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Toxicity profile of bevacizumab in the UK Neurofibromatosis type 2 cohort

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Abstract

Bevacizumab is considered an established part of the treatment strategies available for schwannomas in patients with Neurofibromatosis type 2 (NF2). In the UK, it is available through NHS National Specialized Commissioning to NF2 patients with a rapidly growing target schwannoma. Regrowth of the tumour on suspension of treatment is often observed resulting in prolonged periods of exposure to bevacizumab to control the disease. Hypertension and proteinuria are common events with bevacizumab use and there are concerns with regards to the long-term risks of prolonged treatment. Dosing, demographic and adverse event (CTCAE 4.03) data from the UK NF2 bevacizumab cohort are reviewed with particular consideration of renal and cardiovascular complications. Eighty patients (48 male:32 female), median age 24.5 years (range 11–66 years), were followed for a median of 32.7 months (range 12.0–60.2 months). The most common adverse events were fatigue, hypertension and infection. A total of 19/80 patients (24 %) had either a grade 2 or grade 3 hypertension event and 14/80 patients (17.5 %) had proteinuria. Of 36 patients followed for 36 months, 78 % were free from hypertension and 86 % were free of proteinuria. Logistic regression modeling identified age and induction dosing regime to be independent predictors of development of hypertension with dose of 7.5 mg/kg 3 weekly and age >30years having higher rates of hypertension. Proteinuria persisted in one of three patients after cessation of bevacizumab. One patient developed congestive heart failure and the details of this case are described. Further work is needed to determine optimal dosing regimes to limit toxicity without impacting on efficacy.

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References

  1. Mautner VF, Nguyen R, Kutta H, Fuensterer C, Bokemeyer C, Hagel C, Friedrich RE, Panse J (2010) Bevacizumab induces regression of vestibular schwannomas in patients with neurofibromatosis type 2. Neuro-Oncol 12(1):14–18. doi:10.1093/neuonc/nop010

    Article  PubMed  Google Scholar 

  2. Plotkin SR, Stemmer-Rachamimov AO, Barker FG 2nd, Halpin C, Padera TP, Tyrrell A, Sorensen AG, Jain RK, di Tomaso E (2009) Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med 361(4):358–367. doi:10.1056/NEJMoa0902579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Plotkin SR, Merker VL, Halpin C, Jennings D, McKenna MJ, Harris GJ, Barker FG, 2nd (2012) Bevacizumab for progressive vestibular schwannoma in neurofibromatosis type 2: a retrospective review of 31 patients. Otol Neuro 33 (6):1046–1052. doi:10.1097/MAO.0b013e31825e73f5

    Article  Google Scholar 

  4. Alanin MC, Klausen C, Caye-Thomasen P, Thomsen C, Fugleholm K, Poulsgaard L, Lassen U, Mau-Sorensen M, Hofland KF (2014) The effect of bevacizumab on vestibular schwannoma tumour size and hearing in patients with neurofibromatosis type 2. Eur Arch Oto-Rhino-Laryngol. doi:10.1007/s00405-014-3398-3

    Google Scholar 

  5. Hochart A, Gaillard V, Baroncini M, Andre N, Vannier JP, Vinchon M, Dubrulle F, Lejeune JP, Vincent C, Neve V, Sudour Bonnange H, Bonne NX, Leblond P (2015) Bevacizumab decreases vestibular schwannomas growth rate in children and teenagers with neurofibromatosis type 2. J Neurooncol 124(2):229–236. doi:10.1007/s11060-015-1828-8

    Article  CAS  PubMed  Google Scholar 

  6. Morris KA, Golding JF, Axon PR, Afridi S, Blesing C, Ferner RE, Halliday D, Jena R, Pretorius PM, Evans DG, McCabe MG, Parry A (2016) Bevacizumab in Neurofibromatosis type 2 (NF2) related vestibular schwannomas: a nationally coordinated approach to delivery and prospective evaluation. Neuro-Oncol Pract. doi:10.1093/nop/npv065 (In press:npv065)

    Google Scholar 

  7. Farschtschi S, Kollmann P, Dalchow C, Stein A, Mautner VF (2015) Reduced dosage of bevacizumab in treatment of vestibular schwannomas in patients with neurofibromatosis type 2. Eur Arch Oto-Rhino-Laryngol 272 (12):3857–3860. doi:10.1007/s00405-015-3604-y

    Article  Google Scholar 

  8. Blakeley JO, Ye X, Duda DG, Halpin CF, Bergner AL, Muzikansky A, Merker VL, Gerstner ER, Fayad LM, Ahlawat S, Jacobs MA, Jain RK, Zalewski C, Dombi E, Widemann BC, Plotkin SR (2016) Efficacy and biomarker study of bevacizumab for hearing loss resulting from Neurofibromatosis Type 2-associated vestibular schwannomas. J Clin Oncol 34(14):1669–1675. doi:10.1200/JCO.2015.64.3817

    Article  PubMed  Google Scholar 

  9. Hexter A, Jones A, Joe H, Heap L, Smith MJ, Wallace AJ, Halliday D, Parry A, Taylor A, Raymond L, Shaw A, Afridi S, Obholzer R, Axon P, King AT, English Specialist NFRG, Friedman JM, Evans DG (2015) Clinical and molecular predictors of mortality in neurofibromatosis 2: a UK national analysis of 1192 patients. J Med Genet 52(10):699–705. doi:10.1136/jmedgenet-2015-103290

    Article  CAS  PubMed  Google Scholar 

  10. Farschtschi S, Merker VL, Wolf D, Schuhmann M, Blakeley J, Plotkin SR, Hagel C, Mautner VF (2015) Bevacizumab treatment for symptomatic spinal ependymomas in neurofibromatosis type 2. Acta Neurol Scand. doi:10.1111/ane.12490

    PubMed  Google Scholar 

  11. Essayed WI, Bernard A, Kalamarides M (2015) Clinical response associated with radiographic regression of a cervicomedullary ependymoma in a NF2 patient treated by bevacizumab. J Neurooncol 125(2):445–446. doi:10.1007/s11060-015-1925-8

    Article  CAS  PubMed  Google Scholar 

  12. Morris KA, Afridi S, Evans DG, Hensiek A, McCabe MG, Kellett M, Halliday D, Pretorius PM, Parry A (in press) The response of spinal cord Ependymomas to Bevacizumab in patients with Neurofibromatosis type 2. JNS (Spine)

  13. Alanin MC, Klausen C, Caye-Thomasen P, Thomsen C, Fugleholm K, Poulsgaard L, Lassen U, Mau-Sorensen M, Hofland KF (2015) Effect of bevacizumab on intracranial meningiomas in patients with neurofibromatosis type 2-a retrospective case series. Int J Neurosci 1–5. doi:10.3109/00207454.2015.1092443

  14. Nunes FP, Merker VL, Jennings D, Caruso PA, di Tomaso E, Muzikansky A, Barker FG 2nd, Stemmer-Rachamimov A, Plotkin SR (2013) Bevacizumab treatment for meningiomas in NF2: a retrospective analysis of 15 patients. PloS One 8(3):e59941. doi:10.1371/journal.pone.0059941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Izzedine H, Rixe O, Billemont B, Baumelou A, Deray G (2007) Angiogenesis inhibitor therapies: focus on kidney toxicity and hypertension. Am J Kidney Dis 50(2):203–218. doi:10.1053/j.ajkd.2007.04.025

    Article  CAS  PubMed  Google Scholar 

  16. Slusarz KM, Merker VL, Muzikansky A, Francis SA, Plotkin SR (2014) Long-term toxicity of bevacizumab therapy in neurofibromatosis 2 patients. Cancer Chemother Pharmacol 73(6):1197–1204. doi:10.1007/s00280-014-2456-2

    Article  CAS  PubMed  Google Scholar 

  17. Hornigold RE, Golding JF, Ferner RE, Ferner RE (2011) Neurofibromatosis 2: a novel risk factor for hypertension? Am J Med Gen Part A 155A(7):1721–1722. doi:10.1002/ajmg.a.34035

    Article  Google Scholar 

  18. Services USDOHAH, Health NIo, Institute NC (2010) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Accessed 12 January 2015 2015

  19. (Nice), NIfHaCE (2011) Hypertension in adults: diagnosis and management Clinical Guideline cg127.

  20. Abbas A, Mirza MM, Ganti AK, Tendulkar K (2015) Renal toxicities of targeted therapies. Target Oncol 10(4):487–499. doi:10.1007/s11523-015-0368-7

    Article  PubMed  Google Scholar 

  21. Zhu X, Wu S, Dahut WL, Parikh CR (2007) Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis 49(2):186–193. doi:10.1053/j.ajkd.2006.11.039

    Article  CAS  PubMed  Google Scholar 

  22. Economopoulou P, Kotsakis A, Kapiris I, Kentepozidis N (2015) Cancer therapy and cardiovascular risk: focus on bevacizumab. Cancer Manag Res 7:133–143. doi:10.2147/CMAR.S77400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Groarke JD, Choueiri TK, Slosky D, Cheng S, Moslehi J (2014) Recognizing and managing left ventricular dysfunction associated with therapeutic inhibition of the vascular endothelial growth factor signaling pathway. Curr Treat Options Cardiovasc Med 16(9):335. doi:10.1007/s11936-014-0335-0

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

English Specialist NF2 Research Group members: Cambridge and Central: Patrick Axon, Neil Burnet, Neil Donnelly, Juliette Durie-Gair, Martin English, Nicola Folland, Fiona Harris, Frances Harris, David Heney, Anke Henseik, Sarah Jeffries, Richard Knight, Tamara Lamb, Robert Macfarlane, Richard Mannion, James Nicholson, Richard Price, Ella Rands, Paul Sanghera, Daniel Scoffings, Amy Taylor, James Tysome, London: Chris Hammond, Karine Lascelles, Charles Nduka, Terry Nunn, Rupert Obholzer, Shakeel Saeed, Adam Shaw, Nick Thomas, Suki Thomson, Daniel Walsh, Victoria Williams, Sue Wood, Manchester: Raji Anup, Chris Duff, Simon R Freeman, Emma Howie, Susan M Huson, Nicola Jarvis, Ian Kamaly-Asi, Mark Kellett, Andrew King, John-Paul Kilday, Simon K Lloyd, Connor Malluci, Deborah Mawman, Sam Mills, Martin O’Driscoll, Sonia Patel, Mary Perry, Scott A Rutherford, Vilka Scott-Kitching, Stavros M Stivaros, Owen Thomas, Grace Vassallo, Charlotte L Ward, Oxford and South West: Lucy Cogswell, Louise Dalton, Caroline Dodridge, John Elston, Henk Giele, C Oliver Hanemann, Wendy Howard, David Johnson, Richard Kerr, Avianna Laws, James Lee, Elle Mace, Anne May, Chris Milford, Pieter Pretorius, James Ramsden, Carolyn Redman.

Funding

Dr Morris: NIHR RCF grant from the University of Oxford (AC12/092).

Author information

Authors and Affiliations

  1. Nuffield Department of Neurosciences and NF2 Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK

    Katrina A. Morris & Allyson Parry

  2. Department of Genetics and NF2 Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK

    Dorothy Halliday

  3. Department of Paediatric Oncology, The West Wing, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK

    Shaun Wilson

  4. John Radcliffe Hospital, Oxford Cancer Centre, The Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK

    Claire Blesing & Nicola Warner

  5. University of New South Wales, Sydney, Australia

    Katrina A. Morris

  6. University of Westminster, London, UK

    John F. Golding

  7. Genomic Medicine, Institute of Human Development, MAHSC, University of Manchester, St Mary’s Hospital, Manchester, UK

    D. Gareth Evans

  8. Department of Neurology, Neurofibromatosis Service, Guy’s & St Thomas’ Hospital, Great Maze Pond, London, SE1 9RT, UK

    Rosalie E. Ferner, Angela Swampillai & Shazia K. Afridi

  9. Nottingham University Hospitals NHS Trust, Nottingham, UK

    Karen Foweraker

  10. Department of Oncology, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK

    Raj Jena

  11. The Christie NHS Foundation Trust, Manchester, UK

    Catherine McBain

  12. Centre for Paediatric, Teenage and Young Adult Cancer, Institute of Cancer Sciences, University of Manchester, Manchester, UK

    Martin G. McCabe

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  1. Katrina A. Morris
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  2. John F. Golding
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  3. Claire Blesing
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  4. D. Gareth Evans
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  5. Rosalie E. Ferner
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  8. Raj Jena
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  9. Catherine McBain
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  10. Martin G. McCabe
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  11. Angela Swampillai
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  13. Shaun Wilson
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  14. Allyson Parry
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  15. Shazia K. Afridi
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On behalf of the UK NF2 research group

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Correspondence to Shazia K. Afridi.

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Morris, K.A., Golding, J.F., Blesing, C. et al. Toxicity profile of bevacizumab in the UK Neurofibromatosis type 2 cohort. J Neurooncol 131, 117–124 (2017). https://doi.org/10.1007/s11060-016-2276-9

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  • DOI: https://doi.org/10.1007/s11060-016-2276-9

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