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Controversies in the Therapy of Low-Grade Gliomas

Current Treatment Options in Oncology volume 20, Article number: 25 (2019) Cite this article

Opinion statement

In the context of the new WHO classification system, all low-grade gliomas must have an IDH mutation, with or without 1p/19q codeletion. Upon discovery of the tumor, maximal safe surgical resection is the most appropriate first step due to the current inability to differentiate between IDH mutant and IDH wild–type tumors by imaging alone. In the postoperative setting, based on the synthesis and interpretation of the available data, we recommend utilizing conventional radiation therapy and PCV in all high-risk–low-grade gliomas. For patients felt to be in a low risk category, we recommend maintaining a low threshold to initiate treatment. In the setting of tumor recurrence, consideration of all treatment options is reasonable, but treatment with alkylator therapy has the strongest supporting data.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Louis DN, Perry A, Reifenberger G, Von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803–20.

    Article  Google Scholar 

  2. Suzuki H, Aoki K, Chiba K, Sato Y, Shiozawa Y, Shiraishi Y, et al. Mutational landscape and clonal architecture in grade II and III gliomas. Nat Genet. 2015;47(5):458–68.

    CAS  Article  Google Scholar 

  3. Labussiere M, Idbaih A, Wang X-W, Marie Y, Boisselier B, Falet C, et al. All the 1p19q codeleted gliomas are mutated on IDH1 or IDH2. Neurology. 2010;74(23):1886–90.

    CAS  Article  Google Scholar 

  4. Chan AK-Y, Yao Y, Zhang Z, Shi Z, Chen L, Chung NY-F, et al. Combination genetic signature stratifies lower-grade gliomas better than histological grade. Oncotarget. 2015;6(25):20885.

    PubMed  PubMed Central  Google Scholar 

  5. Tabouret E, Nguyen AT, Dehais C, Carpentier C, Ducray F, Idbaih A, et al. Prognostic impact of the 2016 WHO classification of diffuse gliomas in the French POLA cohort. Acta Neuropathol. 2016;132(4):625–34.

    Article  Google Scholar 

  6. Coons SW, Johnson PC, Scheithauer BW, Yates AJ, Pearl DK. Improving diagnostic accuracy and interobserver concordance in the classification and grading of primary gliomas. Cancer. 1997;79(7):1381–93.

    CAS  Article  Google Scholar 

  7. van den Bent MJ. Interobserver variation of the histopathological diagnosis in clinical trials on glioma: a clinician’s perspective. Acta Neuropathol. 2010;120(3):297–304.

    Article  Google Scholar 

  8. Cancer Genome Atlas Research N, Brat DJ, Verhaak RG, Aldape KD, Yung WK, Salama SR, et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med. 2015;372(26):2481–98.

    Article  Google Scholar 

  9. Eckel-Passow JE, Lachance DH, Molinaro AM, Walsh KM, Decker PA, Sicotte H, et al. Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med. 2015;372(26):2499–508.

    CAS  Article  Google Scholar 

  10. Liu X-Y, Gerges N, Korshunov A, Sabha N, Khuong-Quang D-A, Fontebasso AM, et al. Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations. Acta Neuropathol. 2012;124(5):615–25.

    CAS  Article  Google Scholar 

  11. Yip S, Butterfield YS, Morozova O, Chittaranjan S, Blough MD, An J, et al. Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers. J Pathol. 2012;226(1):7–16.

    CAS  Article  Google Scholar 

  12. Cryan JB, Haidar S, Ramkissoon LA, Bi WL, Knoff DS, Schultz N, et al. Clinical multiplexed exome sequencing distinguishes adult oligodendroglial neoplasms from astrocytic and mixed lineage gliomas. Oncotarget. 2014;5(18):8083.

    Article  Google Scholar 

  13. Cohen AL, Holmen SL, Colman H. IDH1 and IDH2 mutations in gliomas. Curr Neurol Neurosci Rep. 2013;13(5):345.

    Article  Google Scholar 

  14. Baumert BG, Hegi ME, van den Bent MJ, von Deimling A, Gorlia T, Hoang-Xuan K, et al. Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol. 2016;17(11):1521–32.

    CAS  Article  Google Scholar 

  15. Bell EH, Zhang P, Fisher BJ, Macdonald DR, McElroy JP, Lesser GJ, et al. Association of MGMT promoter methylation status with survival outcomes in patients with high-risk glioma treated with radiotherapy and temozolomide: an analysis from the NRG oncology/RTOG 0424 trial. JAMA Oncol. 2018;4:1405.

    Article  Google Scholar 

  16. Wijnenga MM, Mattni T, French PJ, Rutten G-J, Leenstra S, Kloet F, et al. Does early resection of presumed low-grade glioma improve survival? A clinical perspective. J Neuro-Oncol. 2017;133(1):137–46.

    Article  Google Scholar 

  17. Aghi MK, Nahed BV, Sloan AE, Ryken TC, Kalkanis SN, Olson JJ. The role of surgery in the management of patients with diffuse low grade glioma: a systematic review and evidence-based clinical practice guideline. J Neuro-Oncol. 2015;125(3):503–30.

    Article  Google Scholar 

  18. Jakola AS, Myrmel KS, Kloster R, Torp SH, Lindal S, Unsgård G, et al. Comparison of a strategy favoring early surgical resection vs a strategy favoring watchful waiting in low-grade gliomas. JAMA. 2012;308(18):1881–8.

    CAS  Article  Google Scholar 

  19. Jakola A, Skjulsvik A, Myrmel K, Sjåvik K, Unsgård G, Torp S, et al. Surgical resection versus watchful waiting in low-grade gliomas. Ann Oncol. 2017;28(8):1942–8.

    CAS  Article  Google Scholar 

  20. Lee S, Choi SH, Ryoo I, Yoon TJ, Kim TM, Lee S-H, et al. Evaluation of the microenvironmental heterogeneity in high-grade gliomas with IDH1/2 gene mutation using histogram analysis of diffusion-weighted imaging and dynamic-susceptibility contrast perfusion imaging. J Neuro-Oncol. 2015;121(1):141–50.

    CAS  Article  Google Scholar 

  21. Villanueva-Meyer JE, Wood MD, Choi BS, Mabray MC, Butowski NA, Tihan T, et al. MRI features and IDH mutational status of grade II diffuse gliomas: impact on diagnosis and prognosis. Am J Roentgenol. 2018;210(3):621–8.

    Article  Google Scholar 

  22. Suh CH, Kim HS, Jung SC, Choi CG, Kim SJ. Imaging prediction of isocitrate dehydrogenase (IDH) mutation in patients with glioma: a systemic review and meta-analysis. Eur Radiol. 2018:1–14.

  23. Shaw EG, Berkey B, Coons SW, Bullard D, Brachman D, Buckner JC, et al. Recurrence following neurosurgeon-determined gross-total resection of adult supratentorial low-grade glioma: results of a prospective clinical trial. J Neurosurg. 2008;109(5):835–41.

    Article  Google Scholar 

  24. Smith JS, Chang EF, Lamborn KR, Chang SM, Prados MD, Cha S, et al. Role of extent of resection in the long-term outcome of low-grade hemispheric gliomas. J Clin Oncol. 2008;26(8):1338–45.

    Article  Google Scholar 

  25. Ius T, Isola M, Budai R, Pauletto G, Tomasino B, Fadiga L, et al. Low-grade glioma surgery in eloquent areas: volumetric analysis of extent of resection and its impact on overall survival. A single-institution experience in 190 patients. J Neurosurg. 2012;117(6):1039–52.

    Article  Google Scholar 

  26. •• Buckner JC, Shaw EG, Pugh SL, Chakravarti A, Gilbert MR, Barger GR, et al. Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med. 2016;374(14):1344–55 Provides highest level of evidence to guide treatment of low-grade gliomas.

    CAS  Article  Google Scholar 

  27. Karim AB, Maat B, Hatlevoll R, Menten J, Rutten EH, Thomas DG, et al. 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. 1996;36(3):549–56.

    CAS  Article  Google Scholar 

  28. Van den Bent M, Afra D, De Witte O, Hassel MB, Schraub S, Hoang-Xuan K, et al. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet. 2005;366(9490):985–90.

    Article  Google Scholar 

  29. Xia L, Fang C, Chen G, Sun C. Relationship between the extent of resection and the survival of patients with low-grade gliomas: a systematic review and meta-analysis. BMC Cancer. 2018;18(1):48.

    Article  Google Scholar 

  30. Shaw EG, Wang M, Coons SW, Brachman DG, Buckner JC, Stelzer KJ, et al. 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. 2012;30(25):3065–70.

    CAS  Article  Google Scholar 

  31. Shaw EG, Berkey B, Coons SW, Bullard D, Brachman D, Buckner JC, et al. Recurrence following neurosurgeon-determined gross-total resection of adult supratentorial low-grade glioma: results of a prospective clinical trial. J Neurosurg. 2008;109(5):835–41.

    Article  Google Scholar 

  32. Brown PD, Buckner JC, Uhm JH, Shaw EG. The neurocognitive effects of radiation in adult low-grade glioma patients. Neuro-Oncology. 2003;5(3):161–7.

    Article  Google Scholar 

  33. Khasraw M, Lassman AB. Neuro-oncology: late neurocognitive decline after radiotherapy for low-grade glioma. Nat Rev Neurol. 2009;5(12):646–7.

    Article  Google Scholar 

  34. Klein M. Neurocognitive functioning in adult WHO grade II gliomas: impact of old and new treatment modalities. Neuro-Oncology. 2012;14(suppl_4):iv17–24.

    PubMed  PubMed Central  Google Scholar 

  35. MF MA, Brown PD. Neurocognitive function following therapy for low-grade gliomas. Semin Radiat Oncol. 2015;25(3):210–8 Elsevier.

  36. Shaw E, Arusell R, Scheithauer B, O’fallon J, O’neill B, Dinapoli R, et al. 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. 2002;20(9):2267–76.

    CAS  Article  Google Scholar 

  37. Shih HA, Sherman JC, Nachtigall LB, Colvin MK, Fullerton BC, Daartz J, et al. Proton therapy for low-grade gliomas: results from a prospective trial. Cancer. 2015;121(10):1712–9.

    Article  Google Scholar 

  38. Bronk JK, Guha-Thakurta N, Allen PK, Mahajan A, Grosshans DR, McGovern SL. Analysis of pseudoprogression after proton or photon therapy of 99 patients with low grade and anaplastic glioma. Clin Transl Radiat Oncol. 2018;9:30–4.

    Article  Google Scholar 

  39. Sherman JC, Colvin MK, Mancuso SM, Batchelor TT, Oh KS, Loeffler JS, et al. Neurocognitive effects of proton radiation therapy in adults with low-grade glioma. J Neuro-Oncol. 2016;126(1):157–64.

    CAS  Article  Google Scholar 

  40. Proton beam or intensity-modulated radiation therapy in preserving brain function in patients with IDH mutant grade II or III glioma. https://ClinicalTrials.gov/show/NCT03180502. Accessed 19 Dec 2018.

  41. Bell EH, Zhang P, Shaw EG, Buckner JC, Barger GR, Coons SW, et al. ACTR-37. Predictive significance of IDH1/2 mutation and 1p/19q co-deletion status in a post-hoc analysis of NRG oncology/rtog 9802: a phase iii trial of RT vs RT + PCV in high risk low-grade gliomas. Neuro-Oncology. 2017;19(suppl_6):vi8–vi.

    Article  Google Scholar 

  42. van den Bent MJ, Brandes AA, Taphoorn MJ, Kros JM, Kouwenhoven MC, 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):344–50.

    Article  Google Scholar 

  43. 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):337–43.

    CAS  Article  Google Scholar 

  44. Van den Bent M, Taphoorn M, Brandes AA, Menten J, Stupp R, Frenay M, et al. Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. J Clin Oncol. 2003;21(13):2525–8.

    Article  Google Scholar 

  45. Fisher BJ, Hu C, Macdonald DR, Lesser GJ, Coons SW, Brachman DG, et al. Phase 2 study of temozolomide-based chemoradiation therapy for high-risk low-grade gliomas: preliminary results of Radiation Therapy Oncology Group 0424. Int J Radiat Oncol Biol Phys. 2015;91(3):497–504.

    CAS  Article  Google Scholar 

  46. •• van den Bent MJ, Baumert B, Erridge SC, Vogelbaum MA, Nowak AK, Sanson M, et al. 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. 2017;390(10103):1645–53 Provides highest level of evidence to guide treatment of anaplastic gliomas.

    Article  Google Scholar 

  47. Chang S, Zhang P, Cairncross JG, Gilbert MR, Bahary JP, Dolinskas CA, et al. Phase III randomized study of radiation and temozolomide versus radiation and nitrosourea therapy for anaplastic astrocytoma: results of NRG oncology RTOG 9813. Neuro-Oncology. 2017;19(2):252–8.

    CAS  PubMed  Google Scholar 

  48. Jaeckle K, Vogelbaum M, Ballman K, Anderson SK, Giannini C, Aldape K, et al. CODEL (alliance-N0577; EORTC-26081/22086; NRG-1071; NCIC-CEC-2): phase III randomized study of RT vs. RT+TMZ vs. TMZ for newly diagnosed 1p/19q-codeleted anaplastic oligodendroglial tumors. Analysis of patients treated on the original protocol design (PL02. 005). Neurology. 2016;86(16 Supplement):PL02.005.

    Google Scholar 

  49. 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):5874–80.

    CAS  Article  Google Scholar 

  50. 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-Oncology. 2011;13(6):649–59.

    Article  Google Scholar 

  51. Johnson BE, Mazor T, Hong C, Barnes M, Aihara K, McLean CY, et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science. 2014;343(6167):189–93.

    CAS  Article  Google Scholar 

  52. Combs SE, Thilmann C, Edler L, Debus JR, Schulz-Ertner D. Efficacy of fractionated stereotactic reirradiation in recurrent gliomas: long-term results in 172 patients treated in a single institution. J Clin Oncol. 2005;23(34):8863–9.

    Article  Google Scholar 

  53. Pace A, Vidiri A, Galie E, Carosi M, Telera S, Cianciulli A, et al. Temozolomide chemotherapy for progressive low-grade glioma: clinical benefits and radiological response. Ann Oncol. 2003;14(12):1722–6.

    CAS  Article  Google Scholar 

  54. Brada M, Viviers L, Abson C, Hines F, Britton J, Ashley S, et al. Phase II study of primary temozolomide chemotherapy in patients with WHO grade II gliomas. Ann Oncol. 2003;14(12):1715–21.

    CAS  Article  Google Scholar 

  55. Quinn JA, Reardon DA, Friedman AH, Rich JN, Sampson JH, Provenzale JM, et al. Phase II trial of temozolomide in patients with progressive low-grade glioma. J Clin Oncol. 2003;21(4):646–51.

    CAS  Article  Google Scholar 

  56. • van den Bent MJ, Klein M, Smits M, Reijneveld JC, French PJ, Clement P, et al. Bevacizumab and temozolomide in patients with first recurrence of WHO grade II and III glioma, without 1p/19q co-deletion (TAVAREC): a randomised controlled phase 2 EORTC trial. Lancet Oncol. 2018;19(9):1170–9 RCT that aims to clarify the role of Bevacizumab in the treatment of gliomas.

    Article  Google Scholar 

  57. Wahl M, Chang SM, Phillips JJ, Molinaro AM, Costello JF, Mazor T, et al. Probing the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in gliomas: a phase 2 study of everolimus for recurrent adult low-grade gliomas. Cancer. 2017;123(23):4631–9.

    CAS  Article  Google Scholar 

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Affiliations

  1. Department of Neurology, Mayo Clinic Rochester, 200 1st St SW, Rochester, MN, 55905, USA

    Ivan D. Carabenciov MD

  2. Department of Medical Oncology, Mayo Clinic Rochester, 200 1st St SW, Rochester, MN, 55905, USA

    Jan C. Buckner MD

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Correspondence to Ivan D. Carabenciov MD.

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Carabenciov, I.D., Buckner, J.C. Controversies in the Therapy of Low-Grade Gliomas. Curr. Treat. Options in Oncol. 20, 25 (2019). https://doi.org/10.1007/s11864-019-0625-6

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Keywords

  • Low-grade glioma
  • Controversy
  • PCV
  • Temozolomide
  • IDH mutation