Anaplastic Oligodendrogliomas – the Age of Personalized Medicine Has Arrived?

Authors: J. Polívka 1;  J. Polívka Jr 2,3;  V. Rohan 1;  V. Přibáň 4
Authors‘ workplace: Neurologická klinika LF UK a FN Plzeň 1;  Ústav histologie a embryologie LF v Plzni 2;  Biomedicínské centrum, LF v Plzni 3;  Neurochirurgické oddělení, FN Plzeň 4
Published in: Cesk Slov Neurol N 2014; 77/110(4): 428-434
Category: Review Article

Podporováno projektem Ministerstva zdravotnictví České republiky pro konceptuální rozvoj výzkumné organizace 00669806 –  Fakultní nemocnice Plzeň.

Podporováno projektem ED2.1.00/ 03.0076 Evropského fondu pro regionální rozvoj.


Oligodendrogliomas are uncommon but extensively investigated tumours in neurooncology. Their superior sensitivity to radiotherapy and chemotherapy compared to other gliomas has long been known. Chromosomal codeletion 1p/19q is frequent in this tumour type. A long-term follow up of two landmark phase III trials – RTOG 9402 and EORTC 26951 has shown a favourable effect of combined radiotherapy and chemotherapy - procarbazine, lomustine (CCNU), vincristine – in patients with anaplastic oligodendrogliomas and anaplastic oligoastrocytomas carrying the codeletion 1p/19q. This codeletion serves as an important diagnostic, positive prognostic and strong predictive biomarker. The role of the other molecular biomarkers (isocitrate dehydrogenase – IDH1, IDH2 mutations, methylation of the MGMT promoter, glioma cytosine - guanine islands methylator phenotype – G-CIMP) in oligodendroglial tumours is also discussed. All these data facilitate the new personalised approach to the management and treatment of anaplastic oligodendroglial tumours.

Key words:
anaplastic oligodendroglioma – chromosome deletion – biomarkers – personalized medicine


1. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007; 114(2): 97– 109.

2. 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 Oncol 2012; 14 (Suppl 5): v1– v49.

3. Ohgaki H, Kleihues P. Population‑based studies on incidence, survival rates and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 2005; 64(6): 479– 489.

4. Engelhard HH, Stelea A, Mundt A. Oligodendroglioma and anaplastic oligodendroglioma: clinical features, treatment and prognosis. Surg Neurol 2003; 60(5): 443– 456.

5. Roth P, Wick W, Weller M. Anaplastic oligodendroglioma: a new treatment paradigm and current controversies. Curr Treat Options Oncol 2013; 14(4): 505– 513. doi: 10.1007/ s11864- 013- 0251- 7.

6. Weller M, Stupp R, Hegi ME, van den Bent M, Tonn JC,Sanson M 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– iv108. doi: 10.1093/ neuonc/ nos206.

7. Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ 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(5): 392– 401.

8. Mraček J, Choc M, Hes O, Vaněček T. Současná dia­gnostika a léčba oligodendrogliomů. Cesk Slov Neurol N 2008; 71(5): 537– 543.

9. Kramář F, Zemanová Z, Michalová K, Babická L, Ransdorfová S, Kozler P et al. Patogeneze mozkových gliomů, II. část: Patogeneze oligodendrogliomů a gliomů v rámci dědičných onemocnění. Cesk Slov Neurol N 2006; 69/ 102(6): 419– 425.

10. Phillips C, Guiney M, Smith J, Hughes P, Narayan K, Quong G. A randomized trial comparing 35Gy in ten fractions with 60Gy in 30 fractions of cerebral irradiation for glioblastoma multiforme and older patients with anaplastic astrocytoma. Radiother Oncol 2003; 68(1): 23– 26.

11. Cairncross JG, Macdonald DR, Ramsay DA. Aggressive oligodendroglioma: a chemosensitive tumor. Neurosurgery 1992; 31(1): 78– 82.

12. Croteau D, Mikkelsen T. Adults with newly dia­gnosed high‑grade gliomas. Curr Treat Options Oncol 2001; 2(6): 507– 515.

13. Cairncross JG, Macdonald DR. Successful chemotherapy for recurrent malignant oligodendroglioma. Ann Neurol 1988; 23(4): 360– 364.

14. Gorlia T, Delattre JY, Brandes AA, Kros JM, Taphoorn MJB, Kouwenhoven MC et al. New clinical, pathological and molecular prognostic models and calculators in patients with locally dia­gnosed anaplastic oligodendroglioma or oligoastrocytoma. A prognostic factor analysis of European Organisation for Research and Treatment of Cancer Brain Tumour Group Study 26951. Eur J Cancer 2013; 49(16): 3477– 3485. doi: 10.1016/ j.ejca.2013.06.039.

15. Reifenberger J, Reifenberger G, Liu L, James CD, Wechsler W, Collins VP. Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am J Pathol 1994; 145(5): 1175– 1190.

16. Griffin CA, Burger P, Morsberger L, Yonescu R, Swierczynski S, Weingart JD et al. Identification of der(1;19)(q10;p10) in five oligodendrogliomas sug­gests mechanism of concurrent 1p and 19q loss. J Neuropathol Exp Neurol 2006; 65(10): 988– 994.

17. Sahm F, Koelsche C, Meyer J, Pusch S, Lindenberg K,Mueller W et al. CIC and FUBP1 mutations in oligodendrogliomas, oligoastrocytomas and astrocytomas. Acta Neuropathol 2012; 123(6): 853– 860. doi: 10.1007/ s00401– 012– 0993– 5.

18. Bettegowda C, Agrawal N, Jiao Y, Sausen M,Wood LD, Hruban RH et al. Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science 2011; 333(6048): 1453– 1455. doi: 10.1126/ science.1210557.

19. Minniti G, Arcella A, Scaringi C, Lanzetta G, Di Stefano D, Scarpino S et al. Chemoradiation for anaplastic oligodendrogliomas: clinical outcomes and prognostic value of molecular markers. J Neurooncol 2013; 116(2): 275– 282. doi: 10.1007/ s11060– 013– 1288– y.

20. Cairncross G, Jenkins R. Gliomas with 1p/ 19q codeletion: a.k.a. oligodendroglioma. Cancer J 2008; 14(6): 352– 357. doi: 10.1097/ PPO.0b013e31818d8178.

21. Aldape K, Burger PC, Perry A. Clinicopathologic aspects of 1p/ 19q loss and the dia­gnosis of oligodendroglioma. Arch Pathol Lab Med 2007; 131(2): 242– 251.

22. Weller M, Felsberg J, Hartmann C, Berger H, Steinbach JP, Schramm J et al. 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 2009; 27(34): 5743– 5750. doi: 10.1200/ JCO.2009.23.0805.

23. Maintz D, Fiedler K, Koopmann J, Rollbrocker B, Nechev S, Lenartz D et al. Molecular genetic evidence for subtypes of oligoastrocytomas. J Neuropathol Exp Neurol 1997; 56(10): 1098– 1104.

24. Idbaih A, Marie Y, Lucchesi C, Pierron G, Manié E,Raynal V et al. BAC array CGH distinguishes mutually exclusive alterations that define clinicogenetic subtypes of gliomas. Int J Cancer 2008; 122(8): 1778– 1786.

25. Intergroup Radiation Therapy Oncology Group Trial 9402, Cairncross G, Berkey B, Shaw E, Jenkins R,Scheithauer B 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(18): 2707– 2714.

26. Cairncross G, Wang M, Shaw E, Jenkins R, Brachman D, Buckner J et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long‑term results of RTOG 9402. J Clin Oncol 2013; 31(3): 337– 343. doi: 10.1200/ JCO.2012.43.2674.

27. van den Bent MJ, Brandes AA, Taphoorn MJB, Kros JM, Kouwenhoven MCM, Delattre JY 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(3): 344– 350. doi: 10.1200/ JCO.2012.43.2229.

28. van den Bent MJ, Carpentier AF, Brandes AA, Sanson M, Taphoorn MJB, Bernsen HJJA 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(18): 2715– 2722.

29. Cairncross JG, Ueki K, Zlatescu MC, Lisle DK, Finkelstein DM, Hammond RR et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 1998; 90(19): 1473– 1479.

30. Levin VA, Yung WK, Bruner J, Kyritsis A, Leeds N, Gleason MJ et al. Phase II study of accelerated fractionation radiation therapy with carboplatin followed by PCV chemotherapy for the treatment of anaplastic gliomas. Int J Radiat Oncol Biol Phys 2002; 53(1): 58– 66.

31. Happold C, Roth P, Wick W, Steinbach JP, Linnebank M, Weller M et al. ACNU‑based chemotherapy for recurrent glioma in the temozolomide era. J Neurooncol 2009; 92(1): 45– 48. doi: 10.1007/ s11060- 008- 9728- 9.

32. Erdem‑ Eraslan L, Gravendeel LA, de Rooi J, Eilers PH,Idbaih A, Spliet WG et al. Intrinsic molecular subtypes of glioma are prognostic and predict benefit from adjuvant procarbazine, lomustine, and vincristine chemotherapy in combination with other prognostic factors in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951. J Clin Oncol 2013; 31(3): 328– 336. doi: 10.1200/ JCO.2012.44.1444.

33. Dixit S, Baker L, Walmsley V, Hingorani M. Temozolomide‑related idiosyncratic and other uncommon toxicities: a systematic review. Anticancer Drugs 2012; 23(10): 1099– 1106.

34. Lashkari HP, Saso S, Moreno L, Athanasiou T, Zacharoulis S. Using different schedules of Temozolomide to treat low grade gliomas: systematic review of their efficacy and toxicity. J Neurooncol 2011; 105(2): 135– 147. doi: 10.1007/ s11060– 011– 0657– 7.

35. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352(10): 987– 996.

36. Panageas KS, Iwamoto FM, Cloughesy TF, Al-dape KD, Rivera AL, Eichler AF et al. Initial treatment patterns over time for anaplastic oligodendroglial tumors. Neuro Oncol 2012; 14(6): 761– 767. doi: 10.1093/ neuonc/ nos065.

37. Abrey LE, Louis DN, Paleologos N, Lassman AB, Raizer JJ, Mason W et al. Survey of treatment recommendations for anaplastic oligodendroglioma. Neuro Oncol 2007; 9(3): 314– 318.

38. Taliansky‑ Aronov A, Bokstein F, Lavon I, Siegal T. Temozolomide treatment for newly dia­gnosed anaplastic oligodendrogliomas: a clinical efficacy trial. J Neurooncol 2006; 79(2): 153– 157.

39. Lassman AB, Iwamoto FM, Cloughesy TF, Aldape KD, Rivera AL, Eichler AF et al. International retrospective study of over 1000 adults with anaplastic oligodendroglial tumors. Neuro Oncol 2011; 13(6): 649– 659. doi: 10.1093/ neuonc/ nor040.

40. Yung WK, Prados MD, Yaya‑ Tur R, Rosenfeld SS, Brada M, Friedman HS 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(9): 2762– 2771.

41. Anderson MD, Gilbert MR. Treatment recommendations for anaplastic oligodendrogliomas that are codeleted. Oncol Williston Park N 2013; 27(4): 315– 320.

42. Parsons DW, Jones S, Zhang X, Lin JC‑ H, Leary RJ,Angenendt P et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008; 321(5897): 1807– 1812. doi: 10.1126/ science.1164382.

43. Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C,von Deimling A. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 2008; 116(6): 597– 602. doi: 10.1007/ s00401- 008- 0455- 2.

44. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA,Yuan W et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009; 360(8): 765– 773. doi: 10.1056/ NEJMoa0808710.

45. Dang L, White DW, Gross S, Bennett BD, Bittinger MA,Driggers EM et al. Cancer‑associated IDH1 mutations produce 2- hydroxyglutarate. Nature 2010; 465(7300): 966. doi: 10.1038/ nature09132.

46. Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel‑ Wahab O et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 2012; 483(7390): 474– 478. doi: 10.1038/ nature10860.

47. Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 2012; 483(7390): 479– 483. doi: 10.1038/ nature10866.

48. Sanson M, Marie Y, Paris S, Idbaih A, Laffaire J,Ducray F et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic bio­marker in gliomas. J Clin Oncol 2009; 27(25): 4150– 4154. doi: 10.1200/ JCO.2009.21.9832.

49. Polívka J, Polívka J jr, Rohan V, Topolčan O. Multiformní glioblastom –  přehled nových poznatků o patogenezi, bio­markerech a perspektivách léčby. Cesk Slov Neurol N 2013; 76/ 109(5): 575– 583.

50. Labussière M, Idbaih A, Wang XW, Marie Y, Boisselier B, Falet C et al. All the 1p19q codeleted gliomas are mutated on IDH1 or IDH2. Neurology 2010; 74(23): 1886– 1890. doi: 10.1212/ WNL.0b013e3181e1cf3a.

51. Theeler BJ, Yung WKA, Fuller GN, De Groot JF. Moving toward molecular classification of diffuse gliomas in adults. Neurology 2012; 79(18): 1917– 1926. doi: 10.1212/ WNL.0b013e318271f7cb.

52. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352(10): 997– 1003.

53. Takahashi Y, Nakamura H, Makino K, Hide T, Muta D,Kamada H et al. Prognostic value of isocitrate dehydrogenase 1, O6- methylguanine‑ DNA methyltransferase promoter methylation, and 1p19q co‑ deletion in Japanese malignant glioma patients. World J Surg Oncol 2013; 11(1): 284. doi: 10.1186/ 1477- 7819- 11- 284.

54. Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F 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(35): 5874– 5880. doi: 10.1200/ JCO.2009.23.6497.

55. van den Bent MJ, Dubbink HJ, Sanson M, van der Lee‑ Haarloo CR, Hegi M, Jeuken JWM et al. MGMT promoter methylation is prognostic but not predictive for outcome to adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors: a report from EORTC Brain Tumor Group Study 26951. J Clin Oncol 2009; 27(35): 5881– 5886. doi: 10.1200/ JCO.2009.24.1034.

56. Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS,Pujara K, Berman BP et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 2010; 17(5): 510– 522. doi: 10.1016/ j.ccr.2010.03.017.

57. Mur P, Mollejo M, Ruano Y, de Lope AR, Fiano C,Garcia JF et al. Codeletion of 1p and 19q determines distinct gene methylation and expression profiles in IDH‑ mutated oligodendroglial tumors. Acta Neuropathol 2013; 126(2): 277– 289. doi: 10.1007/ s00401- 013- 1130- 9.

58. Jeuken JW, von Deimling A, Wesseling P. Molecular pathogenesis of oligodendroglial tumors. J Neurooncol 2004; 70(2): 161– 181.

59. Polivka J jr, Janku F. Molecular targets for cancer therapy in the PI3K/ AKT/ mTOR pathway. Pharmacol Ther 2014; 142(2): 164– 175. doi: 10.1016/ j.pharmthera.2013.12.004.

60. Preusser M, Hoeftberger R, Woehrer A, Gelpi E, Kouwenhoven M, Kros JM et al. Prognostic value of Ki67 index in anaplastic oligodendroglial tumours‑ – a translational study of the European Organization for Research and Treatment of Cancer Brain Tumor Group. Histopathology 2012; 60(6): 885– 894. doi: 10.1111/ j.1365– 2559.2011.04134.x.

61. Galanis E, Wu W, Sarkaria J, Chang SM, Colman H, Sargent D et al. Incorporation of bio­marker assessment in novel clinical trial designs: personalizing brain tumor treatments. Curr Oncol Rep 2011; 13(1): 42– 49. doi: 10.1007/ s11912-010- 0144- x.

62. Golubnitschaja O, Costigliola V, EPMA. General report & recommendations in predictive, preventive and personalised medicine 2012: white paper of the European Association for Predictive, Preventive and Personalised Medicine. EPMA J 2012; 3(1): 14. doi: 10.1186/ 1878– 5085– 3– 14.

Paediatric neurology Neurosurgery Neurology

Article was published in

Czech and Slovak Neurology and Neurosurgery

Issue 4

2014 Issue 4

Most read in this issue
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account