Individual dose of intravitreal conbercept for efficacy in retinopathy of prematurity_Chinese Journal of Ocular Fundus Diseases

Authors：

Jiang Keke ^1,2 , Yu Penglin ² , Li Shuchan ² , Wang Wenting ² , Liu Hangyu ² , Ran Hongyun ² ,  Zhang Jie ²

1. Weifang Meidical University, Weifang 261000, China;
2. Weifang Eye Hospital, Weifang 261031, China;

Corresponding author：

Zhang Jie, Email: 15963688601@126.com

Keywords：

Retinopathy of prematurity; Angiogenesis inhibitors; Vascular endothelial growth factors

DOI：

10.3760/cma.j.cn511434-20200810-00385

Video：

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Objective To observe the efficacy and safety of individual dose of intravitreal conbercept (IVC) in the treatment of retinopathy of prematurity (ROP) before type 1 threshold.Methods A retrospective case study. From January to July, 2019, 23 cases (46 eyes) of children with type 1 pre-threshold ROP were included in the study. Among them, 14 cases (28 eyes) were male and 9 cases (18 eyes) were female. The mean gestational age at birth was 28.06±1.73 weeks. The average birth weight was 1.14±0.19 kg. The mean corrected gestational age was 34.38±1.41 weeks at the time of first intravitreal injection of IVC. The axial length (AL) of children was measured by A-mode ultrasound before IVC for the first time. According to the calculation of AL, the corresponding injection dose range was 14.23-16.19, 16.20-17.57, 17.58-18.63 mm and the injection dose of IVC was 0.015, 0.020, 0.025 ml (including IVC was 0.15, 0.20, 0.25 mg, respectively). The first IVC dose was 0.015 ml. On the first day before IVC and on the first and seventh days after IVC, 2 ml of arterial blood was taken from children, serum vascular endothelial growth factor (VEGF) concentration was detected. The follow-up time after treatment was ≥1 year. After one year of follow-up, the effective rate and recurrence rate of IVC for the first time were tested by χ² tests. The short-term changes of injection times, injection intervals, retinal vascularization time and serum VEGF concentration in children were tested by t test.Results Retinal neovascularization subsided and vascular buckling decreased in all eyes. Iris neovascularization subsided, 1-3 weeks after IVC for the first time. Within one year after the first IVC, 16 eyes underwent IVC twice with or without new blood vessels at the junction of the vascular area. The average corrected gestational age was 40.56±3.81 weeks. The injection dose of IVC was 0.015 ml and 0.020 ml for 2 eyes and 14 eyes, respectively.The mean interval from IVC for the first time was 40.89±8.99 days. Of the 16 eyes who underwent IVC twice, 8 eyes showed neovascularization again in the retinal area with or without blood vessels. The average corrected gestational age was 43.00±1.41 weeks. The injection dose of IVC was 0.020 ml and 0.025 ml for 3 eyes and 5 eyes, respectively. The mean interval of the second IVC was 28.60±6.07 days. The mean interval from the first IVC was 69.20±12.40 days. At the end of follow-up, all eyes were treated effectively (100%, 46/46). The mean time of retinal vascularization was 46.31±3.42 weeks. The average number of injections was 1.52±0.76. On the first day before IVC and on the first and seventh days after IVC, the average serum VEGF concentrations were 111.21±148.71, 25.60±27.71 and 42.99±38.01 pg/ml, respectively. Serum VEGF concentration was significantly lower than that before IVC on the 1st and 7th day after IVC (Z=−4.054, −2.779; P＜0.05). Serum VEGF concentration was higher 7 days after IVC than 1 day after IVC, and the difference was statistically significant (Z=−2.505, P＜0.05). All eyes were not treated by laser photocoagulation or vitrectomy. No eye complications such as lens opacification, endophthalmitis and retinal detachment related to drugs or treatment methods were found in all patients.Conclusion Intravitreal injection of individualized dose of IVC is effective in the treatment of type 1 pre-threshold ROP. Seven days after treatment, serum VEGF concentration of patients’serum decreases.

Citation： Jiang Keke, Yu Penglin, Li Shuchan, Wang Wenting, Liu Hangyu, Ran Hongyun, Zhang Jie. Individual dose of intravitreal conbercept for efficacy in retinopathy of prematurity. Chinese Journal of Ocular Fundus Diseases, 2021, 37(5): 338-343. doi: 10.3760/cma.j.cn511434-20200810-00385 Copy

1.	中华医学会眼科学会眼底病学组. 中国早产儿视网膜病变筛查指南(2014年)[J]. 中华眼科杂志, 2014, 50(12): 933-935. DOI: 10.3760/cma.j.issn.0412-4081.2014.12.017.Fundus Ophthalmology Group of Chinese Medical Association Ophthalmology Society. Screening guide for retinopathy of premature infants in China (2014)[J]. Chin J Ophthalmol, 2014, 50(12): 933-935. DOI: 10.3760/cma.j.issn.0412-4081.2014.12.017.
2.	Blencowe H, Lawn JE, Vazquez T, et al. Preterm-associated visual impairment and estimates of retinopathy of prematurity at regional and global levels for 2010[J]. Pediatr Res, 2013, 74(Suppl 1): S35-49. DOI: 10.1038/pr.2013.205.
3.	Goswami B, Goyal M, Beri S, et al. Role of serum levels of vascular endothelial growth factor and its receptor in retinopathy of prematurity[J/OL]. Iran J Pediatr, 2015, 25(4): e2373[2015-08-24]. https://pubmed.ncbi.nlm.nih.gov/26396701/. DOI: 10.5812/ijp.2373.
4.	Kwinta P, Bik-Multanowski M, Mitkowska Z, et al. The clinical role of vascular endothelial growth factor (VEGF) system in the pathogenesis of retinopathy of prematurity[J]. Graefe’s Arch Clin Exp Ophthalmol, 2008, 246(10): 1467-1475. DOI: 10.1007/s00417-008-0865-9.
5.	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.
6.	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.
7.	Bai Y, Nie H, Wei S, et al. Efficacy of intravitreal conbercept injection in the treatment of retinopathy of prematurity[J]. Br J Ophthalmol, 2019, 103(4): 494-498. DOI: 10.1136/bjophthalmol-2017-311662.
8.	Sukgen EA, Koçluk Y. Comparison of clinical outcomes of intravitreal ranibizumab and aflibercept treatment for retinopathy of prematurity[J]. Graefe’s Arch Clin Exp Ophthalmol, 2019, 257(1): 49-55. DOI: 10.1007/s00417-018-4168-5.
9.	Sato T, Wada K, Arahori H, et al. Serum concentrations of bevacizumab (Avastin) and vascular endothelial growth factor in infants with retinopathy of prematurity[J]. Am J Ophthalmol, 2012, 153(2): 327-333. DOI: 10.1016/j.ajo.2011.07.005.
10.	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.
11.	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.
12.	Kong L, Demny AB, Sajjad A, et al. Assessment of plasma cytokine profile changes in bevacizumab-treated retinopathy of prematurity infants[J]. Invest Ophthalmol Vis Sci, 2016, 57(4): 1649-1654. DOI: 10.1167/iovs.15-18528.
13.	Chen X, Zhou L, Zhang Q, et al. Serum vascular endothelial growth factor levels before and after intravitreous ranibizumab injection for retinopathy of prematurity[J/OL]. J Ophthalmol, 2019, 2019: 2985161[2019-05-20]. https://doi.org/10.1155/2019/2985161. DOI: 10.1155/2019/2985161.
14.	Jin E, Bai Y, Luo L, et al. Serum levels of vascular endothelial growth factor before and after intravitreal injection of ranibizumab or conbercept for neovascular age-related macular degeneration[J]. Retina, 2017, 37(5): 971-977. DOI: 10.1097/IAE.0000000000001274.
15.	Sentilhes L, Michel C, Lecourtois M, et al. Vascular endothelial growth factor and its high-affinity receptor (VEGFR-2) are highly expressed in the human forebrain and cerebellum during development[J]. J Neuropathol Exp Neurol, 2010, 69(2): 111-128. DOI: 10.1097/NEN.0b013e3181ccc9a9.
16.	Şahin A, Türkcü FM, Özkurt ZG. A lower dose of intravitreal bevacizumab effectively treats retinopathy of prematurity[J]. J AAPOS, 2018, 22(1): 83. DOI: 10.1016/j.jaapos.2017.06.001.
17.	Kong L, Bhatt AR, Demny AB, et al. Pharmacokinetics of bevacizumab and its effects on serum VEGF and IGF-1 in infants with retinopathy of prematurity[J]. Invest Ophthalmol Vis Sci, 2015, 56(2): 956-961. DOI: 10.1167/iovs.14-15842.
18.	Khodabande A, Niyousha MR, Roohipoor R. A lower dose of intravitreal bevacizumab effectively treats retinopathy of prematurity[J]. J AAPOS, 2016, 20(6): 490-492. DOI: 10.1016/j.jaapos.2016.09.012.
19.	Stahl A, Lepore D, Fielder A, et al. Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): an open-label randomised controlled trial[J]. Lancet, 2019, 394(10208): 1551-1559. DOI: 10.1016/S0140-6736(19)31344-3.
20.	Ells AL, Wesolosky JD, Ingram AD, et al. Low-dose ranibizumab as primary treatment of posterior type Ⅰ retinopathy of prematurity[J]. Can J Ophthalmol, 2017, 52(5): 468-474. DOI: 10.1016/j.jcjo.2017.02.012.
21.	孙爽, 孙先桃, 卢跃兵. 玻璃体内注射不同剂量康柏西普治疗早产儿视网膜病变效果[J]. 中华眼外伤职业眼病杂志, 2020, 42(2): 109-112. DOI: 10.3760/cma.j.issn.2095-1477.2020.02.006.Sun S, Sun XY, Lu YB. The efficacy among different dose of intravitreal conbercept injection for the treatment of retinopathy of prematurity[J]. Chin J Ocul Traum Occupat Eye Dis, 2020, 42(2): 109-112. DOI: 10.3760/cma.j.issn.2095-1477.2020.02.006.
22.	Connor AJ, Shafiq A. Globe size and bevacizumab treatment in retinopathy of prematurity: should we adjust the dose?[J]. Eye (Lond), 2016, 30(11): 1401-1403. DOI: 10.1038/eye.2016.173.
23.	International Committee for the Classification of Retinopathy of Prematurity. The international classification of retinopathy of prematurity revisited[J]. Arch Ophthalmol, 2005, 123(7): 991-999. DOI: 10.1001/archopht.123.7.991.
24.	Cheng Y, Zhu X, Linghu D, et al. Comparison of the effectiveness of conbercept and ranibizumab treatment for retinopathy of prematurity[J/OL]. Acta Ophthalmol, 2020, 98(8): e1004-e1008. https://doi.org/10.1111/aos.14460. DOI: 10.1111/aos.14460.
25.	Cheng Y, Meng Q, Linghu D, et al. A lower dose of intravitreal conbercept effectively treats retinopathy of prematurity[J/OL]. Sci Rep, 2018, 8(1): 10732[2018-07-16]. https://doi.org/10.1038/s41598-018-28987-6. DOI: 10.1038/s41598-018-28987-6.
26.	Şahin A, Gürsel-Özkurt Z, Şahin M, et, al. Ultra-low dose of intravitreal bevacizumab in retinopathy of prematurity[J]. Ir J Med Sci, 2018, 187(2): 417-421. DOI: 10.1007/s11845-017-1684-y.
27.	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.
28.	Karkhaneh R, Khodabande A, Riazi-Eafahani M, et al. Efficacy of intravitreal bevacizumab for zone-Ⅱretinopathy of prematurity[J/OL]. Acta Ophthalmol, 2016, 94(6): e417-e420. https://doi.org/10.1111/aos.13008. DOI: 10.1111/aos.13008.
29.	Stahl A, Krohne TU, Eter N, et al. Comparing alternative ranibizumab dosages for safety and efficacy in retinopathy of prematurity: a randomized clinical trial[J]. JAMA Pediatr, 2018, 172(3): 278-286. DOI: 10.1001/jamapediatrics.2017.4838.
30.	Cheng Y, Zhu X, Linghu D, et al. Serum levels of cytokines in infants treated with conbercept for retinopathy of prematurity[J/OL]. Sci Rep, 2020, 10(1): 12695[2020-07-29]. https://pubmed.ncbi.nlm.nih.gov/32728160/. DOI: 10.1038/s41598-020-69684-7.

1. 中华医学会眼科学会眼底病学组. 中国早产儿视网膜病变筛查指南(2014年)[J]. 中华眼科杂志, 2014, 50(12): 933-935. DOI: 10.3760/cma.j.issn.0412-4081.2014.12.017.Fundus Ophthalmology Group of Chinese Medical Association Ophthalmology Society. Screening guide for retinopathy of premature infants in China (2014)[J]. Chin J Ophthalmol, 2014, 50(12): 933-935. DOI: 10.3760/cma.j.issn.0412-4081.2014.12.017.
2. Blencowe H, Lawn JE, Vazquez T, et al. Preterm-associated visual impairment and estimates of retinopathy of prematurity at regional and global levels for 2010[J]. Pediatr Res, 2013, 74(Suppl 1): S35-49. DOI: 10.1038/pr.2013.205.
3. Goswami B, Goyal M, Beri S, et al. Role of serum levels of vascular endothelial growth factor and its receptor in retinopathy of prematurity[J/OL]. Iran J Pediatr, 2015, 25(4): e2373[2015-08-24]. https://pubmed.ncbi.nlm.nih.gov/26396701/. DOI: 10.5812/ijp.2373.
4. Kwinta P, Bik-Multanowski M, Mitkowska Z, et al. The clinical role of vascular endothelial growth factor (VEGF) system in the pathogenesis of retinopathy of prematurity[J]. Graefe’s Arch Clin Exp Ophthalmol, 2008, 246(10): 1467-1475. DOI: 10.1007/s00417-008-0865-9.
5. 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.
6. 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.
7. Bai Y, Nie H, Wei S, et al. Efficacy of intravitreal conbercept injection in the treatment of retinopathy of prematurity[J]. Br J Ophthalmol, 2019, 103(4): 494-498. DOI: 10.1136/bjophthalmol-2017-311662.
8. Sukgen EA, Koçluk Y. Comparison of clinical outcomes of intravitreal ranibizumab and aflibercept treatment for retinopathy of prematurity[J]. Graefe’s Arch Clin Exp Ophthalmol, 2019, 257(1): 49-55. DOI: 10.1007/s00417-018-4168-5.
9. Sato T, Wada K, Arahori H, et al. Serum concentrations of bevacizumab (Avastin) and vascular endothelial growth factor in infants with retinopathy of prematurity[J]. Am J Ophthalmol, 2012, 153(2): 327-333. DOI: 10.1016/j.ajo.2011.07.005.
10. 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.
11. 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.
12. Kong L, Demny AB, Sajjad A, et al. Assessment of plasma cytokine profile changes in bevacizumab-treated retinopathy of prematurity infants[J]. Invest Ophthalmol Vis Sci, 2016, 57(4): 1649-1654. DOI: 10.1167/iovs.15-18528.
13. Chen X, Zhou L, Zhang Q, et al. Serum vascular endothelial growth factor levels before and after intravitreous ranibizumab injection for retinopathy of prematurity[J/OL]. J Ophthalmol, 2019, 2019: 2985161[2019-05-20]. https://doi.org/10.1155/2019/2985161. DOI: 10.1155/2019/2985161.
14. Jin E, Bai Y, Luo L, et al. Serum levels of vascular endothelial growth factor before and after intravitreal injection of ranibizumab or conbercept for neovascular age-related macular degeneration[J]. Retina, 2017, 37(5): 971-977. DOI: 10.1097/IAE.0000000000001274.
15. Sentilhes L, Michel C, Lecourtois M, et al. Vascular endothelial growth factor and its high-affinity receptor (VEGFR-2) are highly expressed in the human forebrain and cerebellum during development[J]. J Neuropathol Exp Neurol, 2010, 69(2): 111-128. DOI: 10.1097/NEN.0b013e3181ccc9a9.
16. Şahin A, Türkcü FM, Özkurt ZG. A lower dose of intravitreal bevacizumab effectively treats retinopathy of prematurity[J]. J AAPOS, 2018, 22(1): 83. DOI: 10.1016/j.jaapos.2017.06.001.
17. Kong L, Bhatt AR, Demny AB, et al. Pharmacokinetics of bevacizumab and its effects on serum VEGF and IGF-1 in infants with retinopathy of prematurity[J]. Invest Ophthalmol Vis Sci, 2015, 56(2): 956-961. DOI: 10.1167/iovs.14-15842.
18. Khodabande A, Niyousha MR, Roohipoor R. A lower dose of intravitreal bevacizumab effectively treats retinopathy of prematurity[J]. J AAPOS, 2016, 20(6): 490-492. DOI: 10.1016/j.jaapos.2016.09.012.
19. Stahl A, Lepore D, Fielder A, et al. Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): an open-label randomised controlled trial[J]. Lancet, 2019, 394(10208): 1551-1559. DOI: 10.1016/S0140-6736(19)31344-3.
20. Ells AL, Wesolosky JD, Ingram AD, et al. Low-dose ranibizumab as primary treatment of posterior type Ⅰ retinopathy of prematurity[J]. Can J Ophthalmol, 2017, 52(5): 468-474. DOI: 10.1016/j.jcjo.2017.02.012.
21. 孙爽, 孙先桃, 卢跃兵. 玻璃体内注射不同剂量康柏西普治疗早产儿视网膜病变效果[J]. 中华眼外伤职业眼病杂志, 2020, 42(2): 109-112. DOI: 10.3760/cma.j.issn.2095-1477.2020.02.006.Sun S, Sun XY, Lu YB. The efficacy among different dose of intravitreal conbercept injection for the treatment of retinopathy of prematurity[J]. Chin J Ocul Traum Occupat Eye Dis, 2020, 42(2): 109-112. DOI: 10.3760/cma.j.issn.2095-1477.2020.02.006.
22. Connor AJ, Shafiq A. Globe size and bevacizumab treatment in retinopathy of prematurity: should we adjust the dose?[J]. Eye (Lond), 2016, 30(11): 1401-1403. DOI: 10.1038/eye.2016.173.
23. International Committee for the Classification of Retinopathy of Prematurity. The international classification of retinopathy of prematurity revisited[J]. Arch Ophthalmol, 2005, 123(7): 991-999. DOI: 10.1001/archopht.123.7.991.
24. Cheng Y, Zhu X, Linghu D, et al. Comparison of the effectiveness of conbercept and ranibizumab treatment for retinopathy of prematurity[J/OL]. Acta Ophthalmol, 2020, 98(8): e1004-e1008. https://doi.org/10.1111/aos.14460. DOI: 10.1111/aos.14460.
25. Cheng Y, Meng Q, Linghu D, et al. A lower dose of intravitreal conbercept effectively treats retinopathy of prematurity[J/OL]. Sci Rep, 2018, 8(1): 10732[2018-07-16]. https://doi.org/10.1038/s41598-018-28987-6. DOI: 10.1038/s41598-018-28987-6.
26. Şahin A, Gürsel-Özkurt Z, Şahin M, et, al. Ultra-low dose of intravitreal bevacizumab in retinopathy of prematurity[J]. Ir J Med Sci, 2018, 187(2): 417-421. DOI: 10.1007/s11845-017-1684-y.
27. 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.
28. Karkhaneh R, Khodabande A, Riazi-Eafahani M, et al. Efficacy of intravitreal bevacizumab for zone-Ⅱretinopathy of prematurity[J/OL]. Acta Ophthalmol, 2016, 94(6): e417-e420. https://doi.org/10.1111/aos.13008. DOI: 10.1111/aos.13008.
29. Stahl A, Krohne TU, Eter N, et al. Comparing alternative ranibizumab dosages for safety and efficacy in retinopathy of prematurity: a randomized clinical trial[J]. JAMA Pediatr, 2018, 172(3): 278-286. DOI: 10.1001/jamapediatrics.2017.4838.
30. Cheng Y, Zhu X, Linghu D, et al. Serum levels of cytokines in infants treated with conbercept for retinopathy of prematurity[J/OL]. Sci Rep, 2020, 10(1): 12695[2020-07-29]. https://pubmed.ncbi.nlm.nih.gov/32728160/. DOI: 10.1038/s41598-020-69684-7.

Chinese Journal of Ocular Fundus Diseases

Individual dose of intravitreal conbercept for efficacy in retinopathy of prematurity

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