The causes and countermeasures of non-response to anti-vascular endothelial growth factor therapy_Chinese Journal of Ocular Fundus Diseases

Authors：

ChenXia ,  XuXun

Department of Ophthalmology, First People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200080, China;

Corresponding author：

XuXun, Email: drxuxun@sjtu.edu.cn

Keywords：

Vascular endothelial growth factor A; Angiogenesis inhibitors/therapeutic use; Antibodies,monoclonal/therapeutic use; Review

DOI：

10.3760/cma.j.issn.1005-1015.2016.04.027

Video：

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Abstract Full text Figures/Tables Video References Cited by

The therapeutic response of anti-vascular endothelial growth factor (VEGF) differs among individuals. According to the changes of central retinal thickness, intraretinal fluid, subretinal fluid, best corrected visual acuity and other morphological or functional manifestations after treatment, the performance of the treated eyes can be classified as optimal response, poor response and non-response. A variety of factors could account for poor or non-response to anti-VEGF, such as genomic polymorphism and specific genomic risk alleles, lesion characteristics, vitreous and macular structural abnormalities, resistance to anti-VEGF drug, and the role of pericytes and others. The common counter measures include increasing the dosage, shortening the injection interval and replacing with another alternative drug, inhibition of pericytes, relieving vitreomacular anatomical abnormalities. It is still worthy of further exploration that how to assess individual reasons for non-response, so that we can give proper treatment to reduce the excessive use of anti-VEGF drugs and improve the clinical management of ocular neovascularization diseases.

Citation： ChenXia, XuXun. The causes and countermeasures of non-response to anti-vascular endothelial growth factor therapy. Chinese Journal of Ocular Fundus Diseases, 2016, 32(4): 444-448. doi: 10.3760/cma.j.issn.1005-1015.2016.04.027 Copy

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7.	Zhang M, Zhang J, Yan M, et al. A phase I study of KH902, a vascular endothelial growth factor receptor decoy, for exudative age-related macular degeneration[J]. Ophthalmology, 2011, 118(4):672-678.DOI:10.1016/j.ophtha.2010.08.008.
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1. Drake CJ, LaRue A, Ferrara N, et al. VEGF regulates cell behavior during vasculogenesis[J]. Dev Biol, 2000, 224(2):178-188.
2. 闫瑾, 刘美欣.抗VEGF药物治疗眼部新生血管性疾病[J]. 中国实用眼科杂志,2014,32(2):97-100. DOI:10.3760/cma.j.issn.1006-4443.2014.02.001. Yan J,Liu MX.Anti-vascular endothelial growth factor for ocular neovascular diseases[J]. Chin J Pract Ophthalmol,2014,32(2):97-100. DOI:10.3760/cma.j.issn.1006-4443.2014.02.001.
3. Rosenfeld RJ, Rich RM, Laiwani GA. Ranibizumab:phase Ⅲ clinical trial results[J]. Ophthalmol Clin North Am, 2006, 19(3):361-372.
4. Stewart MW, Grippon S, Kirkpatriek P. Aflibercept[J]. Nat Rev Drag Discov, 2012, 11(4):269-270.DOI:10.1038/nrd3700.
5. Heier JS, Clark WL, Boyer DS, et al. Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion:two-year results from the COPERNICUS study[J]. Ophthalmology, 2014, 121(7):1414-1420. DOI:10.1016/j.ophtha.2014.01.027.
6. Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al.Intravitreal aflibercept injection for neovascular age-related macular degeneration:ninety-six-week results of the VIEW studies[J]. Ophthalmology, 2014, 121(1):193-201. DOI:10.1016/j.ophtha.2013.08.011.
7. Zhang M, Zhang J, Yan M, et al. A phase I study of KH902, a vascular endothelial growth factor receptor decoy, for exudative age-related macular degeneration[J]. Ophthalmology, 2011, 118(4):672-678.DOI:10.1016/j.ophtha.2010.08.008.
8. 戴虹,卢颖毅.全面评估抗血管内皮生长因子药物治疗新生血管性老年性黄斑变性的影响因素,努力提高治疗效果的综合收益[J].中华眼底病杂志,2016, 32(1):8-11. DOI:10.3760/cma.j.issn.1005-1015.2016.01.003. Dai H,Lu YY. Overall assessment of the factors influencing the effect of anti-vascular endothelial growth factor for neovascular age-related macular degeneration to improve the comprehensive benefit of treatment[J]. Chin J Ocul Fundus Dis,2016, 32(1):8-11. DOI:10.3760/cma.j.issn.1005-1015.2016.01.003.
9. Jampol L, Bressler NB, Glassman AR. Revolution to a new standard treatment of diabetic macular edema[J]. JAMA,2014,311:2269-2270.DOI:10.1001/jama.2014.2536.
10. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration:two-year results[J]. Ophthalmology,2012,119(7):1388-1398.DOI:10.1016/j.ophtha.2012.03.053.
11. Campochiaro PA, Sophie R, Pearlman J, et al. Long-term outcomes in patients with retinal vein occlusion treated with ranibizumab:the RETAIN study[J]. Ophthalmology, 2014,121(1):209-219.DOI:10.1016/j.ophtha.2013.08.038.
12. Amoaku WM, Chakravarthy U, Gale R, et al. Defining response to anti-VEGF therapies in neovascular AMD[J]. Eye (Lond), 2015, 29(6):721-731. DOI:10.1038/eye.2015.48.
13. Otsuji T, Nagai Y, Sho K, et al. Initial non-responders to ranibizumab in the treatment of age-related macular degeneration(AMD)[J]. Clin Ophthalmol, 2013, 7:1487-1490.DOI:10.2147/OPTH.S46317.
14. Finger RP, Wickremasinghe SS, Baird PN, et al. Predictors of anti-VEGF treatment response in neovascular age-related macular degeneration[J]. Surv Ophthalmol, 2014, 59(1):1-18. DOI:10.1016/j.survophthal.2013.03.009.
15. 戚沆, 陈长征.影响渗出型老年性黄斑变性患者玻璃体腔注射雷珠单抗治疗反应的临床特征与基因因素[J]. 中华眼底病杂志, 2015, 31(1):95-97.DOI:10.3760/cma.j.issn.1005-1015.2015.01.027. Qi H,Chen CZ.Clinical features and genetic factors influencing the effect of intravitreal ranibizumab for exudative age-related macular degeneration[J].Chin J Ocul Fundus Dis,2015,31(1):95-97. DOI:10.3760/ema.j.issn.1005-1015.2015.01.027.
16. Dedania VS, Grob S, Zhang K, et al. Pharmacogenomics of response to anti-VEGF therapy in exudative age-related macular degeneration[J]. Retina, 2015,35(3):381-391.DOI:10.1097/IAE.0000000000000466.
17. Nischler C, Oberkofler H, Ortner C, et al. Complement factor H Y402H gene polymorphism and response to intravitreal bevacizumab in exudative age-related macular degeneration[J]. Acta Ophthalmol,2011,89(4):344-349. DOI:10.1111/j.1755-3768.2010.02080.x.
18. Smailhodzic D, Muether PS, Chen J, et al. Cumulative effect of risk alleles in CFH, ARMS2, and VEGF-A on the response to ranibizumab treatment in age-related macular degeneration[J]. Ophthalmology, 2012,119(11):2304-2311. DOI:10.1016/j.ophtha.2012.05.040.
19. Brantley MA, Fang AMM, King JM, et al. Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to intravitreal bevacizumab[J]. Ophthalmology,2007,114(12):2168-2173.
20. Skeie JM, Mahajan VB. Proteomic landscape of the human choroidretinal pigment epithelial complex[J]. JAMA Ophthalmol,2014,132(11):1271-1281.DOI:10.1001/jamaophthalmol.2014.2065.
21. Kang HM, Koh HJ. Long-term visual outcome and prognostic factors after intravitreal ranibizumab injections for polypoidal choroidal vasculopathy[J]. Am J Ophthalmol, 2013, 156(4):652-660.DOI:10.1016/j.ajo.2013.05.038.
22. Kuroda Y, Yamashiro K, Miyake M,et al.Factors associated with recurrence of age-related macular degeneration after anti-vascular endothelial growth factor treatment:a retrospective cohort study[J].Ophthalmology, 2015,122(11):2303-2310. DOI:10.1016/j.ophtha.2015.06.053.
23. Krishnan R,Arora R, De Salvo G, et al. Vitreomacular traction affects anti-vascular endothelial growth factor treatment outcomes for exudative age-related macular degeneration[J]. Retina,2015,35(9):1750-1756. DOI:10.1097/IAE.0000000000000714.
24. Karaca EE, Kepez Yldz B, Çubuk MÖ, et al. Epiretinal membranes in neovascular age-related macular degeneration:effect on outcomes of anti-vascular endothelial growth factor therapy[J]. Retina,2015,35(8):1540-1546. DOI:10.1097/IAE.0000000000000531.
25. Abdullah SE, Perez-Soler R. Mechanisms of resistance to vascular endothelial growth factor blockade[J]. Cancer,2012,118(14):3455-3467. DOI:10.1002/cncr.26540.
26. Forooghian F, Cukras C, Meyerle CB, et al. Tachyphylaxis after intravitreal bevacizumab for exudative age-related macular degeneration[J].Retina,2009,29(6):723-731.DOI:10.1097/IAE.0b013e3181a2c1c3.
27. Stangos AN, Gandhi JS, Nair-Sahni J, et al. Polypoidal choroidal vasculopathy masquerading as neovascular age-related macular degeneration refractory to ranibizumab[J]. Am J Ophthalmol, 2010, 150(5):666-673. DOI:10.1016/j.ajo.2010.05.035.
28. Tomita K, Tsujikawa A, Yamashiro K, et al. Treatment of polypoidal choroidal vasculopathy with photodynamic therapy combined with intravitreal injections of ranibizumab[J]. Am J Ophthalmol, 2012,153(1):68-80.DOI:10.1016/j.ajo.2011.07.001.
29. Xian X, Hakansson J, Stahlberg A, et al. Pericytes limit tumor cell metastasis[J]. J Clin Invest, 2006, 116(3):642-651.
30. Mancuso MR, Davis R, Norberg SM, et al. Rapid vascular regrowth in tumors after reversal of VEGF inhibition[J].J Clin Invest, 2006,116(10):2610-2621. DOI:10.1172/JCI24612.
31. Grgic I, Duffield JS, Humphreys BD.The origin of interstitial myofibroblasts in chronic kidney disease[J]. Pediatr Nephrol,2012,27(2):183-193. DOI:10.1007/s00467-011-1772-6.
32. Waisbourd M, Levinger E, Varssano D, et al. High-dose topical bevacizumab for corneal neovascularization[J]. Pharmacology, 2013, 92(5-6):310-314.DOI:10.1159/000356407.
33. Wykoff CC, Brown DM, Croft DE, et al. Two year SAVE Outcomes:2.0 mg ranibizumab for recalcitrant neovascular AMD[J]. Ophthalmology, 2013, 120(9):1945-1946.DOI:10.1016/j.ophtha.2013.06.030.
34. Dhoot DS, Pieramici DJ, Nasir M, et al. Residual edema evaluation with ranibizumab 0.5 mg and 2.0 mg formulations for diabetic macular edema (REEF study)[J]. Eye (Lond),2015,29(4):534-541.DOI:10.1038/eye.2014.338.
35. Stewart MW, Rosenfeld PJ, Penha FM, et al. Pharmacokinetic rationale for dosing every 2 weeks versus 4 weeks with intravitreal ranibizumab, bevacizumab, and aflibercept (vascular endothelial growth factor Trap-eye)[J]. Retina, 2012, 32(3):434-457.DOI:10.1097/IAE.0B013E31822C290F.
36. 白玉婧, 黎晓新.新生血管性老年性黄斑变性药物治疗面临的挑战与未来的发展趋势[J].中华眼底病杂志,2016,32(1):3-7. DOI:10.3760/cma.j.issn.1005-1015.2016.01.002. Bai YJ,Li XX.Progression and challenge of therapeutic strategies in neovascular age-related macular degeneration[J].Chin J Ocul Fundus Dis,2016,31(1):3-7. DOI:10.3760/cma.j.issn.1005-1015.2016.01.002.
37. Gasperini JL,Fawzi AA, Khondkaryan A, et al. Bevacizumab and ranibizumab tachyphylaxis in the treatment of choroidal neovascularisation[J]. Br J Ophthalmol,2012,96(1):14-20. DOI:10.1136/bjo.2011.204685.
38. Eadie JA, Ip MS, Kulkarni AD. Response to aflibercept as secondary therapy in patients with persistent retinal edema due to central retinal vein occlusion initially treated with bevacizumab or ranibizumab[J]. Retina, 2014, 34(12):2439-2443. DOI:10.1097/IAE.0000000000000238.
39. Kuhnert F,Tam BY,Sennino B,et al.Soluble receptor-mediated selective inhibition of VEGFR and PDGFR-signaling during physiologic and tumor angiogenesis[J]. Proc Natl Acad Sci USA, 2008, 22, 105(29):10185-10190. DOI:10.1073/pnas.0803194105.
40. Chaoran Z, Zhirong L, Gezhi X. Combination of vascular endothelial growth factor receptor/platelet-derived growth factor receptor inhibition markedly improves the antiangiogenic efficacy for advanced stage mouse corneal neovascularization[J]. Graefe's Arch Clin Exp Ophthalmol, 2011,249(10):1493-1501.DOI:10.1007/s00417-011-1709-6.
41. Jo N, Mailhos C, Ju M, et al. Inhibition of platelet-derived growth factor B signaling enhances the efficacy of anti-vascular endothelial growth factor therapy in multiple models of ocular neovascularization[J]. Am J Pathol,2006,168(6):2036-2053.
42. Jaffe GJ, Eliott D, Wells JA, et al. A Phase 1 study of intravitreous E10030 in combination with ranibizumab in neovascular age-related macular degeneration[J]. Ophthalmology,2016,123(1):78-85.DOI:10.1016/j.ophtha.2015.09.004.
43. Mojana F, Cheng L, Bartsch D-UG, et al. The role of abnormal vitreomacular adhesion in age-related macular degeneration:spectral optical coherence tomography and surgical results[J]. Am J Ophthalmol, 2008, 146(2):218-227.DOI:10.1016/j.Ajo.2008.04.027.
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