, Dello-Iacono D, Talos F et al (2005) Survival rates in patients with low-grade glioma after intraoperative magnetic resonance image guidance. Cancer 103(6):1227–1233. Scholar
  62. 62.
    Yeh SA, Ho JT, Lui CC, Huang YJ, Hsiung CY, Huang EY (2005) Treatment outcomes and prognostic factors in patients with supratentorial low-grade gliomas. Br J Radiol 78(927):230–235. Scholar
  63. 63.
    Shibamoto Y, Kitakabu Y, Takahashi M, Yamashita J, Oda Y, Kikuchi H et al (1993) Supratentorial low-grade astrocytoma. Correlation of computed tomography findings with effect of radiation therapy and prognostic variables. Cancer 72(1):190–195CrossRefGoogle Scholar
  64. 64.
    Sanai N, Berger MS (2008) Glioma extent of resection and its impact on patient outcome. Neurosurgery 62(4):753–764.; ; discussion 264–6. Scholar
  65. 65.
    Bauman G, Fisher B, Watling C, Cairncross JG, Macdonald D (2009) Adult supratentorial low-grade glioma: long-term experience at a single institution. Int J Radiat Oncol Biol Phys 75(5):1401–1407. Scholar
  66. 66.
    Incekara F, Olubiyi O, Ozdemir A, Lee T, Rigolo L, Golby A (2016) The value of pre- and intraoperative adjuncts on the extent of resection of hemispheric low-grade gliomas: a retrospective analysis. J Neurol Surg A Cent Eur Neurosurg 77(2):79–87. Scholar
  67. 67.
    Jakola AS, Myrmel KS, Kloster R, Torp SH, Lindal S, Unsgard G et al (2012) Comparison of a strategy favoring early surgical resection vs a strategy favoring watchful waiting in low-grade gliomas. JAMA 308(18):1881–1888. Scholar
  68. 68.
    Hervey-Jumper SL, Li J, Lau D, Molinaro AM, Perry DW, Meng L et al (2015) Awake craniotomy to maximize glioma resection: methods and technical nuances over a 27-year period. J Neurosurg 123(2):325–339. Scholar
  69. 69.
    Penfield W, Boldrey E (1937) Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation. Brain 60(4):389–443. Scholar
  70. 70.
    Foerster O (1931) The cerebral cortex in man. Lancet 221:309–312Google Scholar
  71. 71.
    Herholz K, Thiel A, Wienhard K, Pietrzyk U, von Stockhausen HM, Karbe H et al (1996) Individual functional anatomy of verb generation. Neuroimage 3(3 Pt 1):185–194. Scholar
  72. 72.
    Sanai N, Berger MS (2009) Operative techniques for gliomas and the value of extent of resection. Neurotherapeutics 6(3):478–486. Scholar
  73. 73.
    Schneider JP, Trantakis C, Rubach M, Schulz T, Dietrich J, Winkler D et al (2005) Intraoperative MRI to guide the resection of primary supratentorial glioblastoma multiforme—a quantitative radiological analysis. Neuroradiology 47(7):489–500. Scholar
  74. 74.
    Senft C, Bink A, Franz K, Vatter H, Gasser T, Seifert V (2011) Intraoperative MRI guidance and extent of resection in glioma surgery: a randomised, controlled trial. Lancet Oncol 12(11):997–1003. Scholar
  75. 75.
    Stummer W, Stocker S, Wagner S, Stepp H, Fritsch C, Goetz C et al (1998) Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence. Neurosurgery 42(3):518–525; discussion 25-6CrossRefGoogle Scholar
  76. 76.
    Marbacher S, Klinger E, Schwyzer L, Fischer I, Nevzati E, Diepers M et al (2014) Use of fluorescence to guide resection or biopsy of primary brain tumors and brain metastases. Neurosurg Focus 36(2):E10. Scholar
  77. 77.
    Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen H-J (2006) Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7(5):392–401. Scholar
  78. 78.
    Cairncross G, Macdonald D, Ludwin S, Lee D, Cascino T, Buckner J et al (1994) Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 12(10):2013–2021. Scholar
  79. 79.
    Yung WK, Prados MD, Yaya-Tur R, Rosenfeld SS, Brada M, Friedman HS et al (1999) Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group J Clin Oncol 17(9):2762–2771. Scholar
  80. 80.
    van den Bent MJ, Taphoorn MJ, Brandes AA, Menten J, Stupp R, Frenay M et al (2003) 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 21(13):2525–2528. Scholar
  81. 81.
    Cairncross JG, Ueki K, Zlatescu MC, Lisle DK, Finkelstein DM, Hammond RR et al (1998) Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 90(19):1473–1479CrossRefGoogle Scholar
  82. 82.
    Taal W, Dubbink HJ, Zonnenberg CB, Zonnenberg BA, Postma TJ, Gijtenbeek JM et al (2011) First-line temozolomide chemotherapy in progressive low-grade astrocytomas after radiotherapy: molecular characteristics in relation to response. Neuro Oncol 13(2):235–241. Scholar
  83. 83.
    Cairncross G, Wang M, Shaw E, Jenkins R, Brachman D, Buckner J et al (2013) Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol 31(3):337–343. Scholar
  84. 84.
    van den Bent MJ, Brandes AA, Taphoorn MJ, Kros JM, Kouwenhoven MC, Delattre JY 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 31(3):344–350. Scholar
  85. 85.
    van den Bent MJ, Baumert B, Erridge SC, Vogelbaum MA, Nowak AK, Sanson M et al (2017) Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet 390(10103):1645–1653. Scholar
  86. 86.
    Cairncross JG, Wang M, Jenkins RB, Shaw EG, Giannini C, Brachman DG et al (2014) Benefit from procarbazine, lomustine, and vincristine in oligodendroglial tumors is associated with mutation of IDH. J Clin Oncol 32(8):783–790. Scholar
  87. 87.
    van den Bent MJ, Erdem-Eraslan L, Idbaih A, de Rooi J, Eilers PH, Spliet WG et al (2013) MGMT-STP27 methylation status as predictive marker for response to PCV in anaplastic oligodendrogliomas and oligoastrocytomas. A report from EORTC study 26951. Clin Cancer Res 19(19):5513–5522. Scholar
  88. 88.
    Wick W, Roth P, Hartmann C, Hau P, Nakamura M, Stockhammer F et al (2016) Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. Neuro Oncol 18(11):1529–1537. Scholar
  89. 89.
    Baumert BG, Hegi ME, van den Bent MJ, von Deimling A, Gorlia T, Hoang-Xuan K et al (2016) Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol 17(11):1521–1532. Scholar
  90. 90.
    Wahl M, Phillips JJ, Molinaro AM, Lin Y, Perry A, Haas-Kogan DA et al (2017) Chemotherapy for adult low-grade gliomas: clinical outcomes by molecular subtype in a phase II study of adjuvant temozolomide. Neuro Oncol 19(2):242–251. Scholar
  91. 91.
    Izquierdo C, Alentorn A, Idbaih A, Simo M, Kaloshi G, Ricard D et al (2018) Long-term impact of temozolomide on 1p/19q-codeleted low-grade glioma growth kinetics. J Neurooncol 136(3):533–539. Scholar
  92. 92.
    Taal W, van der Rijt CC, Dinjens WN, Sillevis Smitt PA, Wertenbroek AA, Bromberg JE et al (2015) Treatment of large low-grade oligodendroglial tumors with upfront procarbazine, lomustine, and vincristine chemotherapy with long follow-up: a retrospective cohort study with growth kinetics. J Neurooncol 121(2):365–372. Scholar
  93. 93.
    Thomas AA, Abrey LE, Terziev R, Raizer J, Martinez NL, Forsyth P et al (2017) Multicenter phase II study of temozolomide and myeloablative chemotherapy with autologous stem cell transplant for newly diagnosed anaplastic oligodendroglioma. Neuro Oncol 19(10):1380–1390. Scholar
  94. 94.
    Johnson BE, Mazor T, Hong C, Barnes M, Aihara K, CY ML et al (2014) Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 343(6167):189–193. Scholar
  95. 95.
    Chang S, Zhang P, Cairncross JG, Gilbert MR, Bahary JP, Dolinskas CA et al (2017) Phase III randomized study of radiation and temozolomide versus radiation and nitrosourea therapy for anaplastic astrocytoma: results of NRG Oncology RTOG 9813. Neuro Oncol 19(2):252–258. Scholar
  96. 96.
    Lassman AB, Iwamoto FM, Cloughesy TF, Aldape KD, Rivera AL, Eichler AF et al (2011) International retrospective study of over 1000 adults with anaplastic oligodendroglial tumors. Neuro Oncol 13(6):649–659. Scholar
  97. 97.
    Figarella-Branger D, Mokhtari K, Dehais C, Jouvet A, Uro-Coste E, Colin C et al (2014) Mitotic index, microvascular proliferation, and necrosis define 3 groups of 1p/19q codeleted anaplastic oligodendrogliomas associated with different genomic alterations. Neuro Oncol 16(9):1244–1254. Scholar
  98. 98.
    Desjardins A, Reardon DA, Herndon JE 2nd, Marcello J, Quinn JA, Rich JN et al (2008) Bevacizumab plus irinotecan in recurrent WHO grade 3 malignant gliomas. Clin Cancer Res 14(21):7068–7073. Scholar
  99. 99.
    Chamberlain MC, Johnston S (2009) Bevacizumab for recurrent alkylator-refractory anaplastic oligodendroglioma. Cancer 115(8):1734–1743. Scholar
  100. 100.
    Chamberlain MC, Johnston S (2009) Salvage chemotherapy with bevacizumab for recurrent alkylator-refractory anaplastic astrocytoma. J Neurooncol 91(3):359–367. Scholar
  101. 101.
    Taillibert S, Vincent LA, Granger B, Marie Y, Carpentier C, Guillevin R et al (2009) Bevacizumab and irinotecan for recurrent oligodendroglial tumors. Neurology 72(18):1601–1606. Scholar
  102. 102.
    Van Den Bent MJ, Klein M, Smits M, Reijneveld JC, Idbaih A, Clement P et al (2017) Final results of the EORTC Brain Tumor Group randomized phase II TAVAREC trial on temozolomide with or without bevacizumab in 1st recurrence grade II/III glioma without 1p/19q co-deletion. J Clin Oncol 35(15):2009CrossRefGoogle Scholar
  103. 103.
    Cairncross JG, Macdonald DR (1988) Successful chemotherapy for recurrent malignant oligodendroglioma. Ann Neurol 23(4):360–364. Scholar
  104. 104.
    van den Bent M, Kros J, Schellens J, Krouwer H, Zonnenberg BA, Heimans J et al (1996) PCV-chemotherapy in anaplastic oligodendroglioma: time for a prospective, randomised study. J Neurooncol 30:130Google Scholar
  105. 105.
    van den Bent MJ, Chinot O, Boogerd W, Bravo Marques J, Taphoorn MJ, Kros JM et al (2003) 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 14(4):599–602CrossRefGoogle Scholar
  106. 106.
    Triebels VH, Taphoorn MJ, Brandes AA, Menten J, Frenay M, Tosoni A et al (2004) Salvage PCV chemotherapy for temozolomide-resistant oligodendrogliomas. Neurology 63(5):904–906CrossRefGoogle Scholar
  107. 107.
    Kouwenhoven MC, Kros JM, French PJ, Biemond-ter Stege EM, Graveland WJ, Taphoorn MJ et al (2006) 1p/19q loss within oligodendroglioma is predictive for response to first line temozolomide but not to salvage treatment. Eur J Cancer 42(15):2499–2503. Scholar
  108. 108.
    Chamberlain MC (2015) Salvage therapy with lomustine for temozolomide refractory recurrent anaplastic astrocytoma: a retrospective study. J Neurooncol 122(2):329–338. Scholar
  109. 109.
    Pignatti F, van den Bent M, Curran D, Debruyne C, Sylvester R, Therasse P et al (2002) Prognostic factors for survival in adult patients with cerebral low-grade glioma. J Clin Oncol 20(8):2076–2084. Scholar
  110. 110.
    Sun H, Yin L, Li S, Han S, Song G, Liu N et al (2013) Prognostic significance of IDH mutation in adult low-grade gliomas: a meta-analysis. J Neurooncol 113(2):277–284. Scholar
  111. 111.
    Reuss DE, Kratz A, Sahm F, Capper D, Schrimpf D, Koelsche C et al (2015) Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities. Acta Neuropathol 130(3):407–417. Scholar
  112. 112.
    Jenkins RB, Blair H, Ballman KV, Giannini C, Arusell RM, Law M et al (2006) 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 66(20):9852–9861. Scholar
  113. 113.
    Brown PD, Buckner JC, O’Fallon JR, Iturria NL, Brown CA, O’Neill BP et al (2003) Effects of radiotherapy on cognitive function in patients with low-grade glioma measured by the folstein mini-mental state examination. J Clin Oncol 21(13):2519–2524. Scholar
  114. 114.
    van den Bent MJ, Afra D, de Witte O, Ben Hassel M, Schraub S, Hoang-Xuan K et al (2005) Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet 366(9490):985–990. Scholar
  115. 115.
    Shaw EG, Berkey B, Coons SW, Bullard D, Brachman D, Buckner JC et al (2008) Recurrence following neurosurgeon-determined gross-total resection of adult supratentorial low-grade glioma: results of a prospective clinical trial. J Neurosurg 109(5):835–841. Scholar
  116. 116.
    Reijneveld JC, Taphoorn MJ, Coens C, Bromberg JE, Mason WP, Hoang-Xuan K et al (2016) Health-related quality of life in patients with high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol 17(11):1533–1542. Scholar
  117. 117.
    Burnet NG, Jena R, Burton KE, Tudor GS, Scaife JE, Harris F et al (2014) Clinical and practical considerations for the use of intensity-modulated radiotherapy and image guidance in neuro-oncology. Clin Oncol (R Coll Radiol) 26(7):395–406. Scholar
  118. 118.
    Hermanto U, Frija EK, Lii MJ, Chang EL, Mahajan A, Woo SY (2007) Intensity-modulated radiotherapy (IMRT) and conventional three-dimensional conformal radiotherapy for high-grade gliomas: does IMRT increase the integral dose to normal brain? Int J Radiat Oncol Biol Phys 67(4):1135–1144. Scholar
  119. 119.
    Navarria P, Pessina F, Cozzi L, Ascolese AM, Lobefalo F, Stravato A et al (2016) Can advanced new radiation therapy technologies improve outcome of high grade glioma (HGG) patients? analysis of 3D-conformal radiotherapy (3DCRT) versus volumetric-modulated arc therapy (VMAT) in patients treated with surgery, concomitant and adjuvant chemo-radiotherapy. BMC Cancer 16:362. Scholar
  120. 120.
    Yang Z, Zhang Z, Wang X, Hu Y, Lyu Z, Huo L et al (2016) Intensity-modulated radiotherapy for gliomas: dosimetric effects of changes in gross tumor volume on organs at risk and healthy brain tissue. OncoTargets and therapy 9:3545–3554. Scholar
  121. 121.
    Gondi V, Pugh SL, Tome WA, Caine C, Corn B, Kanner A et al (2014) Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol 32(34):3810–3816. Scholar
  122. 122.
    Vieira WA, Weltman E, Chen MJ, da Silva NS, Cappellano AM, Pereira LD et al (2014) Ototoxicity evaluation in medulloblastoma patients treated with involved field boost using intensity-modulated radiation therapy (IMRT): a retrospective review. Radiat Oncol 9:158. Scholar
  123. 123.
    Hauswald H, Rieken S, Ecker S, Kessel KA, Herfarth K, Debus J et al (2012) First experiences in treatment of low-grade glioma grade I and II with proton therapy. Radiat Oncol 7:189. Scholar
  124. 124.
    Wilkinson B, Morgan H, Gondi V, Larson GL, Hartsell WF, Laramore GE et al (2016) Low levels of acute toxicity associated with proton therapy for low-grade glioma: a Proton Collaborative Group Study. Int J Radiat Oncol Biol Phys 96(2s):E135. Scholar
  125. 125.
    Sherman JC, Colvin MK, Mancuso SM, Batchelor TT, Oh KS, Loeffler JS et al (2016) Neurocognitive effects of proton radiation therapy in adults with low-grade glioma. J Neurooncol 126(1):157–164. Scholar
  126. 126.
    Shih HA, Sherman JC, Nachtigall LB, Colvin MK, Fullerton BC, Daartz J et al (2015) Proton therapy for low-grade gliomas: results from a prospective trial. Cancer 121(10):1712–1719. Scholar
  127. 127.
    van Thuijl HF, Mazor T, Johnson BE, Fouse SD, Aihara K, Hong C et al (2015) Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment. Acta Neuropathol 129(4):597–607. Scholar
  128. 128.
    Choi S, Yu Y, Grimmer MR, Wahl M, Chang SM, Costello JF (2018) Temozolomide-associated hypermutation in gliomas. Neuro Oncol 20(10):1300–1309. Scholar
  129. 129.
    Platten M, Bunse L, Riehl D, Bunse T, Ochs K, Wick W (2018) Vaccine strategies in gliomas. Curr Treat Options Neurol 20(5):11. Scholar
  130. 130.
    Clark O, Yen K, Mellinghoff IK (2016) Molecular pathways: isocitrate dehydrogenase mutations in cancer. Clin Cancer Res 22(8):1837–1842. Scholar
  131. 131.
    Molenaar RJ, Botman D, Smits MA, Hira VV, van Lith SA, Stap J et al (2015) Radioprotection of IDH1-mutated cancer cells by the IDH1-mutant inhibitor AGI-5198. Cancer Res 75(22):4790–4802. Scholar
  132. 132.
    Wang P, Wu J, Ma S, Zhang L, Yao J, Hoadley KA et al (2015) Oncometabolite D-2-hydroxyglutarate inhibits ALKBH DNA repair enzymes and sensitizes IDH mutant cells to alkylating agents. Cell Rep 13(11):2353–2361. Scholar
  133. 133.
    Mazor T, Chesnelong C, Pankov A, Jalbert LE, Hong C, Hayes J et al (2017) Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1. Proc Natl Acad Sci U S A 114(40):10743–10748. Scholar
  134. 134.
    Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK et al (2017) Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 130(6):722–731. Scholar
  135. 135.
    Lu Y, Kwintkiewicz J, Liu Y, Tech K, Frady LN, Su YT et al (2017) Chemosensitivity of IDH1-mutated gliomas due to an impairment in PARP1-mediated DNA repair. Cancer Res 77(7):1709–1718. Scholar
  136. 136.
    Sulkowski PL, Corso CD, Robinson ND, Scanlon SE, Purshouse KR, Bai H et al (2017) 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci Transl Med 9(375).
  137. 137.
    Tateishi K, Higuchi F, Miller JJ, Koerner MVA, Lelic N, Shankar GM et al (2017) The alkylating chemotherapeutic temozolomide induces metabolic stress in IDH1-mutant cancers and potentiates NAD(+) depletion-mediated cytotoxicity. Cancer Res 77(15):4102–4115. Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Shawn L. Hervey-Jumper
    • 1
  • M. J. van de Bent
    • 2
  • Minesh P. Mehta
    • 3
  • Mitchel S. Berger
    • 1
    Email author
  1. 1.Department of NeurosurgeryUniversity of California San FranciscoSan FranciscoUSA
  2. 2.Brain Tumor Center at Erasmus MC Cancer InstituteRotterdamthe Netherlands
  3. 3.Miami Cancer Institute, Baptist HospitalMiamiUSA

Personalised recommendations