Analysis of Ocular and Neurodevelopmental Function in Patients With History of Retinopathy of Prematurity and Prior Treatments: 3 to 12 Years Outcome

Retinopathy of Prematurity and Vascular Endothelial Growth Factor (VEGF) Retinopathy of prematurity (ROP) is a retinal disease in preterm infants due to retinal vessels immaturity, characterized by retinal hypoxia in early stage and neovascularization in late stage leading to retinal traction and retinal detachment.3, 4 Being one of the primary causes of childhood blindness,5 prompt diagnosis and treatment of ROP are of paramount importance. The treatment of ROP aims halting the neovascularization process driven by elevated intraocular vascular endothelial growth factor (VEGF).6 Laser photocoagulation of peripheral avascular retina remains the standard treatment of ROP. Though effective, laser photocoagulation destroys a sizable portion of retina, and is associated with the narrower anterior chamber angle,7 development of myopia,8 and reduction in visual field. A new treatment modality using intravitreal injection (IVI) of anti-vascular endothelial growth factor (anti-VEGF) to treat ROP patients has been increasingly used after the Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP)study showed a significant benefit of intravitreal injections of bevacizumab (IVB) for zone I stage 3+ (i.e., stage 3 with plus disease) ROP compared with conventional laser treatment.9 The advantages of IVI of anti-VEGF include a less time-consuming procedure, fewer risks from general anesthesia in a physically compromised preterm newborn,10-16 and a potentially lower chance of unfavorable outcomes in zone 1 ROP.9, 17-19 For these reasons, the use of IVI of anti-VEGF for treatment of ROP has gained in popularity.

Intravitreal Injection of Anti-VEGFs for ROP Anti-VEGF agents for ROP include bevacizumab (Avastin; Genentech Inc., South San Francisco, CA, USA), ranibizumab (Lucentis; Genentech Inc., South San Francisco, CA, USA), pegaptanib (Macugen; Eyetech Inc., Cedar Knolls, NJ, USA), and aflibercept (Eylea; Regeneron Pharmaceuticals, Tarrytown, NY, USA). Each of them has different pharmacokinetic effects, molecular sizes, structures, and half-lives.8, 9, 20-23 Pegaptanib is a single strand nucleotide that binds specifically VEGF165and it was the first VEGF inhibitor approved by the United States Food and Drug Administration (FDA) for the treatment of neovascular age-related macular degeneration (AMD) in December 2004.24, 25 However, it is rarely used in most countries now because this drug was proven to be less effective than the other anti-pan-VEGF compounds.

Bevacizumab is a humanized murine antiangiogenic monoclonal antibody, originally developed for the treatment of metastatic colorectal cancer, and used with good results in treating many retinopathies. Currently, bevacizumab is the most commonly studied intravitreal anti-VEGF therapy for the treatment of severe ROP and has demonstrated promising results, particularly in severe cases of posterior disease.9, 19, 26-28 A much smaller humanized monoclonal antibody Fab fragment, ranibizumab was later used with the aim of being a safer treatment option. Ranibizumab bind to all VEGF-A isoforms and have demonstrated its efficacy in the treatment of Type 1 ROP.21 It is rapidly eliminated from the blood stream because of its shorter half-life and thus has the potential of decreased systemic toxicity.29Although ranibizumab has been included in an increasing number of studies in recent year, the rate of ROP recurrence following its use has varied somewhat between different studies.21, 30 Aflibercept is a "VEGF trap"-a fusion protein that binds VEGF-A with high affinity. It is approved by FDA for the treatment of neovascular AMD in 2011 and it is the only anti-angiogenic therapy that inhibits VEGF-A and placental growth factor.31Intravitreal administration of aflibercept should have a more potent and prolonged clinical action because of its high binding affinity and estimated intraocular half-life.32, 33 Although none of these drugs have been approved for intraocular use in children to date, many investigators have evaluated the off-label use of these agents in infants with ROP. Bevacizumab and ranibizumab are the more commonly used agents and the other two are less frequent used for treating ROP.

Systemic VEGF Suppression after Intravitreal Injection of Anti-VEGFs in Adults Because of structural differences, a much longer systemic half-life has been noted with bevacizumab than that with ranibizumab in adult patients (20 days vs. 2 hours for bevacizumab and ranibizumab, respectively).29, 34 In addition, the median plasma level of VEGF has been noted to be reduced by 42% in patients with age-related macular degeneration 28 days after receiving the third monthly IVI of bevacizumab, in contrast to no changes in patients treated with ranibizumab.35 In the "alternative treatments to inhibit VEGF in age-related choroidal neovascularization" (IVAN) study,36 the serum level of VEGF in patients receiving bevacizumab was suppressed to about one half of that in patients receiving ranibizumab.

Systemic VEGF Suppression after Intravitreal Injection of Anti- VEGF s in Newborns The pharmacokinetics of IVB may be different between newborns and adults.37, 38In an animal study, IVB at an early age could result in more systemic bevacizumab exposure.39Sato et al.37 found that systemic VEGF levels were depressed for at least 2 weeks after the administration of either 0.25 mg or 0.5 mg IVB in patients with stages 3, 4, and 5 ROP. Kong et al.40 demonstrated that Serum free VEGF levels decreased 2 days following treatment of either 0.25 mg or 0.625 mg IVB or laser photocoagulation, and the reductions were more significant in both IVB-treated groups. They also found that clearance of bevacizumab from the bloodstream in premature infants takes at least 2 months after IVB.40 Our previous studies had further shown that VEGF levels in type 1 ROP infants were significantly decreased up to 12 weeks after administration of 0.625 mg IVB.41-43 As for the effect of systemic VEGF suppressioninnewborns receiving intravitreal injection of ranibizumab (IVR), Zhou et al.44 found that IVR reduced plasma VEGF levels 1 day after injection in infants with ROP. This phenomenon disappeared 1 week after the injection. They concluded that IVR did not induce prolonged systemic VEGF suppression. Recently, Wu et al.42 also reported that IVR for ROP resulted in no or barely detected suppression of systemic VEGF, compared with IVB.