Malignant Glioma: Chemotherapy Perspective

  • Roger Stupp
  • J. Gregory Cairncross


Despite optimal surgery and adjuvant radiotherapy, malignant gliomas almost always recur. One cause of failure is explained by the diffusely infiltrating pattern of growth displayed by most gliomas, with malignant cells disseminated far beyond the initial bulky tumor. Although most relapses occur at or near the initial site of tumor, either along the resection margin or at the edge of the radiation field, distant recurrences or seeding of the cerebrospinal fluid (CSF) occurs in long-surviving patients. Malignant gliomas are not a localized disease but instead affect the whole brain and may display wide dissemination even at early stages. Thus, therapeutic strategies aiming only at bulky local disease are doomed to fail. The successful treatments of the future will need to eradicate microscopic disease in many sites within the brain and do so without neurotoxic effects. Here, we summarize progress in the medical treatment of malignant glioma.


Clin Oncol Malignant Glioma Radiat Oncol Biol Phys Glioblastoma Multiforme Radiation Therapy Oncology Group 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Balis FM, Blaney SM, McCully CL, et al. Methotrexate distribution within the subarachnoid space after intraventricular and intravenous administration. Cancer Chemother Pharmacol 2000;45(3):259–264.CrossRefPubMedGoogle Scholar
  2. 2.
    Dichter MA, Brodie MJ. New antiepileptic drugs. N Engl J Med 1996;334(24):1583–1590.CrossRefPubMedGoogle Scholar
  3. 3.
    Kanner AM, Balabanov AJ. The use of monotherapy in patients with epilepsy: an appraisal of the new antiepileptic drugs. Curr Neurol Neurosci Rep 2005;5(4):322–328.CrossRefPubMedGoogle Scholar
  4. 4.
    Vecht CJ, Wagner GL, Wilms EB. Interactions between antiepileptic and chemotherapeutic drugs. Lancet Neurol 2003;2(7):404–409.CrossRefPubMedGoogle Scholar
  5. 5.
    Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 1990;8(7):1277–1280.PubMedGoogle Scholar
  6. 6.
    Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92(3):205–216.CrossRefPubMedGoogle Scholar
  7. 7.
    Leimgruber A, Ostermann S, Yeon E, et al. Perfusion and diffusion MRI of glioblastoma progression in a 4 years prospective temozolomide clinical trial. Int J Radiat Oncol Biol Phys 2006;64(3):869–875.PubMedGoogle Scholar
  8. 8.
    Moffat BA, Chenevert TL, Lawrence TS, et al. Functional diffusion map: a noninvasive MRI biomarker for early stratification of clinical brain tumor response. Proc Natl Acad Sci U S A 2005;102(15):5524–5529.CrossRefPubMedGoogle Scholar
  9. 9.
    Wong ET, Hess KR, Gleason MJ, et al. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 1999;17(8):2572.PubMedGoogle Scholar
  10. 10.
    Irish WD, Macdonald DR, Cairncross JG. Measuring bias in uncontrolled brain tumor trials—to randomize or not to randomize? Can J Neurol Sci 1997;24(4):307–312.PubMedGoogle Scholar
  11. 11.
    Frenay M, Giroux B, Khoury S, et al. Phase II study of fotemustine in recurrent supratentorial malignant gliomas. Eur J Cancer 1991;27(7):852–856.CrossRefPubMedGoogle Scholar
  12. 12.
    Takakura K, Abe H, Tanaka R, et al. Effects of ACNU and radiotherapy on malignant glioma. J Neurosurg 1986;64(1):53–57.CrossRefPubMedGoogle Scholar
  13. 13.
    Yoshida J, Kajita Y, Wakabayashi T, Sugita K. Long-term followup results of 175 patients with malignant glioma: importance of radical tumour resection and postoperative adjuvant therapy with interferon, ACNU and radiation. Acta Neurochir 1994;127(1–2):55–59.CrossRefGoogle Scholar
  14. 14.
    Kochii M, Kitamura I, Goto T, et al. Randomized comparison of intra-arterial versus intravenous infusion of ACNU for newly diagnosed patients with glioblastoma. J Neurooncol 2000;49(1):63–70.CrossRefPubMedGoogle Scholar
  15. 15.
    Weller M, Muller B, Koch R, et al. Neuro-Oncology Working Group 01 trial of nimustine plus teniposide versus nimustine plus cytarabine chemotherapy in addition to involved-field radiotherapy in the first-line treatment of malignant glioma. J Clin Oncol 2003;21(17):3276–3284.CrossRefPubMedGoogle Scholar
  16. 16.
    Green SB, Byar DP, Walker MD, et al. Comparisons of carmustine, procarbazine, and high-dose methylprednisolone as additions to surgery and radiotherapy for the treatment of malignant glioma. Cancer Treat Rep 1983;67(2):121–132.PubMedGoogle Scholar
  17. 17.
    Rodriguez LA, Prados M, Silver P, Levin VA. Reevaluation of procarbazine for the treatment of recurrent malignant central nervous system tumors. Cancer 1989;64(12):2420–2423.CrossRefPubMedGoogle Scholar
  18. 18.
    Newton HB, Junck L, Bromberg J, et al. Procarbazine chemotherapy in the treatment of recurrent malignant astrocytomas after radiation and nitrosourea failure. Neurology 1990;40(11):1743–1746.PubMedGoogle Scholar
  19. 19.
    Levin VA, Silver P, Hannigan J, et al. Superiority of postradiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys 1990;18(2):321–324.PubMedGoogle Scholar
  20. 20.
    Prados MD, Scott C, Curran WJ Jr, et al. Procarbazine, lomustine, and vincristine (PCV) chemotherapy for anaplastic astrocytoma: A retrospective review of radiation therapy oncology group protocols comparing survival with carmustine or PCV adjuvant chemotherapy. J Clin Oncol 1999;17(11):3389–3395.PubMedGoogle Scholar
  21. 21.
    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(2):509–518.Google Scholar
  22. 22.
    Stupp R, Gander M, Leyvraz S, Newlands E. Current and future developments in the use of temozolomide in the treatment of brain tumors. Lancet Oncol 2001;2(9):552–560.CrossRefPubMedGoogle Scholar
  23. 23.
    Brada M, Judson I, Beale P, et al. Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies. Br J Cancer 1999;81(6):1022–1030.CrossRefPubMedGoogle Scholar
  24. 24.
    Ostermann S, Csajka C, Buclin T, et al. Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients. Clin Cancer Res 2004;10(11):3728–3736.CrossRefPubMedGoogle Scholar
  25. 25.
    Yung WK, Prados MD, Yaya-Tur R, 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):2762–27671.PubMedGoogle Scholar
  26. 26.
    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(5):588–593.CrossRefPubMedGoogle Scholar
  27. 27.
    Brada M, Hoang-Xuang K, Rampling R, et al. Multicenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse. Ann Oncol 2001;12:259–266.CrossRefPubMedGoogle Scholar
  28. 28.
    Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352(10):987–996.CrossRefPubMedGoogle Scholar
  29. 29.
    Walker MD, Alexander E Jr, Hunt WE, et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg 1978;49(3):333–343.CrossRefPubMedGoogle Scholar
  30. 30.
    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(23):1323–1329.PubMedGoogle Scholar
  31. 31.
    Kristiansen K, Hagen S, Kollevold T, et al. Combined modality therapy of operated astrocytomas grade III and IV. Confirmation of the value of postoperative irradiation and lack of potentiation of bleomycin on survival time: a prospective multicenter trial of the Scandinavian Glioblastoma Study Group. Cancer 1981;47(4):649–652.CrossRefPubMedGoogle Scholar
  32. 32.
    Fine HA, Dear KB, Loeffler JS, et al. Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 1993;71(8):2585–2597.CrossRefPubMedGoogle Scholar
  33. 33.
    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(9311):1011–1018.CrossRefPubMedGoogle Scholar
  34. 34.
    Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352(10):997–1003.CrossRefPubMedGoogle Scholar
  35. 35.
    Hildebrand J, Sahmoud T, Mignolet F, et al. Adjuvant therapy with dibromodulcitol and BCNU increases survival of adults with malignant gliomas. EORTC Brain Tumor Group. Neurology 1994;44(8):1479–1483.PubMedGoogle Scholar
  36. 36.
    Levin VA, Hess KR, Choucair A, et al. Phase III randomized study of postradiotherapy chemotherapy with combination alphadifluoromethylornithine-PCV versus PCV for Anaplastic Gliomas. Clin Cancer Res 2003;9(3):981–990.PubMedGoogle Scholar
  37. 37.
    Levin VA, Uhm JH, Jaeckle KA, et al. Phase III randomized study of postradiotherapy chemotherapy with alpha-difluoromethylornithine-procarbazine, N-(2-chloroethyl)-N′-cyclohexyl-Nnitrosurea, vincristine (DFMO-PCV) versus PCV for glioblastoma multiforme. Clin Cancer Res 2000;6(10):3878–3884.PubMedGoogle Scholar
  38. 38.
    Kleihues P, Cavenee WK. Pathology and Genetics of Tumours of the Nervous System. Lyon: IARC Press, 2000.Google Scholar
  39. 39.
    Cairncross JG, Ueki K, Zlatescu MC, et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 1998;90(19):1473–1479.CrossRefPubMedGoogle Scholar
  40. 40.
    Cairncross G, Berkey B, Shaw E, 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.CrossRefPubMedGoogle Scholar
  41. 41.
    van den Bent MJ, Carpentier AF, Brandes AA, 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.CrossRefPubMedGoogle Scholar
  42. 42.
    Lacroix M, Abi-Said D, Fourney DR, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 2001;95(2):190–198.CrossRefPubMedGoogle Scholar
  43. 43.
    Keime-Guibert F, Chinot O, Taillandier F, et al. Radiotherapy for glioblastoma in the elderly. N Engl J Med 2007;356(15):1527–1535.CrossRefPubMedGoogle Scholar
  44. 44.
    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(9):1583–1588.CrossRefPubMedGoogle Scholar
  45. 45.
    Curran WJ Jr, Scott CB, Horton J, et al. Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 1993;85(9):704–710.CrossRefPubMedGoogle Scholar
  46. 46.
    Scott CB, Scarantino C, Urtasun R, et al. Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: a report using RTOG 90-06. Int J Radiat Oncol Biol Phys 1998;40(1):51–55.PubMedGoogle Scholar
  47. 47.
    Hegi ME, Diserens AC, Godard S, et al. Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res 2004;10(6):1871–1874.CrossRefPubMedGoogle Scholar
  48. 48.
    Godard S, Getz G, Delorenzi M, et al. Classification of human astrocytic gliomas on the basis of gene expression: a correlated group of genes with angiogenic activity emerges as a strong predictor of subtypes. Cancer Res 2003;63(20):6613–6625.PubMedGoogle Scholar
  49. 49.
    O’Driscoll BR, Hasleton PS, Taylor PM, et al. Active lung fibrosis up to 17 years after chemotherapy with carmustine (BCNU) in childhood. N Engl J Med 1990;323(6):378–382.PubMedCrossRefGoogle Scholar
  50. 50.
    Kreisman H, Wolkove N. Pulmonary toxicity of antineoplastic therapy. Semin Oncol 1992;19(5):508–520.PubMedGoogle Scholar
  51. 51.
    Schmitz N, Diehl V. Carmustine and the lungs. Lancet 1997;349(9067):1712–1713.CrossRefPubMedGoogle Scholar
  52. 52.
    Brock CS, Newlands ES, Wedge SR, et al. Phase I trial of temozolomide using an extended continuous oral schedule. Cancer Res 1998;58(19):4363–4367.PubMedGoogle Scholar
  53. 53.
    Stupp R, Dietrich P, Ostermann Kraljevic S, et al. Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J Clin Oncol 2002;20(5):1375–1382.CrossRefPubMedGoogle Scholar
  54. 54.
    Su YB, Sohn S, Krown SE, et al. Selective CD4+ lymphopenia in melanoma patients treated with temozolomide: a toxicity with therapeutic implications. J Clin Oncol 2004;22(4):610–616.CrossRefPubMedGoogle Scholar
  55. 55.
    Kovacs JA, Masur H. Prophylaxis against opportunistic infections in patients with human immunodeficiency virus infection. N Engl J Med 2000;342(19):1416–1429.CrossRefPubMedGoogle Scholar
  56. 56.
    Osoba D, Brada M, Yung W, Prados M. Health-related quality of life in patients treated with temozolomide versus procarbazine for recurrent glioblastoma multiforme. J Clin Oncol 2000;18(7):1481–1491.PubMedGoogle Scholar
  57. 57.
    Osoba D, Brada M, Yung WK, Prados MD. Health-related quality of life in patients with anaplastic astrocytoma during treatment with temozolomide. Eur J Cancer 2000;36(14):1788–1795.CrossRefPubMedGoogle Scholar
  58. 58.
    Taphoorn MJ, Stupp R, Coens C, et al. Health-related quality of life in patients with glioblastoma: a randomised controlled trial. Lancet Oncol 2005;6(12):937–944.CrossRefPubMedGoogle Scholar
  59. 59.
    Tsao MN, Mehta MP, Whelan TJ, et al. The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for malignant glioma. Int J Radiat Oncol Biol Phys 2005;63(1):47–55.PubMedGoogle Scholar
  60. 60.
    Curran WJ Jr, Scott CB, Weinstein AS, et al. Survival comparison of radiosurgery-eligible and-ineligible malignant glioma patients treated with hyperfractionated radiation therapy and carmustine: a report of Radiation Therapy Oncology Group 83-02. J Clin Oncol 1993;11(5):857–862.PubMedGoogle Scholar
  61. 61.
    Souhami L, Seiferheld W, Brachman D, et al. Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol. Int J Radiat Oncol Biol Phys 2004;60(3):853–860.PubMedGoogle Scholar
  62. 62.
    Brada M, Baumert B. Focal fractionated conformal stereotactic boost following conventional radiotherapy of high-grade gliomas: a randomized phase III study. A joint study of the EORTC (22972) and the MRC (BR10). Front Radiat Ther Oncol 1999;33:241–243.CrossRefPubMedGoogle Scholar
  63. 63.
    Stupp R, Weber DC. The role of radio-and chemotherapy in glioblastoma. Onkologie 2005;28(6–7):315–317.CrossRefPubMedGoogle Scholar
  64. 64.
    Hochberg FH, Pruitt A. Assumptions in the radiotherapy of glioblastoma. Neurology 1980;30(9):907–911.PubMedGoogle Scholar
  65. 65.
    Stupp R, Hegi ME. Treatment of brain tumors (author reply). N Engl J Med 2005;352(22):2350–2353.CrossRefGoogle Scholar
  66. 66.
    Mirimanoff RO, Gorlia T, Mason W, et al. Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol 2006;24(16):2563–2569.CrossRefPubMedGoogle Scholar
  67. 67.
    Walker MD, Strike TA, Sheline GE. An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys 1979;5(10):1725–1731.PubMedGoogle Scholar
  68. 68.
    Stupp R, van den Bent MJ, Hegi ME. Optimal role of temozolomide in the treatment of malignant gliomas. Curr Neurol Neurosci Rep 2005;5(3):198–206.CrossRefPubMedGoogle Scholar
  69. 69.
    van den Bent MJ, Taphoorn MJ, Brandes AA, 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):2525–2528.CrossRefPubMedGoogle Scholar
  70. 70.
    Triebels VH, Taphoorn MJ, Brandes AA, et al. Salvage PCV chemotherapy for temozolomide-resistant oligodendrogliomas. Neurology 2004;63(5):904–906.PubMedGoogle Scholar
  71. 71.
    Friedman HS, Petros WP, Friedman AH, et al. Irinotecan therapy in adults with recurrent or progressive malignant glioma. J Clin Oncol 1999;17(5):1516–1525.PubMedGoogle Scholar
  72. 72.
    Raymond E, Fabbro M, Boige V, et al. Multicentre phase II study and pharmacokinetic analysis of irinotecan in chemotherapy-naive patients with glioblastoma. Ann Oncol 2003;14(4):603–614.CrossRefPubMedGoogle Scholar
  73. 73.
    Buckner JC, Reid JM, Wright K, et al. Irinotecan in the treatment of glioma patients: current and future studies of the North Central Cancer Treatment Group. Cancer 2003;97(9 Suppl):2352–2358.CrossRefPubMedGoogle Scholar
  74. 74.
    Raizer JJ, Abrey LE, Wen P, et al. A phase II trial of erlotinib (OSI-774) in patients with recurrent malignant glioma not on EIAEDs. J Clin Oncol [Proc Am Soc Clin Oncol, Post-Meeting Edition] 2004;22(14S):107s.Google Scholar
  75. 75.
    Rich JN, Reardon DA, Peery T, et al. Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 2004;22(1):133–142.CrossRefPubMedGoogle Scholar
  76. 76.
    Raymond E, Brandes A, Van Osterom A, et al. Muticentre phase II study of imatinib mesylate in patients with recurrent glioblastoma: An EORTC NCCG/BTG Intergroup study. J Clin Oncol [Proc Am Soc Clin Oncol, Post-Meeting Edition] 2004;14S:107s.Google Scholar
  77. 77.
    van den Bent M, Brandes A, Frenay M, et al. Multicentre phase II study of imatinib mesylate in patients with recurrent anaplastic oligodendroglioma (AOD)/mixed oligoastrocytoma (MOA) and anaplastic astrocytoma (AA)/low grade astrocytoma (LGA): An EORTC New Drug Development Group (NDDG) and Brain Tumor Group (BTG) study. J Clin Oncol [Meeting Abstracts] 2005;23(16 Suppl):118s.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Roger Stupp
    • 1
  • J. Gregory Cairncross
    • 2
  1. 1.Multidisciplinary Oncology CenterUniversity of Lausanne Hospitals (CHUV)LausanneSwitzerland
  2. 2.Department of Clinical NeurosciencesUniversity of Calgary, Foothills HospitalAlbertaCanada

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