Current status and progress of recurrence of retinopathy in prematurity after intravitreal injection with anti-vascular endothelial growth factor drugs_Chinese Journal of Ocular Fundus Diseases

Authors：

Yang Qian ,  Huang Xin

Department of Ophthalmology, EYE & ENT Hospital, Fudan University, Shanghai 200031, China;

Corresponding author：

Huang Xin, Email: huangxin2007@aliyun.com

Keywords：

Retinopathy of prematurity/drug therapy; Angiogenesis inhibitors/therapeutic use; Recurrence; Review

DOI：

10.3760/cma.j.issn.1005-1015.2019.06.024

Video：

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Intravitreal injection of anti-VEGF drugs for the treatment of retinopathy of prematurity (ROP) is a hot topic of research, and it can be used to treat the ROP (Ⅰzone). The current anti-VEGF drugs include bevacizumab, ranibizumab, aflibercept and conbercept, etc. However, in recent years, several studies have confirmed that anti-VEGF drugs have an increased recurrence rate and a longer recurrence time than conventional laser photocoagulation therapy. The follow-up period should be extended and repeated injections may be required. Due to the lack of large-scale prospective clinical studies, the recurrence rate, time window of recurrence, risk factors and treatment methods of various anti-VEGF drugs for ROP are still unclear. Anti-VEGF drugs in the treatment of ROP needs to accumulate more evidence-based medical evidence.

Citation： Yang Qian, Huang Xin. Current status and progress of recurrence of retinopathy in prematurity after intravitreal injection with anti-vascular endothelial growth factor drugs. Chinese Journal of Ocular Fundus Diseases, 2019, 35(6): 621-624. doi: 10.3760/cma.j.issn.1005-1015.2019.06.024 Copy

1.	Hellstrom A, Smith LE, Dammann O. Retinopathy of prematurity[J]. Lancet, 2013, 382(9902): 1445-1457. DOI: 10.1016/S0140-6736(13)60178-6.
2.	Ittiara S, Blair MP, Shapiro MJ, et al. Exudative retinopathy and detachment: a late reactivation of retinopathy of prematurity after intravitreal bevacizumab[J]. J AAPOS, 2013, 17(3): 323-325. DOI: 10.1016/j.jaapos.2013.01.004.
3.	Karkhaneh R, Khodabande A, Riazi-Eafahani M, et al. Efficacy of intravitreal bevacizumab for zone-Ⅱ retinopathy of prematurity[J]. Acta Ophthalmol, 2016, 94(6): 417-420. DOI: 10.1111/aos.13008.
4.	Hartnett ME, Penn JS. Mechanisms and management of retinopathy of prematurity[J]. N Engl J Med, 2012, 367(26): 2515-2526. DOI: 10.1056/NEJMra1208129.
5.	Stahl A, Hellstrom A, Smith LE. Insulin-like growth factor-1 and anti-vascular endothelial growth factor in retinopathy of prematurity: has the time come?[J]. Neonatology, 2014, 106(3): 254-260. DOI: 10.1159/000365132.
6.	Sato T, Shima C, Kusaka S. Vitreous levels of angiopoietin-1 and angiopoietin-2 in eyes with retinopathy of prematurity[J]. Am J Ophthalmol, 2011, 151(2): 353-357. DOI: 10.1016/j.ajo.2010.08.037.
7.	Xiang N, Zhao MJ, Li XY, et al. Redundant mechanisms for vascular growth factors in retinopathy of prematurity in vitro[J]. Ophthalmic Res, 2011, 45(2): 92-101. DOI: 10.1159/000316134.
8.	Hu J, Blair MP, Shapiro MJ, et al. Reactivation of retinopathy of prematurity after bevacizumab injection[J]. Arch Ophthalmol, 2012, 130(8): 1000-1006. DOI: 10.1001/archophthalmol.2012.592.
9.	Mueller B, Salchow DJ, Waffenschmidt E, et al. Treatment of type I ROP with intravitreal bevacizumab or laser photocoagulation according to retinal zone[J]. Br J Ophthalmol, 2017, 101(3): 365-370. DOI: 10.1136/bjophthalmol-2016-308375.
10.	Hwang CK, Hubbard GB, Hutchinson AK, et al. Outcomes after intravitreal bevacizumab versus laser photocoagulation for retinopathy of prematurity: a 5-year retrospective analysis[J]. Ophthalmology, 2015, 122(5): 1008-1015. DOI: 10.1016/j.ophtha.2014.12.017.
11.	Yi Z, Su Y, Zhou Y, et al. Effects of intravitreal ranibizumab in the treatment of retinopathy of prematurity in Chinese infants[J]. Curr Eye Res, 2016, 41(8): 1092-1097. DOI: 10.3109/02713683.2015.1084643.
12.	Chen SN, Lian I, Hwang YC, et al. Intravitreal anti-vascular endothelial growth factor treatment for retinopathy of prematurity: comparison between ranibizumab and bevacizumab[J]. Retina, 2015, 35(4): 667-674. DOI: 10.1097/IAE.0000000000000380.
13.	Moran S, O'Keefe M, Hartnett C, et al. Bevacizumab versus diode laser in stage 3 posterior retinopathy of prematurity[J]. Acta Ophthalmol, 2014, 92(6): 496-497. DOI: 10.1111/aos.12339.
14.	Kuniyoshi K, Sugioka K, Sakuramoto H, et al. Intravitreal injection of bevacizumab for retinopathy of prematurity[J]. Jpn J Ophthalmol, 2014, 58(3): 237-243. DOI: 10.1007/s10384-014-0310-z.
15.	Mintz-Hittner HA, Kennedy KA, Chuang AZ. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity[J]. N Engl J Med, 2011, 364(7): 603-615. DOI: 10.1056/NEJMoa1007374.
16.	Mintz-Hittner HA, Geloneck MM, Chuang AZ. Clinical management of recurrent retinopathy of prematurity after intravitreal bevacizumab monotherapy[J]. Ophthalmology, 2016, 123(9): 1845-1855. DOI: 10.1016/j.ophtha.2016.04.028.
17.	Pertl L, Steinwender G, Mayer C, et al. A systematic review and meta-analysis on the safety of vascular endothelial growth factor (VEGF) inhibitors for the treatment of retinopathy of prematurity[J/OL]. PLoS One, 2015, 10(6): 129383[2015-06-17]. https://doi.org/10.1371/journal.pone.0129383.DOI: 10.1371/journal.pone.0129383.
18.	Gunay M, Sukgen EA, Celik G, et al. Comparison of bevacizumab, ranibizumab, and laser photocoagulation in the treatment of retinopathy of prematurity in Turkey[J]. Curr Eye Res, 2017, 42(3): 462-469. DOI: 10.1080/02713683.2016.1196709.
19.	Walz JM, Bemme S, Pielen A, et al. The German ROP Registry: data from 90 infants treated for retinopathy of prematurity[J]. Acta Ophthalmol, 2016, 94(8): 744-752. DOI: 10.1111/aos.13069.
20.	Erol MK, Coban DT, Sari ES, et al. Comparison of intravitreal ranibizumab and bevacizumab treatment for retinopathy of prematurity[J]. Arq Bras Oftalmol, 2015, 78(6): 340-343. DOI: 10.5935/0004-2749.20150090.
21.	Patel RD, Blair MP, Shapiro MJ, et al. Significant treatment failure with intravitreous bevacizumab for retinopathy of prematurity[J]. Arch Ophthalmol, 2012, 130(6): 801-802. DOI: 10.1001/archophthalmol.2011.1802.
22.	Hoerster R, Muether P, Dahlke C, et al. Serum concentrations of vascular endothelial growth factor in an infant treated with ranibizumab for retinopathy of prematurity[J]. Acta Ophthalmol, 2013, 91(1): 74-75. DOI: 10.1111/j.1755-3768.2012.02469.x.
23.	Castellanos MA, Schwartz S, Garcia-Aguirre G, et al. Short-term outcome after intravitreal ranibizumab injections for the treatment of retinopathy of prematurity[J]. Br J Ophthalmol, 2013, 97(7): 816-819. DOI: 10.1136/bjophthalmol-2012-302276.
24.	Chan JJT, Lam CPS, Kwok MKM, et al. Risk of recurrence of retinopathy of prematurity after initial intravitreal ranibizumab therapy[J/OL]. Sci Rep, 2016, 6: 27082[2016-06-01]. https://www.nature.com/articles/srep27082. DOI: 10.1038/srep27082.
25.	Wong RK, Hubschman S, Tsui I. Reactivation of retinopathy of prematurity after ranibizumab treatment[J]. Retina, 2015, 35(4): 675-680. DOI: 10.1097/IAE.0000000000000578.
26.	Zhang G, Yang M, Zeng J, et al. Comparison of intravitreal injection of ranibizumab versus laser therapy for zone Ⅱ treatment-requiring retinopathy of prematurity[J]. Retina, 2017, 37(4): 710-717. DOI: 10.1097/IAE.0000000000001241.
27.	Hong YR, Kim YH, Kim SY, et al. Plasma concentrations of vascular endothelial growth factor in retinopathy of prematurity after intravitreal bevacizumab injection[J]. Retina, 2015, 35(9): 1772-1777. DOI: 10.1097/IAE.0000000000000535.
28.	Wu WC, Lien R, Liao PJ, et al. Serum levels of vascular endothelial growth factor and related factors after intravitreous bevacizumab injection for retinopathy of prematurity[J]. JAMA Ophthalmol, 2015, 133(4): 391-397. DOI: 10.1001/jamaophthalmol.2014.5373.
29.	Avery RL, Castellarin AA, Steinle NC, et al. Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD[J]. Br J Ophthalmol, 2014, 98(12): 1636-1641. DOI: 10.1136/bjophthalmol-2014-305252.
30.	Carneiro AM, Costa R, Falcao MS, et al. Vascular endothelial growth factor plasma levels before and after treatment of neovascular age-related macular degeneration with bevacizumab or ranibizumab[J]. Acta Ophthalmol, 2012, 90(1): 25-30. DOI: 10.1111/j.1755-3768.2011.02240.x.
31.	Zehetner C, Kirchmair R, Huber S, et al. Plasma levels of vascular endothelial growth factor before and after intravitreal injection of bevacizumab, ranibizumab and pegaptanib in patients with age-related macular degeneration, and in patients with diabetic macular oedema[J]. Br J Ophthalmol, 2013, 97(4): 454-459. DOI: 10.1136/bjophthalmol-2012-302451.
32.	Salman AG, Said AM. Structural, visual and refractive outcomes of intravitreal aflibercept injection in high-risk prethreshold type 1 retinopathy of prematurity[J]. Ophthalmic Res, 2015, 53(1): 15-20. DOI: 10.1159/000364809.
33.	Sukgen EA, Söker G, Koçluk Y, et al. Effect of intravitreal aflibercept on central retinal arterial blood flow in type 1 retinopathy of prematurity[J]. Eur J Ophthalmol, 2017, 27(6): 751-755. DOI: 10.5301/ejo.5000938.
34.	Jin E, Yin H, Li X, et al. Short-term outcomes after intravitreal injections of conbercept versus ranibizumab for the treatment of retinopathy of prematurity[J]. Retina, 2018, 38(8): 1595-1604. DOI: 10.1097/IAE.0000000000001763.
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.	Huang Q, Zhang Q, Fei P, et al. Ranibizumab injection as primary treatment in patients with retinopathy of prematurity: anatomic outcomes and influencing factors[J]. Ophthalmology, 2017, 124(8): 1156-1164. DOI: 10.1016/j.ophtha.2017.03.018.
37.	Hu Q, Bai Y, Chen X, et al. Recurrence of retinopathy of prematurity in zone Ⅱ stage 3+ after ranibizumab treatment: a retrospective study[J/OL]. J Ophthalmol, 2017, 2017: 5078565[2017- 04-09]. https://doi.org/10.1155/2017/5078565.DOI: 10.1155/2017/5078565.
38.	Lyu J, Zhang Q, Chen CL, et al. Recurrence of retinopathy of prematurity after intravitreal ranibizumab monotherapy: timing and risk factors[J]. Invest Ophthalmol Vis Sci, 2017, 58(3): 1719-1725. DOI: 10.1167/iovs.16-20680.
39.	Harder BC, von Baltz S, Jonas JB, et al. Intravitreal low-dosage bevacizumab for retinopathy of prematurity[J]. Acta Ophthalmol, 2014, 92(6): 577-581. DOI: 10.1111/aos.12266.

1. Hellstrom A, Smith LE, Dammann O. Retinopathy of prematurity[J]. Lancet, 2013, 382(9902): 1445-1457. DOI: 10.1016/S0140-6736(13)60178-6.
2. Ittiara S, Blair MP, Shapiro MJ, et al. Exudative retinopathy and detachment: a late reactivation of retinopathy of prematurity after intravitreal bevacizumab[J]. J AAPOS, 2013, 17(3): 323-325. DOI: 10.1016/j.jaapos.2013.01.004.
3. Karkhaneh R, Khodabande A, Riazi-Eafahani M, et al. Efficacy of intravitreal bevacizumab for zone-Ⅱ retinopathy of prematurity[J]. Acta Ophthalmol, 2016, 94(6): 417-420. DOI: 10.1111/aos.13008.
4. Hartnett ME, Penn JS. Mechanisms and management of retinopathy of prematurity[J]. N Engl J Med, 2012, 367(26): 2515-2526. DOI: 10.1056/NEJMra1208129.
5. Stahl A, Hellstrom A, Smith LE. Insulin-like growth factor-1 and anti-vascular endothelial growth factor in retinopathy of prematurity: has the time come?[J]. Neonatology, 2014, 106(3): 254-260. DOI: 10.1159/000365132.
6. Sato T, Shima C, Kusaka S. Vitreous levels of angiopoietin-1 and angiopoietin-2 in eyes with retinopathy of prematurity[J]. Am J Ophthalmol, 2011, 151(2): 353-357. DOI: 10.1016/j.ajo.2010.08.037.
7. Xiang N, Zhao MJ, Li XY, et al. Redundant mechanisms for vascular growth factors in retinopathy of prematurity in vitro[J]. Ophthalmic Res, 2011, 45(2): 92-101. DOI: 10.1159/000316134.
8. Hu J, Blair MP, Shapiro MJ, et al. Reactivation of retinopathy of prematurity after bevacizumab injection[J]. Arch Ophthalmol, 2012, 130(8): 1000-1006. DOI: 10.1001/archophthalmol.2012.592.
9. Mueller B, Salchow DJ, Waffenschmidt E, et al. Treatment of type I ROP with intravitreal bevacizumab or laser photocoagulation according to retinal zone[J]. Br J Ophthalmol, 2017, 101(3): 365-370. DOI: 10.1136/bjophthalmol-2016-308375.
10. Hwang CK, Hubbard GB, Hutchinson AK, et al. Outcomes after intravitreal bevacizumab versus laser photocoagulation for retinopathy of prematurity: a 5-year retrospective analysis[J]. Ophthalmology, 2015, 122(5): 1008-1015. DOI: 10.1016/j.ophtha.2014.12.017.
11. Yi Z, Su Y, Zhou Y, et al. Effects of intravitreal ranibizumab in the treatment of retinopathy of prematurity in Chinese infants[J]. Curr Eye Res, 2016, 41(8): 1092-1097. DOI: 10.3109/02713683.2015.1084643.
12. Chen SN, Lian I, Hwang YC, et al. Intravitreal anti-vascular endothelial growth factor treatment for retinopathy of prematurity: comparison between ranibizumab and bevacizumab[J]. Retina, 2015, 35(4): 667-674. DOI: 10.1097/IAE.0000000000000380.
13. Moran S, O'Keefe M, Hartnett C, et al. Bevacizumab versus diode laser in stage 3 posterior retinopathy of prematurity[J]. Acta Ophthalmol, 2014, 92(6): 496-497. DOI: 10.1111/aos.12339.
14. Kuniyoshi K, Sugioka K, Sakuramoto H, et al. Intravitreal injection of bevacizumab for retinopathy of prematurity[J]. Jpn J Ophthalmol, 2014, 58(3): 237-243. DOI: 10.1007/s10384-014-0310-z.
15. Mintz-Hittner HA, Kennedy KA, Chuang AZ. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity[J]. N Engl J Med, 2011, 364(7): 603-615. DOI: 10.1056/NEJMoa1007374.
16. Mintz-Hittner HA, Geloneck MM, Chuang AZ. Clinical management of recurrent retinopathy of prematurity after intravitreal bevacizumab monotherapy[J]. Ophthalmology, 2016, 123(9): 1845-1855. DOI: 10.1016/j.ophtha.2016.04.028.
17. Pertl L, Steinwender G, Mayer C, et al. A systematic review and meta-analysis on the safety of vascular endothelial growth factor (VEGF) inhibitors for the treatment of retinopathy of prematurity[J/OL]. PLoS One, 2015, 10(6): 129383[2015-06-17]. https://doi.org/10.1371/journal.pone.0129383.DOI: 10.1371/journal.pone.0129383.
18. Gunay M, Sukgen EA, Celik G, et al. Comparison of bevacizumab, ranibizumab, and laser photocoagulation in the treatment of retinopathy of prematurity in Turkey[J]. Curr Eye Res, 2017, 42(3): 462-469. DOI: 10.1080/02713683.2016.1196709.
19. Walz JM, Bemme S, Pielen A, et al. The German ROP Registry: data from 90 infants treated for retinopathy of prematurity[J]. Acta Ophthalmol, 2016, 94(8): 744-752. DOI: 10.1111/aos.13069.
20. Erol MK, Coban DT, Sari ES, et al. Comparison of intravitreal ranibizumab and bevacizumab treatment for retinopathy of prematurity[J]. Arq Bras Oftalmol, 2015, 78(6): 340-343. DOI: 10.5935/0004-2749.20150090.
21. Patel RD, Blair MP, Shapiro MJ, et al. Significant treatment failure with intravitreous bevacizumab for retinopathy of prematurity[J]. Arch Ophthalmol, 2012, 130(6): 801-802. DOI: 10.1001/archophthalmol.2011.1802.
22. Hoerster R, Muether P, Dahlke C, et al. Serum concentrations of vascular endothelial growth factor in an infant treated with ranibizumab for retinopathy of prematurity[J]. Acta Ophthalmol, 2013, 91(1): 74-75. DOI: 10.1111/j.1755-3768.2012.02469.x.
23. Castellanos MA, Schwartz S, Garcia-Aguirre G, et al. Short-term outcome after intravitreal ranibizumab injections for the treatment of retinopathy of prematurity[J]. Br J Ophthalmol, 2013, 97(7): 816-819. DOI: 10.1136/bjophthalmol-2012-302276.
24. Chan JJT, Lam CPS, Kwok MKM, et al. Risk of recurrence of retinopathy of prematurity after initial intravitreal ranibizumab therapy[J/OL]. Sci Rep, 2016, 6: 27082[2016-06-01]. https://www.nature.com/articles/srep27082. DOI: 10.1038/srep27082.
25. Wong RK, Hubschman S, Tsui I. Reactivation of retinopathy of prematurity after ranibizumab treatment[J]. Retina, 2015, 35(4): 675-680. DOI: 10.1097/IAE.0000000000000578.
26. Zhang G, Yang M, Zeng J, et al. Comparison of intravitreal injection of ranibizumab versus laser therapy for zone Ⅱ treatment-requiring retinopathy of prematurity[J]. Retina, 2017, 37(4): 710-717. DOI: 10.1097/IAE.0000000000001241.
27. Hong YR, Kim YH, Kim SY, et al. Plasma concentrations of vascular endothelial growth factor in retinopathy of prematurity after intravitreal bevacizumab injection[J]. Retina, 2015, 35(9): 1772-1777. DOI: 10.1097/IAE.0000000000000535.
28. Wu WC, Lien R, Liao PJ, et al. Serum levels of vascular endothelial growth factor and related factors after intravitreous bevacizumab injection for retinopathy of prematurity[J]. JAMA Ophthalmol, 2015, 133(4): 391-397. DOI: 10.1001/jamaophthalmol.2014.5373.
29. Avery RL, Castellarin AA, Steinle NC, et al. Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD[J]. Br J Ophthalmol, 2014, 98(12): 1636-1641. DOI: 10.1136/bjophthalmol-2014-305252.
30. Carneiro AM, Costa R, Falcao MS, et al. Vascular endothelial growth factor plasma levels before and after treatment of neovascular age-related macular degeneration with bevacizumab or ranibizumab[J]. Acta Ophthalmol, 2012, 90(1): 25-30. DOI: 10.1111/j.1755-3768.2011.02240.x.
31. Zehetner C, Kirchmair R, Huber S, et al. Plasma levels of vascular endothelial growth factor before and after intravitreal injection of bevacizumab, ranibizumab and pegaptanib in patients with age-related macular degeneration, and in patients with diabetic macular oedema[J]. Br J Ophthalmol, 2013, 97(4): 454-459. DOI: 10.1136/bjophthalmol-2012-302451.
32. Salman AG, Said AM. Structural, visual and refractive outcomes of intravitreal aflibercept injection in high-risk prethreshold type 1 retinopathy of prematurity[J]. Ophthalmic Res, 2015, 53(1): 15-20. DOI: 10.1159/000364809.
33. Sukgen EA, Söker G, Koçluk Y, et al. Effect of intravitreal aflibercept on central retinal arterial blood flow in type 1 retinopathy of prematurity[J]. Eur J Ophthalmol, 2017, 27(6): 751-755. DOI: 10.5301/ejo.5000938.
34. Jin E, Yin H, Li X, et al. Short-term outcomes after intravitreal injections of conbercept versus ranibizumab for the treatment of retinopathy of prematurity[J]. Retina, 2018, 38(8): 1595-1604. DOI: 10.1097/IAE.0000000000001763.
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. Huang Q, Zhang Q, Fei P, et al. Ranibizumab injection as primary treatment in patients with retinopathy of prematurity: anatomic outcomes and influencing factors[J]. Ophthalmology, 2017, 124(8): 1156-1164. DOI: 10.1016/j.ophtha.2017.03.018.
37. Hu Q, Bai Y, Chen X, et al. Recurrence of retinopathy of prematurity in zone Ⅱ stage 3+ after ranibizumab treatment: a retrospective study[J/OL]. J Ophthalmol, 2017, 2017: 5078565[2017- 04-09]. https://doi.org/10.1155/2017/5078565.DOI: 10.1155/2017/5078565.
38. Lyu J, Zhang Q, Chen CL, et al. Recurrence of retinopathy of prematurity after intravitreal ranibizumab monotherapy: timing and risk factors[J]. Invest Ophthalmol Vis Sci, 2017, 58(3): 1719-1725. DOI: 10.1167/iovs.16-20680.
39. Harder BC, von Baltz S, Jonas JB, et al. Intravitreal low-dosage bevacizumab for retinopathy of prematurity[J]. Acta Ophthalmol, 2014, 92(6): 577-581. DOI: 10.1111/aos.12266.

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