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Management of recurrent high-grade gliomas

Tracy Batchelor, MD, MPH
Helen A Shih, MD
Bob S Carter, MD, PhD
Section Editors
Jay S Loeffler, MD
Patrick Y Wen, MD
Deputy Editor
April F Eichler, MD, MPH


High-grade gliomas are malignant and often rapidly progressive brain tumors that are divided into anaplastic gliomas (anaplastic astrocytoma, anaplastic oligodendroglioma) and glioblastoma based upon their histopathologic and molecular features [1]. (See "Classification and pathologic diagnosis of gliomas", section on 'Histopathologic and molecular classification'.)

Despite the survival benefit associated with adjuvant radiation and chemotherapy, the majority of patients relapse following initial therapy. Progressive disease can be difficult to distinguish from radiation necrosis or other radiation-induced imaging changes, and this distinction has important implications for further treatment.

Treatment decisions for patients with recurrent or progressive high-grade glioma must be individualized, since therapy is not curative and there are no randomized trials that directly compare active intervention versus supportive care. The benefit of reintervention must be balanced by the risk of iatrogenic neurotoxicity and its impact on quality of life.

The management of patients with recurrent or progressive high-grade glioma, including surgery, radiation therapy, and systemic therapy, is discussed here.

Other aspects of the management of high-grade gliomas that are covered separately include:

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Literature review current through: Nov 2017. | This topic last updated: Nov 14, 2017.
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  1. WHO Classification of Tumours of the Central Nervous System, 4th ed, Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (Eds), IARC, Lyon 2016.
  2. de Wit MC, de Bruin HG, Eijkenboom W, et al. Immediate post-radiotherapy changes in malignant glioma can mimic tumor progression. Neurology 2004; 63:535.
  3. Taal W, Brandsma D, de Bruin HG, et al. Incidence of early pseudo-progression in a cohort of malignant glioma patients treated with chemoirradiation with temozolomide. Cancer 2008; 113:405.
  4. O'Brien BJ, Colen RR. Post-treatment imaging changes in primary brain tumors. Curr Oncol Rep 2014; 16:397.
  5. Chamberlain MC, Glantz MJ, Chalmers L, et al. Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma. J Neurooncol 2007; 82:81.
  6. Young RJ, Gupta A, Shah AD, et al. Potential utility of conventional MRI signs in diagnosing pseudoprogression in glioblastoma. Neurology 2011; 76:1918.
  7. Brandes AA, Franceschi E, Tosoni A, et al. MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol 2008; 26:2192.
  8. Brandsma D, Stalpers L, Taal W, et al. Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol 2008; 9:453.
  9. Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 1990; 8:1277.
  10. 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.
  11. Pace A, Dirven L, Koekkoek JAF, et al. European Association for Neuro-Oncology (EANO) guidelines for palliative care in adults with glioma. Lancet Oncol 2017; 18:e330.
  12. Ammirati M, Galicich JH, Arbit E, Liao Y. Reoperation in the treatment of recurrent intracranial malignant gliomas. Neurosurgery 1987; 21:607.
  13. Harsh GR 4th, Levin VA, Gutin PH, et al. Reoperation for recurrent glioblastoma and anaplastic astrocytoma. Neurosurgery 1987; 21:615.
  14. Barker FG 2nd, Chang SM, Gutin PH, et al. Survival and functional status after resection of recurrent glioblastoma multiforme. Neurosurgery 1998; 42:709.
  15. Kappelle AC, Postma TJ, Taphoorn MJ, et al. PCV chemotherapy for recurrent glioblastoma multiforme. Neurology 2001; 56:118.
  16. Keles GE, Lamborn KR, Chang SM, et al. Volume of residual disease as a predictor of outcome in adult patients with recurrent supratentorial glioblastomas multiforme who are undergoing chemotherapy. J Neurosurg 2004; 100:41.
  17. Rostomily RC, Spence AM, Duong D, et al. Multimodality management of recurrent adult malignant gliomas: results of a phase II multiagent chemotherapy study and analysis of cytoreductive surgery. Neurosurgery 1994; 35:378.
  18. Gutin PH, Phillips TL, Wara WM, et al. Brachytherapy of recurrent malignant brain tumors with removable high-activity iodine-125 sources. J Neurosurg 1984; 60:61.
  19. Lederman G, Wronski M, Arbit E, et al. Treatment of recurrent glioblastoma multiforme using fractionated stereotactic radiosurgery and concurrent paclitaxel. Am J Clin Oncol 2000; 23:155.
  20. Dirks P, Bernstein M, Muller PJ, Tucker WS. The value of reoperation for recurrent glioblastoma. Can J Surg 1993; 36:271.
  21. National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
  22. Weller M, van den Bent M, Tonn JC, et al. European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas. Lancet Oncol 2017; 18:e315.
  23. Ringel F, Pape H, Sabel M, et al. Clinical benefit from resection of recurrent glioblastomas: results of a multicenter study including 503 patients with recurrent glioblastomas undergoing surgical resection. Neuro Oncol 2016; 18:96.
  24. van Linde ME, Brahm CG, de Witt Hamer PC, et al. Treatment outcome of patients with recurrent glioblastoma multiforme: a retrospective multicenter analysis. J Neurooncol 2017; 135:183.
  25. Landy HJ, Feun L, Schwade JG, et al. Retreatment of intracranial gliomas. South Med J 1994; 87:211.
  26. Young B, Oldfield EH, Markesbery WR, et al. Reoperation for glioblastoma. J Neurosurg 1981; 55:917.
  27. Bloch O, Han SJ, Cha S, et al. Impact of extent of resection for recurrent glioblastoma on overall survival: clinical article. J Neurosurg 2012; 117:1032.
  28. Oppenlander ME, Wolf AB, Snyder LA, et al. An extent of resection threshold for recurrent glioblastoma and its risk for neurological morbidity. J Neurosurg 2014; 120:846.
  29. Park CK, Kim JH, Nam DH, et al. A practical scoring system to determine whether to proceed with surgical resection in recurrent glioblastoma. Neuro Oncol 2013; 15:1096.
  30. Brem H, Piantadosi S, Burger PC, et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet 1995; 345:1008.
  31. Valtonen S, Timonen U, Toivanen P, et al. Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study. Neurosurgery 1997; 41:44.
  32. Nieder C, Astner ST, Mehta MP, et al. Improvement, clinical course, and quality of life after palliative radiotherapy for recurrent glioblastoma. Am J Clin Oncol 2008; 31:300.
  33. 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.
  34. Cabrera AR, Cuneo KC, Desjardins A, et al. Concurrent stereotactic radiosurgery and bevacizumab in recurrent malignant gliomas: a prospective trial. Int J Radiat Oncol Biol Phys 2013; 86:873.
  35. Gutin PH, Iwamoto FM, Beal K, et al. Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Int J Radiat Oncol Biol Phys 2009; 75:156.
  36. Kong DS, Lee JI, Park K, et al. Efficacy of stereotactic radiosurgery as a salvage treatment for recurrent malignant gliomas. Cancer 2008; 112:2046.
  37. 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; 63:47.
  38. Fogh SE, Andrews DW, Glass J, et al. Hypofractionated stereotactic radiation therapy: an effective therapy for recurrent high-grade gliomas. J Clin Oncol 2010; 28:3048.
  39. Clarke J, Neil E, Terziev R, et al. Multicenter, Phase 1, Dose Escalation Study of Hypofractionated Stereotactic Radiation Therapy With Bevacizumab for Recurrent Glioblastoma and Anaplastic Astrocytoma. Int J Radiat Oncol Biol Phys 2017; 99:797.
  40. Scharfen CO, Sneed PK, Wara WM, et al. High activity iodine-125 interstitial implant for gliomas. Int J Radiat Oncol Biol Phys 1992; 24:583.
  41. Simon JM, Cornu P, Boisserie G, et al. Brachytherapy of glioblastoma recurring in previously irradiated territory: predictive value of tumor volume. Int J Radiat Oncol Biol Phys 2002; 53:67.
  42. Larson DA, Suplica JM, Chang SM, et al. Permanent iodine 125 brachytherapy in patients with progressive or recurrent glioblastoma multiforme. Neuro Oncol 2004; 6:119.
  43. Chamberlain MC, Barba D, Kormanik P, et al. Concurrent cisplatin therapy and iodine 125 brachytherapy for recurrent malignant brain tumors. Arch Neurol 1995; 52:162.
  44. Patel S, Breneman JC, Warnick RE, et al. Permanent iodine-125 interstitial implants for the treatment of recurrent glioblastoma multiforme. Neurosurgery 2000; 46:1123.
  45. Chan TA, Weingart JD, Parisi M, et al. Treatment of recurrent glioblastoma multiforme with GliaSite brachytherapy. Int J Radiat Oncol Biol Phys 2005; 62:1133.
  46. Tatter SB, Shaw EG, Rosenblum ML, et al. An inflatable balloon catheter and liquid 125I radiation source (GliaSite Radiation Therapy System) for treatment of recurrent malignant glioma: multicenter safety and feasibility trial. J Neurosurg 2003; 99:297.
  47. Welsh J, Sanan A, Gabayan AJ, et al. GliaSite brachytherapy boost as part of initial treatment of glioblastoma multiforme: a retrospective multi-institutional pilot study. Int J Radiat Oncol Biol Phys 2007; 68:159.
  48. 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.
  49. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009; 27:4733.
  50. Cloughesy T, Vredenburgh JJ, Day B, et al. Updated safety and survival of patients with relapsed glioblastoma treated with bevacizumab in the BRAIN study (abstract #2008). J Clin Oncol 2010; 28:181s.
  51. 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.
  52. Brandes AA, Finocchiaro G, Zagonel V, et al. AVAREG: a phase II, randomized, noncomparative study of fotemustine or bevacizumab for patients with recurrent glioblastoma. Neuro Oncol 2016; 18:1304.
  53. Wick W, Brandes AA, Gorlia T, et al. EORTC 26101 phase III trial exploring the combination of bevacizumab and lomustine in patients with first progression of glioblastoma. J Clin Oncol 2016; 34:suppl (abstr 2001).
  54. Zuniga RM, Torcuator R, Jain R, et al. Rebound tumour progression after the cessation of bevacizumab therapy in patients with recurrent high-grade glioma. J Neurooncol 2010; 99:237.
  55. Omuro A, Chan TA, Abrey LE, et al. Phase II trial of continuous low-dose temozolomide for patients with recurrent malignant glioma. Neuro Oncol 2013; 15:242.
  56. Reardon DA, Desjardins A, Peters K, et al. Phase II study of metronomic chemotherapy with bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy. J Neurooncol 2011; 103:371.
  57. Reardon DA, Desjardins A, Peters KB, et al. Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy. Cancer 2011; 117:5351.
  58. 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.
  59. Rahman R, Hempfling K, Norden AD, et al. Retrospective study of carmustine or lomustine with bevacizumab in recurrent glioblastoma patients who have failed prior bevacizumab. Neuro Oncol 2014; 16:1523.
  60. Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 2014; 370:709.
  61. Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 2014; 370:699.
  62. Wong ET, Gautam S, Malchow C, et al. Bevacizumab for recurrent glioblastoma multiforme: a meta-analysis. J Natl Compr Canc Netw 2011; 9:403.
  63. Raizer JJ, Grimm S, Chamberlain MC, et al. A phase 2 trial of single-agent bevacizumab given in an every-3-week schedule for patients with recurrent high-grade gliomas. Cancer 2010; 116:5297.
  64. Blumenthal DT, Mendel L, Bokstein F. The optimal regimen of bevacizumab for recurrent glioblastoma: does dose matter? J Neurooncol 2016; 127:493.
  65. Levin VA, Mendelssohn ND, Chan J, et al. Impact of bevacizumab administered dose on overall survival of patients with progressive glioblastoma. J Neurooncol 2015; 122:145.
  66. Brandes AA, Bartolotti M, Tosoni A, et al. Practical management of bevacizumab-related toxicities in glioblastoma. Oncologist 2015; 20:166.
  67. Norden AD, Bartolomeo J, Tanaka S, et al. Safety of concurrent bevacizumab therapy and anticoagulation in glioma patients. J Neurooncol 2012; 106:121.
  68. Fraum TJ, Kreisl TN, Sul J, et al. Ischemic stroke and intracranial hemorrhage in glioma patients on antiangiogenic therapy. J Neurooncol 2011; 105:281.
  69. Simonetti G, Trevisan E, Silvani A, et al. Safety of bevacizumab in patients with malignant gliomas: a systematic review. Neurol Sci 2014; 35:83.
  70. Nghiemphu PL, Green RM, Pope WB, et al. Safety of anticoagulation use and bevacizumab in patients with glioma. Neuro Oncol 2008; 10:355.
  71. Brandes AA, Tosoni A, Amistà P, et al. How effective is BCNU in recurrent glioblastoma in the modern era? A phase II trial. Neurology 2004; 63:1281.
  72. Schmidt F, Fischer J, Herrlinger U, et al. PCV chemotherapy for recurrent glioblastoma. Neurology 2006; 66:587.
  73. Fabrini MG, Silvano G, Lolli I, et al. A multi-institutional phase II study on second-line Fotemustine chemotherapy in recurrent glioblastoma. J Neurooncol 2009; 92:79.
  74. Chamberlain MC. Salvage therapy with lomustine for temozolomide refractory recurrent anaplastic astrocytoma: a retrospective study. J Neurooncol 2015; 122:329.
  75. 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.
  76. 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.
  77. 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.
  78. 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.
  79. Khan RB, Raizer JJ, Malkin MG, et al. A phase II study of extended low-dose temozolomide in recurrent malignant gliomas. Neuro Oncol 2002; 4:39.
  80. Brandes AA, Tosoni A, Cavallo G, et al. Temozolomide 3 weeks on and 1 week off as first-line therapy for recurrent glioblastoma: phase II study from gruppo italiano cooperativo di neuro-oncologia (GICNO). Br J Cancer 2006; 95:1155.
  81. Wick A, Felsberg J, Steinbach JP, et al. Efficacy and tolerability of temozolomide in an alternating weekly regimen in patients with recurrent glioma. J Clin Oncol 2007; 25:3357.
  82. Abacioglu U, Caglar HB, Yumuk PF, et al. Efficacy of protracted dose-dense temozolomide in patients with recurrent high-grade glioma. J Neurooncol 2011; 103:585.
  83. Kong DS, Lee JI, Kim JH, et al. Phase II trial of low-dose continuous (metronomic) treatment of temozolomide for recurrent glioblastoma. Neuro Oncol 2010; 12:289.
  84. Norden AD, Lesser GJ, Drappatz J, et al. Phase 2 study of dose-intense temozolomide in recurrent glioblastoma. Neuro Oncol 2013; 15:930.
  85. Han SJ, Rolston JD, Molinaro AM, et al. Phase II trial of 7 days on/7 days off temozolmide for recurrent high-grade glioma. Neuro Oncol 2014; 16:1255.
  86. Weller M, Tabatabai G, Kästner B, et al. MGMT Promoter Methylation Is a Strong Prognostic Biomarker for Benefit from Dose-Intensified Temozolomide Rechallenge in Progressive Glioblastoma: The DIRECTOR Trial. Clin Cancer Res 2015; 21:2057.
  87. Desjardins A, Reardon DA, Coan A, et al. Bevacizumab and daily temozolomide for recurrent glioblastoma. Cancer 2012; 118:1302.
  88. Verhoeff JJ, Lavini C, van Linde ME, et al. Bevacizumab and dose-intense temozolomide in recurrent high-grade glioma. Ann Oncol 2010; 21:1723.
  89. Blumenthal DT, Yalon M, Vainer GW, et al. Pembrolizumab: first experience with recurrent primary central nervous system (CNS) tumors. J Neurooncol 2016; 129:453.
  90. Chamberlain MC, Kim BT. Nivolumab for patients with recurrent glioblastoma progressing on bevacizumab: a retrospective case series. J Neurooncol 2017; 133:561.
  91. Bouffet E, Larouche V, Campbell BB, et al. Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency. J Clin Oncol 2016; 34:2206.
  92. Stupp R, Wong ET, Kanner AA, et al. NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer 2012; 48:2192.
  93. Stupp R, Taillibert S, Kanner AA, et al. Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial. JAMA 2015; 314:2535.
  94. Mrugala MM, Engelhard HH, Dinh Tran D, et al. Clinical practice experience with NovoTTF-100A™ system for glioblastoma: The Patient Registry Dataset (PRiDe). Semin Oncol 2014; 41 Suppl 6:S4.