Skip to main content
SpringerLink
Log in

Pharmacologic Therapies for Malignant Glioma: A Guide for Clinicians

  • Therapy in Practice
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

This review covers the medical options for malignant gliomas based on the results of recent clinical trials and updated information on molecular markers of prognostic and predictive value. In addition to alkylating agents, the antiangiogenic drug bevacizumab is increasingly used, particularly in cases of recurrence. Supportive care, including antiedema agents, antiepileptic drugs and anticoagulants, represent complementary treatment approaches of the utmost clinical importance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114:97–109.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360:765–73.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Sanson M, Marie Y, Paris S, et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol. 2009;27:4150–4.

    Article  CAS  PubMed  Google Scholar 

  4. Gorovets D, Kannan K, Shen R, et al. IDH mutation and neuroglial developmental features define clinically distinct subclasses of lower grade diffuse astrocytic glioma. Clin Cancer Res. 2012;18:2490–501.

    Article  CAS  PubMed  Google Scholar 

  5. Verhaak RG, Hoadley KA, Purdom E, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17:98–110.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Noushmehr H, Weisenberger DJ, Diefes K, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010;17:510–22.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Lacroix M, Toms SA. Maximum safe resection of glioblastoma multiforme. J Clin Oncol. 2014;32:727–8.

    Article  PubMed  Google Scholar 

  8. Stummer W, Tonn JC, Mehdorn HM, et al. Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5-aminolevulinic acid glioma resection study. Clinical article. J Neurosurg. 2011;114:613–23.

    Article  PubMed  Google Scholar 

  9. Walker MD, Green SB, Byar DP, et al. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med. 1980;303:1323–29.

  10. Combs SE, Thilmann C, Edler L, et al. Efficacy of fractionated stereotactic reirradiation in recurrent gliomas: long-term results in 172 patients treated in a single institution. J Clin Oncol. 2005;23:8863–9.

    Article  PubMed  Google Scholar 

  11. Dietrich J, Rao K, Pastorino S, et al. Corticosteroids in brain cancer patients: benefits and pitfalls. Expert Rev Clin Pharmacol. 2011;4:233–42.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Glantz MJ, Cole BF, Forsyth PA, et al. Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;54:1886–93.

    Article  CAS  PubMed  Google Scholar 

  13. Rudà R, Trevisan E, Soffietti R. Epilepsy and brain tumors. Curr Opin Oncol. 2010;22:611–20.

    Article  PubMed  Google Scholar 

  14. Weller M, Gorlia T, Cairncross JG, et al. Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. Neurology. 2011;77:1156–64.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Akl EA, Kahale L, Neumann I, et al. Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev. 2014;(6):CD006649.

  16. Vedovati MC, Germini F, Agnelli G, et al. Direct oral anticoagulants in patients with venous thromboembolism and cancer: a systematic review and meta-analysis. Chest. Epub 11 Sep 2014. Doi: 10.1378/chest.14-0402.

  17. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.

    Article  CAS  PubMed  Google Scholar 

  18. Stupp R, Hegi ME, Mason WP, et al. 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;10:459–66.

    Article  CAS  PubMed  Google Scholar 

  19. Herbert C, Williams M, Sawyer H, et al. Treatment of glioblastoma multiforme with radiotherapy and concomitant and adjuvant temozolomide: translation of randomised controlled trial evidence into routine clinical practice. Clin Oncol (R Coll Radiol). 2011;23:372–3.

    Article  CAS  Google Scholar 

  20. Taphoorn MJ, Stupp R, Coens C, et al. Health-related quality of life in patients with glioblastoma: a randomized controlled trial. Lancet Oncol. 2005;6:937–44.

    Article  PubMed  Google Scholar 

  21. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352:997–1003.

    Article  CAS  PubMed  Google Scholar 

  22. 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.

    Article  PubMed  Google Scholar 

  23. Tolcher AW, Gerson SL, Denis L, et al. Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Br J Cancer. 2003;88:1004–11.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. 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;31:4085–91.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Armstrong TS, Wefel JS, Wang M, et al. Net clinical benefit analysis of radiation therapy oncology group 0525: a phase III trial comparing conventional adjuvant temozolomide with dose-intensive temozolomide in patients with newly diagnosed glioblastoma. J Clin Oncol. 2013;31:4076–84.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Laperrière N, Weller M, Stupp R, et al. Optimal management of elderly patients with glioblastoma. Cancer Treat Rev. 2013;39:350–7.

    Article  PubMed  Google Scholar 

  27. Holdhoff M, Chamberlain MC. Controversies in the treatment of elderly patients with newly diagnosed glioblastoma. J Natl Compr Cancer Netw. 2013;11:1165–72.

    CAS  Google Scholar 

  28. Keime-Guibert F, Chinot O, Taillandier L, et al. Radiotherapy for glioblastoma in the elderly. N Engl J Med. 2007;35:1527–35.

    Article  Google Scholar 

  29. 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;22:1583–8.

    Article  CAS  PubMed  Google Scholar 

  30. Wick W, Platten M, Meisner C, et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012;13:707–15.

    Article  CAS  PubMed  Google Scholar 

  31. Malmström A, Grønberg BH, Marosi C, et al. 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;13:916–26.

    Article  PubMed  Google Scholar 

  32. Gállego Pérez-Larraya J, Ducray F, Chinot O, et al. Temozolomide in elderly patients with newly diagnosed glioblastoma and poor performance status: an ANOCEF phase II trial. J Clin Oncol. 2011;29:3050–55.

  33. 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 Oncol. 2003;5:79–88.

    CAS  PubMed Central  PubMed  Google Scholar 

  34. McGirt MJ, Than KD, Weingart JD, et al. Gliadel (BCNU) wafer plus concomitant temozolomide therapy after primary resection of glioblastoma multiforme. J Neurosurg. 2009;110:583–8.

    Article  CAS  PubMed  Google Scholar 

  35. Noël G, Schott R, Froelich S, et al. Retrospective comparison of chemoradiotherapy followed by adjuvant chemotherapy, with or without prior Gliadel implantation (carmustine) after initial surgery in patients with newly diagnosed high-grade gliomas. Int J Radiat Oncol Biol Phys. 2012;82:749–55.

    Article  PubMed  Google Scholar 

  36. Lechapt-Zalcman E, Levallet G, Dugué AE, et al. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation and low MGMT-encoded protein expression as prognostic markers in glioblastoma patients treated with biodegradable carmustine wafer implants after initial surgery followed by radiotherapy with concomitant and adjuvant temozolomide. Cancer. 2012;118:4545–54.

    Article  CAS  PubMed  Google Scholar 

  37. Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370:709–22.

    Article  CAS  PubMed  Google Scholar 

  38. Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370:699–708.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Soffietti R, Trevisan E, Rudà R. What have we learned from trials on antiangiogenic agents in glioblastoma? Expert Rev Neurother. 2014;14:1–3.

    Article  CAS  PubMed  Google Scholar 

  40. Herrlinger TT, et al. Survival and quality of life in the randomized, multicenter GLARIUS trial investigating bevacizumab/irinotecan versus standard temozolomide in newly diagnosed, MGMT-non-methylated glioblastoma patients [abstract no. 2042]. 2014 ASCO Annual Meeting. J Clin Oncol. 2014;32 (5 Suppl).

  41. Weller M, Cloughesy T, Perry JR, et al. Standards of care for treatment of recurrent glioblastoma-are we there yet? Neuro Oncol. 2013;15:4–27.

    Article  PubMed Central  PubMed  Google Scholar 

  42. Yung WK, Albright RE, Olson J, et al. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer. 2000;83:588–93.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Brada M, Stenning S, Gabe R, et al. Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma. J Clin Oncol. 2010;28:4601–8.

    Article  CAS  PubMed  Google Scholar 

  44. Perry JR, Bélanger K, Mason WP, et al. Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol. 2010;28:2051–7.

    Article  CAS  PubMed  Google Scholar 

  45. Tabatabai G, Wick W, Steinbach, et al. MGMT promoter methylation as a prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive glioblastoma: first results from the randomized phase II DIRECTOR trial [abstract no. 2015]. 2014 ASCO proceedings. J Clin Oncol. 2014;32 (5 Suppl).

  46. Wick W, Puduvalli VK, Chamberlain MC, et al. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol. 2010;28:1168–74.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Batchelor TT, Mulholland P, Neyns B, et al. Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol. 2013;31:3212–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Addeo R, Caraglia M, De Santi MS, et al. A new schedule of fotemustine in temozolomide-pretreated patients with relapsing glioblastoma. J Neurooncol. 2011;102:417–24.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Chamberlain MC, Johnston SK. Salvage therapy with single agent bevacizumab for recurrent glioblastoma. J Neurooncol. 2010;96:259–69.

    Article  CAS  PubMed  Google Scholar 

  50. Soffietti R, Trevisan E, Bertero L, Bosa C, Ruda R. Anti-angiogenic approaches to malignant gliomas. Curr Cancer Drug Targets. 2012;12:279–88.

    Article  CAS  PubMed  Google Scholar 

  51. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27:4733–40.

    Article  CAS  PubMed  Google Scholar 

  52. Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27:740–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Wong ET, Gautam S, Malchow C, et al. Bevacizumab for recurrent glioblastoma multiforme: a meta-analysis. J Natl Compr Cancer Netw. 2011;9:403–7.

    CAS  Google Scholar 

  54. Soffietti R, Trevisan E, Bertero L, et al. Bevacizumab and fotemustine for recurrent glioblastoma: a phase II study of AINO (Italian Association of Neuro-Oncology). J Neurooncol. 2014;116:533–41.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Taal W, Oosterkamp HM, Walenkamp AM, et al. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol. 2014;15:943–53.

    Article  CAS  PubMed  Google Scholar 

  56. Piccioni DE, Selfridge J, Mody RR, et al. Deferred use of bevacizumab for recurrent glioblastoma is not associated with diminished efficacy. Neuro Oncol. 2014;16:815–22.

    Article  CAS  PubMed  Google Scholar 

  57. Pope WB, Xia Q, Paton VE, et al. Patterns of progression in patients with recurrent glioblastoma treated with bevacizumab. Neurology. 2011;76:432–7.

    Article  CAS  PubMed  Google Scholar 

  58. Nowosielski M, Wiestler B, Goebel G, et al. Progression types after antiangiogenic therapy are related to outcome in recurrent glioblastoma. Neurology. 2014;82:1684–92.

    Article  CAS  PubMed  Google Scholar 

  59. Stewart LA. Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet. 2002;359:1011–8.

    Article  CAS  PubMed  Google Scholar 

  60. Wick W, Hartmann C, Engel C, 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;27:5874–80.

    Article  CAS  PubMed  Google Scholar 

  61. 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.

    Google Scholar 

  62. Wick W, Meisner C, Hentschel B, et al. Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation. Neurology. 2013;22(81):1515–22.

    Article  Google Scholar 

  63. Hartmann C, Hentschel B, Tatagiba M, et al. Molecular markers in low-grade gliomas: predictive or prognostic? Clin Cancer Res. 2011;17:4588–99.

    Article  CAS  PubMed  Google Scholar 

  64. Cairncross G, Wang M, Shaw E, et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2013;31:337–43.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. van den Bent MJ, Erdem-Eraslan L, Idbaih A, et al. 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. 2013;19:5513–22.

    Article  PubMed  Google Scholar 

  66. Lassman AB, Iwamoto FM, Cloughesy TF, et al. International retrospective study of over 1000 adults with anaplastic oligodendroglial tumors. Neuro Oncol. 2011;13:649–59.

    Article  PubMed Central  PubMed  Google Scholar 

  67. Cairncross G, Macdonald D, Ludwin S, et al. Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1994;12:2013–21.

    CAS  PubMed  Google Scholar 

  68. Soffietti R, Rudà R, Bradac GB, Schiffer D. PCV chemotherapy for recurrent oligodendrogliomas and oligoastrocytomas. Neurosurgery. 1998;43:1066–73.

    Article  CAS  PubMed  Google Scholar 

  69. van den Bent MJ, Chinot O, Boogerd W, et al. 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. 2003;14:599–602.

    Article  PubMed  Google Scholar 

  70. Taillibert S, Vincent LA, Granger B, et al. Bevacizumab and irinotecan for recurrent oligodendroglial tumors. Neurology. 2009;72:1601–6.

    Article  CAS  PubMed  Google Scholar 

  71. Weller M, van den Bent M, Hopkins K, et al. EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma. Lancet Oncol. 2014;15:e395–403.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Riccardo Soffietti, Luca Bertero, Lorenzo Pinessi and Roberta Rudà have no conflicts of interest to declare. No sources of funding were used in the preparation of this manuscript.

Author information

Authors and Affiliations

  1. Department of Neuro-Oncology, University of Turin, Via Cherasco 15, 10126, Turin, Italy

    Riccardo Soffietti, Luca Bertero, Lorenzo Pinessi & Roberta Rudà

Authors
  1. Riccardo Soffietti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luca Bertero
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lorenzo Pinessi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roberta Rudà
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Riccardo Soffietti.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Soffietti, R., Bertero, L., Pinessi, L. et al. Pharmacologic Therapies for Malignant Glioma: A Guide for Clinicians. CNS Drugs 28, 1127–1137 (2014). https://doi.org/10.1007/s40263-014-0215-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-014-0215-x

Keywords

Search

Navigation