Abstract
Bevacizumab is an antiangiogenic agent approved for recurrent glioblastoma due to high response rates. Prior reviews focused on severe or cardiovascular bevacizumab toxicities. We performed a comprehensive review of toxicities experienced among 210 patients enrolled in 3 phase II bevacizumab trials for recurrent malignant gliomas at the National Cancer Institute. No bevacizumab toxicities were experienced by 20 % patients, 40.2 % on monotherapy versus ≤9.5 % on combination therapy. Hypertension and proteinuria occurred in ~25 %. Fatigue, hypophosphatemia, aspartate aminotransferase elevation, rashes were common. Low grade headache, hoarseness, myalgias/arthralgias, liver enzyme elevation, azotemia and electrolyte abnormalities were noted. Rare severe toxicities, including thrombosis, hemorrhage, wound complications and colonic perforations, occurred at rates seen in other diseases. Leukopenia and neutropenia occurred solely with combination therapy, while thrombocytopenia occurred in 12.5 % on bevacizumab monotherapy. Thrombocytopenia was generally mild, but severe in (1.4 %) and increased in frequency with prolonged or combination therapy. Bevacizumab-related deaths occurred in 4 (1.9 %) patients, including brain ischemia (n = 1) and sudden unexplained deaths (n = 2). Prior hypertension increased the odds of hypertension by ≥3.4-fold (p < 0.001) and grade 3+ hypertension by ≥11.2 (p < 0.001). Prior hypertension increased the odds of hypophosphatemia by 2.4-fold (p = 0.011), but failed to predict proteinuria or azotemia. Age did not greatly impact toxicity. Hypertension, proteinuria and hypophosphatemia often occurred concurrently, more frequently and severely with prolonged use. Our study shows bevacizumab monotherapy is well tolerated, but toxicity increases with combination therapy. Balancing the risks and benefits of bevacizumab requires understanding the spectrum of bevacizumab toxicities and predisposing factors.
Similar content being viewed by others
References
Dolecek TA, Propp JM, Stroup NE, Kruchko C (2012) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro-Oncology 14(Suppl 5):v1–v49
Louis D, Ohgaki H, Wiestler O et al (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2):97–109
Frankel SA, German WJ (1958) Glioblastoma multiforme. J Neurosurg 15(5):489–503
Pichlmeier U, Bink A, Schackert G, Stummer W (2008) Resection and survival in glioblastoma multiforme: an RTOG recursive partitioning analysis of ALA study patients. Neuro-Oncology 10(6):1025–1034
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(8):2572
Laperriere N, Zuraw L, Cairncross G (2002) Radiotherapy for newly diagnosed malignant glioma in adults: a systematic review. Radiother Oncol 64(3):259–273
Scott CB, Scarantino C, Urtasun R et al (1998) 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 40(1):51–55
Tsao MN, Mehta MP, Whelan TJ et al (2005) 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 63(1):47–55
Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996
Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359(5):492–507
Maxwell M, Naber SP, Wolfe HJ et al (1991) Expression of angiogenic growth factor genes in primary human astrocytomas may contribute to their growth and progression. Cancer Res 51(4):1345–1351
Millauer B, Shawver LK, Plate KH, Risaui W, Ullrich A (1994) Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367(6463):576–579
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(2):91–100
Plate KH, Breier G, Weich HA, Risau W (1992) Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359(6398):845–848
Presta LG, Chen H, O’Connor SJ et al (1997) Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 57(20):4593–4599
Kabbinavar FF, Hambleton J, Mass RD, Hurwitz HI, Bergsland E, Sarkar S (2005) Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol 23(16):3706–3712
Kerr C (2005) Bevacizumab and chemotherapy improves survival in NSCLC. Lancet Oncol 6(5):266
Escudier B, Pluzanska A, Koralewski P et al (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370(9605):2103–2111
Vredenburgh JJ, Desjardins A, Herndon JE et al (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25(30):4722–4729
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(5):740–745
Kreisl TN, Zhang W, Odia Y et al (2011) A phase II trial of single-agent bevacizumab in patients with recurrent anaplastic glioma. Neuro-Oncology 13(10):1143–1150
Chen HX, Cleck JN (2009) Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev Clin Oncol 6(8):465–477
Gressett SM, Shah SR (2009) Intricacies of bevacizumab-induced toxicities and their management. Ann Pharmacother 43(3):490–501
Vaklavas C, Lenihan D, Kurzrock R, Tsimberidou AM (2010) Anti-vascular endothelial growth factor therapies and cardiovascular toxicity: what are the important clinical markers to target? Oncol 15(2):130–141
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
Chinot OL, Wick W, Mason W et al (2014) Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 370(8):709–722
Gilbert MR, Dignam JJ, Armstrong TS et al (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370(8):699–708
Amit L, Ben-Aharon I, Vidal L, Leibovici L, Stemmer S (2013) The impact of bevacizumab (Avastin) on survival in metastatic solid tumors—a meta-analysis and systematic review. PLoS ONE 8(1):e51780
Elice F, Rodeghiero F, Falanga A, Rickles FR (2009) Thrombosis associated with angiogenesis inhibitors. Best Pract Res Clin Haematol 22(1):115–128
Hutson TE, Figlin RA, Kuhn JG, Motzer RJ (2008) Targeted therapies for metastatic renal cell carcinoma: an overview of toxicity and dosing strategies. Oncol 13(10):1084–1096
Laskin J, Crinò L, Felip E et al (2012) Safety and efficacy of first-line bevacizumab plus chemotherapy in elderly patients with advanced or recurrent nonsquamous non-small cell lung cancer: safety of avastin in lung trial (MO19390). J Thorac Oncol 7(1):203–211. doi:10.1097/JTO.0b013e3182370e02
Peters K, Coyle T, Vredenburgh J, Desjardins A, Friedman H, Reardon D (2011) Ulceration of Striae distensae in high-grade glioma patients on concurrent systemic corticosteroid and bevacizumab therapy. J Neurooncol 101(1):155–159
Ricciardi S, Tomao S, de Marinis F (2009) Toxicity of targeted therapy in non–small-cell lung cancer management. Clin Lung Cancer 10(1):28–35
Schuster C, Eikesdal HP, Puntervoll H et al (2012) Clinical efficacy and safety of bevacizumab monotherapy in patients with metastatic melanoma: predictive importance of induced early hypertension. PLoS ONE 7(6):e38364
Shepard DR, Garcia JA (2009) Toxicity associated with the long-term use of targeted therapies in patients with advanced renal cell carcinoma. Expert Rev Anticancer Ther 9(6):795–805
Thomssen C, Pierga JY, Pritchard KI et al (2012) First-line bevacizumab-containing therapy for triple-negative breast cancer: analysis of 585 patients treated in the ATHENA study. Oncology 82(4):218–227
Girardi F, Franceschi E, Brandes AA (2010) Cardiovascular safety of VEGF-targeting therapies: current evidence and handling strategies. Oncol 15(7):683–694
Fraum T, Kreisl T, Sul J, Fine H, Iwamoto F (2011) Ischemic stroke and intracranial hemorrhage in glioma patients on antiangiogenic therapy. J Neurooncol 105(2):281–289
Wheeler H, Black J, Webb S, Shen H (2012) Dehiscence of corticosteroid-induced abdominal striae in a 14-year-old boy treated with bevacizumab for recurrent glioblastoma. J Child Neurol 27(7):927–929
Vredenburgh JJ, Desjardins A, Herndon JE et al (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13(4):1253–1259
Gururangan S, Chi SN, Young Poussaint T et al (2010) Lack of efficacy of bevacizumab plus irinotecan in children with recurrent malignant glioma and diffuse brainstem glioma: a pediatric brain tumor consortium study. J Clin Oncol 28(18):3069–3075
Liu AK, Macy ME, Foreman NK (2009) Bevacizumab as therapy for radiation necrosis in four children with pontine gliomas. Int J Radiat Oncol Biol Phys 75(4):1148–1154
Acknowledgments
The National Cancer Institute (NCI) Intramural Research Program provided grant funding for this project and the NCI phase II trial of bevacizumab as single agent [NCT00271609]. The NCI phase II trial of combination with enzastaurin (LY317615) and bevacizumab [NCT00586508] was sponsored by Eli Lilly and funded by the NCI via a CRADA. The NCI phase II trial of tandutinib (MLN518) and bevacizumab [NCT00667394] was sponsored and funded by Millennium Pharmaceuticals via a Clinical Trial Agreement (CTA). Tetiana Wiggington, Leslie Moses, Laurie Rosenblatt, Julie Peretti, Tracy Cropper, and Maria Gonzalez provided administrative assistance with medical records and database management.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Odia, Y., Shih, J.H., Kreisl, T.N. et al. Bevacizumab-related toxicities in the National Cancer Institute malignant glioma trial cohort. J Neurooncol 120, 431–440 (2014). https://doi.org/10.1007/s11060-014-1571-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11060-014-1571-6