Abstract
Angiogenesis has recently become a major target for the development of new antineoplastic drugs. The most serious adverse events linked to angiogenesis inhibitors are venous or arterial thromboembolism and haemorrhage. Thus, there is need to define with more certainty the impact of these new drugs in terms of adverse effects in neurological patients. The aim of the study is to assess the risk of venous thromboembolism (VTE) and bleeding in patients with malignant gliomas treated with bevacizumab with or without concomitant anticoagulant therapy. A review of published literature was performed in Medline, from which 476 records were identified. A total of 27 full-text articles, including retrospective analyses, retrospective reviews, and open label trials, were assessed for eligibility. The investigated drugs included bevacizumab alone, bevacizumab plus chemotherapy with/without concomitant radiation therapy; only two articles dealt with bevacizumab in association with anticoagulant treatment. A total of 2,208 patients with malignant gliomas, were identified and included in the analysis. From data it appears that patients receiving bevacizumab had a major risk of developing VTE that increased when bevacizumab is associated with radio-chemotherapy (4.27 vs 7.46 %). Regarding bleeding, data showed that patients treated with anticoagulant had a significantly increased risk of severe central nervous system (CNS) bleeding compared to patients not receiving anticoagulant therapy (0.6 vs 8.2 %). The use of bevacizumab combined with chemo-radiotherapy seems to be associated with a higher risk for VTE compared to patients receiving antiangiogenic therapy alone. The associated use of anticoagulants and bevacizumab far increases the risk of developing CNS and non-CNS bleeding higher than grade 3, compared to patients receiving bevacizumab alone.
Similar content being viewed by others
References
Stupp R, Hegi ME, Mason WP et al (2009) European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. 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 10(5):459–466
Tuettenberg J, Friedel C, Vajkoczy P (2006) Angiogenesis in malignant glioma: a target for antitumor therapy? Crit Rev Oncol Hematol 59(3):181–193
Norden AD, Young GS, Setayesh K et al (2008) Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 70:779–787
Kargiotis O, Rao JS, Kyritsis AP (2006) Mechanisms of angiogenesis in gliomas. J Neurooncol 78(3):281–293
Vredenburgh JJ, Desjardins A, Herndon JE 2nd et al (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13(4):1253–1259
Friedman HS, Prados MD, Wen PY et al (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27(28):4733–4740
Zuniga RM, Torcuator R, Jain R et al (2009) Efficacy, safety and patterns of response and recurrence in patients with recurrent high-grade gliomas treated with bevacizumab plus irinotecan. J Neurooncol 91:329–336
Batchelor TT, Sorensen AG, di Tomaso E et al (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11(1):83–95
Vredenburgh JJ, Cloughesy T, Samant M et al (2010) Corticosteroid use in patients with glioblastoma at first or second relapse treated with bevacizumab in the BRAIN study. Oncologist 15(12):1329–1334
Raizer JJ, Grimm S, Chamberlain MC et al (2010) A phase 2 trial of single-agent bevacizumab given in an every-3-week schedule for patients with recurrent high-grade gliomas. Cancer 116(22):5297–5305. doi:10.1002/cncr.25462
Armstrong TS, Wen PY, Gilbert MR et al (2012) Management of treatment-associated toxicities of anti-angiogenic therapy in patients with brain tumors. Neuro Oncol 14(10):1203–1214
Nghiemphu PL, Green RM, Pope WB et al (2008) Safety of anticoagulation use and bevacizumab in patients with glioma. Neuro Oncol 10(3):355–360
Norden AD, Bartolomeo J, Tanaka S et al (2011) Safety of concurrent bevacizumab therapy and anticoagulation in glioma patients. J Neurooncol 106(1):121–125
Chamberlain MC, Johnston S (2009) Bevacizumab for recurrent alkylator-refractory anaplastic oligodendroglioma. Cancer 115(8):1734–1743. doi:10.1002/cncr.24179
Bokstein F, Shpigel S, Blumenthal DT (2008) Treatment with bevacizumab and irinotecan for recurrent high-grade glial tumors. Cancer 112:2267–2273
Kang TY, Jin T, Elinzano H, Peereboom D (2008) Irinotecan and bevacizumab in progressive primary brain tumors, an evaluation of efficacy and safety. J Neurooncol 89:113–118
Socinski MA, Langer CJ, Huang JE et al (2009) Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases. J Clin Oncol 27:5255–5261
Taillibert S, Vincent LA, Granger B et al (2009) Bevacizumab and irinotecan for recurrent oligodendroglial tumors. Neurology 72:1601–1606
Poulsen HS, Grunnet K, Sorensen M et al (2009) Bevacizumab plus irinotecan in the treatment patients with progressive recurrent malignant brain tumours. Acta Oncol 48(1):52–58
Thompson EM, Dosa E, Kraemer DF et al (2010) Treatment with bevacizumab plus carboplatin for recurrent malignant glioma. Neurosurgery 67(1):87–93
Hasselbalch B, Lassen U, Hansen S et al (2010) Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide: a phase II trial. Neuro Oncol 12:508–516
Verhoeff JJ, Lavini C, van Linde ME et al (2010) Bevacizumab and dose-intense temozolomide in recurrent high-grade glioma. Ann Oncol 21:1723–1727
Scott BJ, Quant EC, McNamara MB et al (2010) Bevacizumab salvage therapy following progression in high-grade glioma patients treated with VEGF receptor tyrosine kinase inhibitors. Neuro Oncol 12(6):603–607
Sathornsumetee S, Desjardins A, Vredenburgh JJ et al (2010) Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma. Neuro Oncol 12:1300–1310
Francesconi AB, Dupre S, Matos M et al (2010) Carboplatin and etoposide combined with bevacizumab for the treatment of recurrent glioblastoma multiforme. J Clin Neurosci 17:970–974
Reardon DA, Desjardins A, Peters KB, Vredenburgh JJ, Gururangan S, Sampson JH, McLendon RE, Herndon JE 2nd, Coan A, Threatt S, Friedman AH, Friedman HS (2011) Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy. Cancer 117(23):5351–5358. doi:10.1002/cncr.26188
Hofer S, Elandt K, Greil R et al (2011) Clinical outcome with bevacizumab in patients with recurrent high-grade glioma treated outside clinical trials. Acta Oncol 50:630–635
Fraum TJ, Kreisl TN, Sul J, Fine HA, Iwamoto FM (2011) Ischemic stroke and intracranial hemorrhage in glioma patients on antiangiogenic therapy. J Neurooncol 105(2):281–289. doi:10.1007/s11060-011-0579-4
Lai A, Filka E, McGibbon B et al (2008) Phase II pilot study of bevacizumab in combination with temozolomide and regional radiation therapy for up-front treatment of patients with newly diagnosed glioblastoma multiforme: interim analysis of safety and tolerability. Int J Radiat Oncol Biol Phys 71(5):1372–1380
Vredenburgh JJ, Desjardins A, Kirkpatrick JP, Reardon DA, Peters KB, Herndon JE 2nd, Marcello J, Bailey L, Threatt S, Sampson J, Friedman A, Friedman HS (2012) Addition of Bevacizumab to Standard Radiation Therapy and Daily Temozolomide Is Associated with Minimal Toxicity in Newly Diagnosed Glioblastoma Multiforme. Int J Radiat Oncol Biol Phys 82(1):58–66. doi:10.1016/j.ijrobp.2010.08.058
Lai A, Tran A, Nghiemphu PL et al (2011) Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. J Clin Oncol 29:142–148
Vredenburgh JJ, Desjardins A, Reardon DA et al (2011) The addition of bevacizumab to standard radiation therapy and temozolomide followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed glioblastoma. Clin Cancer Res 17:4119–4124
Niyazi M, Ganswindt U, Schwarz SB et al (2010) Irradiation and bevacizumab in high-grade glioma retreatment settings. Int J Radiat Oncol Biol Phys 82(1):67–76
Khorana AA, Connolly GC (2009) OncolAssessing risk of venous thromboembolism in the patient with cancer. J Clin 27(29):4839–4847
Chew HK, Wun T, Harvey D et al (2006) Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 166(4):458–464
Lee AY (2005) Deep vein thrombosis and cancer: survival, recurrence, and anticoagulant choices. Dis Mon 51(2–3):150–157
Gao S, Escalante C (2004) Venous thromboembolism and malignancy. Expert Rev Anticancer Ther 4(2):303–320
Levitan N, Dowlati A, Remick SC et al (1999) Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using medicare claims data. Medicine (Baltimore) 78(5):285–291
Constantini S, Kornowski R, Pomeranz S, Rappaport ZH (1991) Thromboembolic phenomena in neurosurgical patients operated upon for primary and metastatic brain tumors. Acta Neurochir (Wien) 109(3–4):93–97
Sawaya R, Zuccarello M, Elkalliny M, Nishiyama H (1992) Postoperative venous thromboembolism and brain tumors: part I. Clinical profile. J Neurooncol 14(2):119–125
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(3):640–646
Semrad TJ, O'Donnell R, Wun T et al (2007) Epidemiology of venous thromboembolism in 9489 patients with malignant glioma. J Neurosurg 106(4):601–608
Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S (2008) Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA 300(19):2277–2285
Kilickap S, Abali H, Celik I (2003) Bevacizumab, bleeding, thrombosis, and warfarin. J Clin Oncol 21(18):3542
Hapani S, Sher A, Chu D, Wu S (2010) Increased risk of serious hemorrhage with bevacizumab in cancer patients: a meta-analysis. Oncology 79(1–2):27–38
Chinot OL, de La Motte Rouge T, Moore N et al (2011) AVAglio: phase 3 trial of bevacizumab plus temozolomide and radiotherapy in newly diagnosed glioblastoma multiforme. Adv Ther 28(4):334–340
Conflict of interest
We declare that we have no conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Simonetti, G., Trevisan, E., Silvani, A. et al. Safety of bevacizumab in patients with malignant gliomas: a systematic review. Neurol Sci 35, 83–89 (2014). https://doi.org/10.1007/s10072-013-1583-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10072-013-1583-6