Journal of Neuro-Oncology

, Volume 96, Issue 2, pp 259–269 | Cite as

Salvage therapy with single agent bevacizumab for recurrent glioblastoma

  • Marc C. ChamberlainEmail author
  • Sandra K. Johnston
Clinical Study - Patient Study


A retrospective evaluation of single agent bevacizumab in adults with recurrent glioblastoma (GBM) with an objective of determining progression free survival (PFS). There is no standard therapy for recurrent GBM after failure of alkylator-based chemotherapy. A total of 50 adults, ages 36–70 years (median 64), with recurrent GBM were treated. All patients had previously been treated with surgery, concurrent radiotherapy and temozolomide, post-radiotherapy temozolomide and in 34 patients, one salvage regimen (PCV: 21, cyclophosphamide: 13). A total of 13 patients underwent repeat surgery. Patients were treated at first or second recurrence with bevacizumab, once every 2 weeks, defined as a single cycle. Neurological evaluation was performed every 2 weeks and neuroradiographic assessment following the initial 2 cycles of bevacizumab and subsequently after every 4 cycles of bevacizumab. A total of 468 cycles of bevacizumab (median 2 cycles; range 1–30) was administered. Bevacizumab-related toxicity included fatigue (16 patients; 4 grade 3), leukopenia (9; 1 grade 3), anemia (5; 0 grade 3), hypertension (7; 1 grade 3), deep vein thrombosis (4; 1 grade 3) and wound dehiscence (2; 1 grade 3). 21 patients (42%) demonstrated a partial radiographic response and 29 (58%) progressive disease following 1–2 cycles of bevacizumab. Time to tumor progression ranged from 0.5 to 15 months (median: 1.0 months). Survival ranged from 2 to 17 months (median: 8.5 months). 6-month and 12-month PFS were 42% and 22% respectively. Single agent bevacizumab demonstrated efficacy and acceptable toxicity in this cohort of adults with recurrent alkylator-refractory GBM.


Single agent bevacizumab Radiotherapy refractory Recurrent glioblastoma Surgery refractory Temozolomide refractory 


  1. 1.
    The Medical Research Council Brain Tumor Working Party (2001) Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: a Medical Research Council Trial. J Clin Oncol 19(2):509–518Google Scholar
  2. 2.
    Prados MD, Scott C, Curran WJ et al (1999) 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 17:3389–3395PubMedGoogle Scholar
  3. 3.
    Westphal M, Hilt DC, Bortey E et al (2003) A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neurooncology 5(2):79–88Google Scholar
  4. 4.
    Grossman SA, O’Neill A, Grunnet M, Mehta M et al (2003) Phase III study comparing three cycles of infusional carmustine and cisplatin followed by radiation therapy with radiation therapy and concurrent carmustine in patients with newly diagnosed supratentorial glioblastoma multiforme: Eastern Cooperative Oncology Group Trial 2394. J Clin Oncol 21:1485–1491CrossRefPubMedGoogle Scholar
  5. 5.
    Prados MD, Levin V (2000) Biology and treatment of malignant glioma. Semin Oncol 27(Suppl 3):1–10PubMedGoogle Scholar
  6. 6.
    Gutin PH, Prados MD, Phillips TL et al (1991) External irradiation followed by an interstitial high activity iodine-125 implant “boost” in the initial treatment of malignant gliomas: NCOG Study 6G82-2. Int J Radiat Oncol Biol Phys 21:601PubMedGoogle Scholar
  7. 7.
    Kornblith PD, Welch WC, Bradley MK (1993) The future of therapy for glioblastoma. Surg Neurol 39:538–543CrossRefPubMedGoogle Scholar
  8. 8.
    Loeffler JS, Alexander E, Shea WM et al (1992) Radiosurgery as part of the initial management of patients with malignant gliomas. J Clin Oncol 10(9):1379–1385PubMedGoogle Scholar
  9. 9.
    Prados MD, Gutin PH, Phillips TL et al (1992) Interstitial brachytherapy for newly diagnosed patients with malignant gliomas: the UCSF experience. Int J Radiat Oncol Biol Phys 24:593PubMedGoogle Scholar
  10. 10.
    Levin VA, Silver P, Hannigan J et al (1990) Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys 18:321–324PubMedGoogle Scholar
  11. 11.
    Stewart LA (2002) Chemotherapy in adult high-grade glioma: a systemic review and meta-analysis of individual patient data from 12 randomized trials. Lancet 359:1011–1018CrossRefPubMedGoogle Scholar
  12. 12.
    Fine HA, Dear KB, Loeffler JS et al (1993) Meta-analysis of radiation therapy and without chemotherapy for malignant gliomas in adults. Cancer 71:2585–2597CrossRefPubMedGoogle Scholar
  13. 13.
    Wong ET, Hess KR, Gleason MJ et al (1999) Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572–2578PubMedGoogle Scholar
  14. 14.
    Yung WKA, Mechtler L, Gleason MJ (1991) Intravenous carboplatin for recurrent malignant gliomas: a phase II study. J Clin Oncol 9:860PubMedGoogle Scholar
  15. 15.
    Allen JC, Walker R, Luks E et al (1987) Carboplatin and recurrent childhood brain tumors. J Clin Oncol 5(3):459–463PubMedGoogle Scholar
  16. 16.
    Yung WK, Prados MD, Yaya-Tur R, Rosenfeld SS, Brada M et al (1999) Multicenter Phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. J Clin Oncol 17:2762–2771PubMedGoogle Scholar
  17. 17.
    See SJ, Levin VA, Yung A et al (2004) 13-cis-Retinoic acid in the treatment of recurrent glioblastoma multiforme. Neurooncology 6:253–258Google Scholar
  18. 18.
    Allen JC, Helson L (1981) High-dose cyclophosphamide chemotherapy for recurrent CNS tumors in children. J Neurosurg 55:749–756CrossRefPubMedGoogle Scholar
  19. 19.
    Longee DC, Friedman HS, Albright RE, Burger PC et al (1990) Treatment of patients with recurrent gliomas with cyclophosphamide and vincristine. J Neurosurg 72:583–588CrossRefPubMedGoogle Scholar
  20. 20.
    Chamberlain MC, Tsao-Wei D (2004) Recurrent glioblastoma multiforme: salvage therapy with cyclophosphamide. Cancer 100:1213–1220CrossRefPubMedGoogle Scholar
  21. 21.
    Brem H, Piantadosi S, Burger PC, Walker M, Selker R et al (1995) Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet 345:1008–1012CrossRefPubMedGoogle Scholar
  22. 22.
    Jaeckle KA, Hess KR, Yung A et al (2003) Phase II evaluation of temozolomide and 13-cis-retinoic acid for the treatment of recurrent and progressive malignant glioma: a North American Brain Tumor Consortium study. J Clin Oncol 21:2305–2311CrossRefPubMedGoogle Scholar
  23. 23.
    Voges J, Reszka R, Grossman A, Dittmar C, Richter R et al (2003) Image-guided convection-enhanced delivery and gene therapy of glioblastoma. Ann Neurol 54:479–487CrossRefPubMedGoogle Scholar
  24. 24.
    Batchelor TT, Gilbert MR, Supko JG et al (2004) Phase 2 study of weekly irinotecan in adults with recurrent malignant glioma: final report of NABTT 97-11. Neurooncology 6:21–27Google Scholar
  25. 25.
    Buckner JC, Reid JM, Wright K et al (2003) Irinotecan in the treatment of glioma patients: current and future studies of the North Cancer Central Treatment Group. Cancer 97:2352–2358CrossRefPubMedGoogle Scholar
  26. 26.
    Chamberlain MC (2002) Salvage chemotherapy with CPT-11 for recurrent glioblastoma. J Neurooncol 56:183–188CrossRefPubMedGoogle Scholar
  27. 27.
    Cloughesy TF, Filka E, Kuhn J et al (2003) Two studies evaluating irinotecan treatment for recurrent malignant glioma using an every 3-week regimen. Cancer 97:2381–2386CrossRefPubMedGoogle Scholar
  28. 28.
    Friedman HS, Petros WP, Friedman AH et al (1999) Irinotecan therapy in adults with progressive malignant glioma. J Clin Oncol 17:1516–1525PubMedGoogle Scholar
  29. 29.
    Prados MD, Yung WKA, Jaeckle KA et al (2004) Phase 1 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: a North American Brain Tumor Consortium study. Neurooncology 6:44–54Google Scholar
  30. 30.
    Prados MD, Lamborn K, Yung WKA et al (2006) A phase 2 trail of irinotecan (CPT-11) in patients with recurrent malignant glioma: a North American Brain Tumor Consortium study. Neurooncology 82:189–193Google Scholar
  31. 31.
    Stark-Vance V (2005) Bevacizumab and CPT-11 in the treatment of relapsed malignant glioma. Neurooncology 7(3):369Google Scholar
  32. 32.
    Pope WB, Lai A, Nghiemphu P, Mischel P, Cloughesy TF (2006) MRI in patients with high-grade gliomas treated with bevacizumab and chemotherapy. Neurology 66(8):1258–1260CrossRefPubMedGoogle Scholar
  33. 33.
    Vredenburgh JJ, Desjardins A, Herndon JEII et al (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13(4):1253–1259CrossRefPubMedGoogle Scholar
  34. 34.
    Vredenburgh JJ, Desjardins A, Herndon JE et al (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25(30):4722–4729CrossRefPubMedGoogle Scholar
  35. 35.
    Chen C, Silverman DHS, Geist C et al (2007) Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: a pilot study. J Clin Oncol 25(30):4714–4721CrossRefPubMedGoogle Scholar
  36. 36.
    Norden AD, Young GS, Setayesh K et al (2008) Bevacizumab for recurrent malignant glioma: efficacy, toxicity and patterns of recurrence. Neurology 70:779–787CrossRefPubMedGoogle Scholar
  37. 37.
    Cloughesy T, Prados MD, Mikkelsen T et al (2008) A phase 2 randomized non-comparative clinical trial of the effect of bevacizumab alone or in combination with irinotecan on 6-month progression free survival in recurrent treatment refractory glioblastoma. J Clin Oncol 26:91s (Abstract)Google Scholar
  38. 38.
    Kreisl TN, Kim L, Moore K et al (2009) Phase II trial of single agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27:1–10CrossRefGoogle Scholar
  39. 39.
    MacDonald DR, Cascino TL, Schold SC et al (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277–1280PubMedGoogle Scholar
  40. 40.
    Miller RG Jr (1981) Survival analysis. Wiley, New York, pp 114–118Google Scholar
  41. 41.
    Pike MC (1972) Contribution to the discussion on the paper by R. Peto and J. Peto, ‘Asymptotically efficient rank invariant procedures’. J R Stat Soc Ser A 135(20):1–203Google Scholar
  42. 42.
    Berry G, Kitchin RM, Mock PA (1991) A comparison of two simple hazard ratio estimators based on the logrank test. Stat Med 10:749–755CrossRefPubMedGoogle Scholar
  43. 43.
    Lawless JF (1982) Statistical models and methods for lifetime data. Wiley, New York, pp 345–354Google Scholar
  44. 44.
    Kaplan EL, Meier P (1958) Nonparametric estimation form incomplete observations. J Am Stat Assoc 53:457–481CrossRefGoogle Scholar
  45. 45.
    Stupp R, Mason WP, Van Den Bent MJ et al (2004) Concomitant and adjuvant temozolomide and radiotherapy for newly diagnosed glioblastoma multiforme. Conclusive results of a randomized phase III trial by the EORTC Brain & RT Groups and NCIC Clinical Trial Groups. J Clin Oncol 22:1sGoogle Scholar
  46. 46.
    Folkman J (2006) Angiogenesis. Ann Rev Med 57:1–18CrossRefPubMedGoogle Scholar
  47. 47.
    Kerbel RS (2006) Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Science 312(5777):1171–1175CrossRefPubMedGoogle Scholar
  48. 48.
    Semenza GL (2008) A new weapon for attaching tumor blood vessels. N Engl J Med 358(19):2066–2067CrossRefPubMedGoogle Scholar
  49. 49.
    Bao S, Wu Q, Sathornsumetee S et al (2006) Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 66(16):7843–7848CrossRefPubMedGoogle Scholar
  50. 50.
    Ferrara N (2005) VEGF as a therapeutic target in cancer. Oncology 69(Suppl 3):11–16CrossRefPubMedGoogle Scholar
  51. 51.
    Jain RK, Xu L (2007) αPIGF: a new kid on the antiangiogenesis block. Cell 131:443–445CrossRefPubMedGoogle Scholar
  52. 52.
    Calabrese C, Poppleton H, Kocak M et al (2007) A perivascular niche for brain tumor stem cells. Cancer Cell 11(1):69–82CrossRefPubMedGoogle Scholar
  53. 53.
    Duda DG, Jain RK, Willett CG (2007) Antiangiogenics: the potential role of integrating this novel treatment modality with chemoradiation for solid cancers. J Clin Oncol 25(26):4033–4042CrossRefPubMedGoogle Scholar
  54. 54.
    Gilbertson RJ, Rich JN (2007) Making a tumour’s bed: glioblastoma stem cells and the vascular niche. Nat Rev Cancer 7(10):733–736CrossRefPubMedGoogle Scholar
  55. 55.
    Gorski DH, Beckert MA, Jaskowiak NT et al (1999) Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res 59(14):3374–3378PubMedGoogle Scholar
  56. 56.
    Tong RT, Boucher Y, Kozin SV et al (2004) Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 64(11):3731–3736CrossRefPubMedGoogle Scholar
  57. 57.
    Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7(9):987–989CrossRefPubMedGoogle Scholar
  58. 58.
    Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706):58–62CrossRefPubMedGoogle Scholar
  59. 59.
    Reardon DA, Wen PY, Desjardins A, Batchelor TT, Vredenburgh JJ (2008) Glioblastoma multiforme: an emerging paradigm of anti-VEGF therapy. Expert Opin Biol Ther 8(4):541–553CrossRefPubMedGoogle Scholar
  60. 60.
    Fischer I, Gagner JP, Law M et al (2005) Angiogenesis in gliomas: biology and molecular pathophysiology. Brain Pathol 15(4):297–310PubMedGoogle Scholar
  61. 61.
    Jain RK, di Tomaso E, Duda DG et al (2007) Angiogenesis in brain tumors. Nat Rev Neurosci 8:610–622CrossRefPubMedGoogle Scholar
  62. 62.
    Kargiotis O, Rao JS, Kyritsis AP (2006) Mechanisms of angiogenesis in gliomas. J Neurooncol 78(3):281–293CrossRefPubMedGoogle Scholar
  63. 63.
    Bao S, Wu Q, McLendon R et al (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444(7120):687–688CrossRefGoogle Scholar
  64. 64.
    Folkins C, Man S, Xu P et al (2007) Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res 67(8):3560–3564CrossRefPubMedGoogle Scholar
  65. 65.
    Fomchenko EI, Holland EC (2006) Origins of brain tumors—a disease of stem cells? Nat Clin Pract Neurol 2:288–289CrossRefPubMedGoogle Scholar
  66. 66.
    Purow B, Fine HA (2004) Antiangiogenic therapy for primary and metastatic brain tumors. Hematol Oncol Clin North Am 18:1161–1181CrossRefPubMedGoogle Scholar
  67. 67.
    Stefanik DF, Fellows WK, Rizkalla LR et al (2001) Monoclonal antibodies to vascular endothelial growth factor (VEGF) and the VEGF receptor, FLT-1, inhibit the growth of C6 glioma in a mouse xenograft. J Neurooncol 55:91–100CrossRefPubMedGoogle Scholar
  68. 68.
    Stefanik DF, Rizkalla LR, Soi A et al (1991) Acidic and basic fibroblast growth factors are present in glioblastoma multiforme. Cancer Res 51(20):5760–5765PubMedGoogle Scholar
  69. 69.
    Sun L, Hui AM, Su Q et al (2006) Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain. Cancer Cell 9(4):287–300CrossRefPubMedGoogle Scholar
  70. 70.
    Weis SM, Cheresh DA (2005) Pathophysiological consequences of VEGF-induced vascular permeability. Nature 437:497–504CrossRefPubMedGoogle Scholar
  71. 71.
    Winkler F, Kozin SV, Tong R et al (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation angiopoietin-1 and matrix metalloproteinases. Cancer Cell 6:553–563PubMedGoogle Scholar
  72. 72.
    Lamszus K, Heese O, Westphal M (2004) Angiogenesis-related growth factors in brain tumors. Cancer Treat Res 117:169–190PubMedGoogle Scholar
  73. 73.
    Yung WK et al (2000) A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 83(5):588–593CrossRefPubMedGoogle Scholar
  74. 74.
    Eremina V, Jefferson JA, Kowalewska J et al (2008) VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 358(11):1129–1136CrossRefPubMedGoogle Scholar
  75. 75.
    Eskens FA, Verweij J (2006) The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors: a review. Eur J Cancer 42:3127–3139CrossRefPubMedGoogle Scholar
  76. 76.
    Verheul HM, Pinedo HM (2007) Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer 7:475–485CrossRefPubMedGoogle Scholar
  77. 77.
    Brandes AA, Scelzi E, Salmistraro G et al (1997) Incidence of risk of thromboembolism during treatment of high-grade gliomas: a prospective study. Eur J Cancer 33:1592–1596CrossRefPubMedGoogle Scholar
  78. 78.
    Marras LC, Geerts WH, Perry JR (2000) The risk of venous thromboembolism is increased throughout the course of malignant glioma: an evidence-based review. Cancer 89:640–646CrossRefPubMedGoogle Scholar
  79. 79.
    Semrad TJ, O’Donnell R, Wun T et al (2007) Epidemiology of venous thromboembolism in 9489 patients with malignant glioma. J Neurosurg l06(4):601–608Google Scholar
  80. 80.
    Simanek R, Vormittag R, Hassler M et al (2007) Venous thromboembolism and survival in patients with high-grade glioma. Neurooncol 9(2):89–95Google Scholar
  81. 81.
    Nghiemphu PL, Green RM, Pope WB, Lai A, Cloughsey TF (2008) Safety of bevacizumab for anticoagulated patients with high grade gliomas. Neurooncology Apr 24 (Epub)Google Scholar
  82. 82.
    Lamborn KR, Yung AWK, Chang SM et al (2008) Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neurooncology 10:162–170Google Scholar
  83. 83.
    Quant EC, Norden AD, Drappatz J et al (2009) Role of a second chemotherapy in recurrent malignant glioma patients who progress on bevacizumab. Neurooncology March 30 (Epub ahead of print)Google Scholar
  84. 84.
    Bokstein F, Shpigel S, Blumenthal DTl (2008) Treatment with bevacizumab and irinotecan for recurrent high-grade glial tumors. Cancer 112(10):2267–2273CrossRefPubMedGoogle Scholar
  85. 85.
    Raizer JJ, Gallot L, Cohn R et al (2007) A phase II safety study of bevacizumab in patients with multiple recurrent or progressive malignant gliomas. J Clin Oncol 25(18S): 2079 (Abstract)Google Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  1. 1.Department of Neurology and NeurosurgeryUniversity of Washington, Fred Hutchinson Cancer Research CenterSeattleUSA
  2. 2.Department of Neurology and NeurosurgeryUniversity of Washington, Fred Hutchinson Cancer Center, Seattle Cancer Care AllianceSeattleUSA
  3. 3.Department of Neurology, Division of Neuro-OncologyUniversity of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care AllianceSeattleUSA

Personalised recommendations