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Retinal Physician

Article

Anti-VEGF Therapy for Management of Retinopathy of Prematurity

Weigh benefits and risks in this vulnerable population.

By: Xiao Chun Ling, MD, Wei-Chi Wu, MD, PhD
Retinal Physician March 1, 2021 Vol 18, Issue March 2021 Page(s): 22-24

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Retinopathy of prematurity (ROP) is characterized by anomalous vascular development due to prematurity and is a leading cause of blindness in prematurely born infants worldwide.1 Advancements in antenatal care, along with the increased establishment of neonatal intensive care units, have resulted in improved survival of preterm and low-birth-weight infants. In consequence, the number of infants at risk for developing ROP is increasing and thus updated management approach is needed in this debilitating disease.

ROLE OF VEGF IN ROP AND TREATMENT EVOLUTION

Vascular endothelial growth factor (VEGF) is an important angiogenic factor during embryonic vascular development. It leads to the growth of retinal blood vessels toward the avascular peripheral retina. Phase 1 ROP occurs during 22 to 30 weeks of gestation, whereby relative hyperoxia causes low VEGF levels and cessation of blood vessels growth (vasoattenuation). Subsequently, phase 2 ROP occurs during 31 to 41 weeks of gestation. The increased metabolic demand in peripheral avascular retina induces a hypoxic milieu, stimulating VEGF release and abnormal vessel proliferation (vasoproliferation).

Over the past 50 years, ROP treatment has limited treatment modalities such as cryotherapy and laser photocoagulation. More recently, there has been growing evidence to support the use of anti-VEGF agents for the treatment of ROP. Figure 1 shows both regression of retinopathy of prematurity (ROP) after treatment by laser photocoagulation or intravitreal injection of anti-VEGF. Currently, the use of anti-VEGFs is off label. However, there are increasing numbers of studies examining their efficacy and safety in treating ROP.2,3 Now at our center, we have used more anti-VEGF treatments for treatment-requiring ROP, namely type-1 ROP, due to its less destructive nature to the retina and good long-term outcome.4

Figure 1. Regressed retinopathy of prematurity (ROP) after treatment by photocoagulation or intravitreal injection (IVI) of anti-VEGF. An 8-year-old patient with posterior zone 2, type 1 ROP was treated by laser photocoagulation (A). Atrophic retinal tissue and diffuse pigmentary changes in the periphery were observed. Although some vessels continued to grow over the lasered area, most of the retinal vessels were destroyed by the laser in the ablated zones (B). A 6-year-old patient previously with zone 2, stage 3 ROP with plus disease were treated with anti-VEGF. The regressed fibrotic ridge (asterisk) and retinal pigment epithelial alterations were observed (C). Looping vessels were visualized well by wide-field fluorescein angiography (D).
Figure 1. Regressed retinopathy of prematurity (ROP) after treatment by photocoagulation or intravitreal injection (IVI) of anti-VEGF. An 8-year-old patient with posterior zone 2, type 1 ROP was treated by laser photocoagulation (A). Atrophic retinal tissue and diffuse pigmentary changes in the periphery were observed. Although some vessels continued to grow over the lasered area, most of the retinal vessels were destroyed by the laser in the ablated zones (B). A 6-year-old patient previously with zone 2, stage 3 ROP with plus disease were treated with anti-VEGF. The regressed fibrotic ridge (asterisk) and retinal pigment epithelial alterations were observed (C). Looping vessels were visualized well by wide-field fluorescein angiography (D).

ANTI-VEGF MEDICATIONS FOR ROP

Bevacizumab

The most commonly used anti-VEGF agents is bevacizumab (Avastin; Genentech), a 148-kDa recombinant humanized antibody that binds to VEGF-A isoforms. The Bevacizumab Eliminates the Angiogenic Threat for Retinopathy of Prematurity (BEAT-ROP) study was the first randomized clinical trial that compared the use of anti-VEGF (bevacizumab) with conventional laser therapy.5 Bevacizumab reduced the risk of reactivation before 54 weeks of postmenstrual age (PMA) by 5 times as compared to conventional laser therapy for infants with zone I disease. Also, the peripheral retina continued to vascularize after treatment with bevacizumab, whereas with conventional laser therapy, the peripheral retina would have been ablated. Anti-VEGF therapy was also useful for very aggressive posterior ROP. However, the trial did not report on mortality or on local or systemic toxicity. There was also a risk of late reactivation up to approximately 16 weeks after bevacizumab injection.

There are other similar studies with smaller sample sizes which compared bevacizumab to laser photocoagulation. Results by Lepore et al6 revealed in his study that 2/11 (18%) laser-treated eyes had reactivation while 0/12 (0%) eyes recurred in bevacizumab-treated eyes. Eyes treated with bevacizumab had abnormal features seen under fluorescein angiography, such as peripheral avascular areas, abnormal vessel branching, or absence of foveal avascular zone, but these were not seen in laser-treated eyes at 9 months of age. The long-term implications of these angiographic abnormalities as patients develop into adulthood are still unknown.

Ranibizumab

Ranibizumab (Lucentis; Genentech) is a smaller molecule than bevacizumab that is more rapidly eliminated from the bloodstream and thus has potentially less systemic toxicity. Recently, the multicenter Ranibizumab Compared With Laser Therapy for the Treatment of Infants Born Prematurely With Retinopathy of Prematurity (RAINBOW) randomized clinical trial was performed to compare intravitreal ranibizumab with laser photocoagulation for treating ROP infants.2 The authors found that treatment success was achieved in 80% of infants treated with a 0.2-mg dose of ranibizumab, 75% with the 0.1-mg dose, and only 66.2% following laser.

However, there are concerns that there is a higher reactivation of ROP with ranibizumab use. For instance, a recurrence rate as high as 83% within 6 weeks of injection was reported.7 On the other hand, the Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity (CARE-ROP) study group revealed that 0.12 mg of ranibizumab was as effective as 0.20 mg in ROP treatment.8 The optimal dose of ranibizumab has not been ascertained and therefore more clinical studies are warranted.

Aflibercept

Approved for the treatment of wet macular degeneration in 2011, aflibercept (Eylea; Regeneron) has been used for ROP treatment only for the past 5 years. Due to high binding affinity and longer intraocular half-life, a longer duration of clinical action is theorized to occur after intravitreal injection of aflibercept. Sukgen et al9 demonstrated that recurrence for aflibercept treatment was less frequent and much later than for ranibizumab, even though the 2 drugs showed comparable activities in the early period, such as prompt regression of ROP and continued peripheral retinal vascularization. Large-scale, multicenter clinical trials are currently ongoing to assess the efficacy and safety of aflibercept in ROP treatment.3

BENEFITS AND CONCERNS FOR THE USE OF ANTI-VEGF FOR ROP

The relative advantages of anti-VEGF treatment over that of laser photocoagulation include that it is useful for patients with media opacity, tunica vasculosa lentis, and rigid pupil; it is readily applicable for patients with unstable systemic conditions; there is no need to intubate; there is increased success rate for zone I disease or aggressive posterior ROP; there is further vascularization of retinal vasculature toward the peripheral retina; it is less likely that myopia or high myopia will develop; there is better bare vision; and there is less foveal hypoplasia in the long run (Figure 2). Desipte the advantanges, there are some concerns about this treatment. The injection technique is different from that for adult patients. It is usually performed at the site of pars plicata with the needle almost perpendicular to the injection surface. The injected dose is half of an adult dose, and optimal dose for pediatric eyes is still unknown. Close follow-up after this treatment is needed to monitor treatment effects.

Figure 2. Representative macular cross-section scanning of patients with a history of retinopathy of prematurity (ROP) treated with intravitreal injection (IVI) or anti-VEGF. The IVI patient showed a greater depressed foveal contour than that of the lasered patient. In short, patients treated with IVI generally show less foveal hypoplasia than patients treated with laser photocoagulation.
Figure 2. Representative macular cross-section scanning of patients with a history of retinopathy of prematurity (ROP) treated with intravitreal injection (IVI) or anti-VEGF. The IVI patient showed a greater depressed foveal contour than that of the lasered patient. In short, patients treated with IVI generally show less foveal hypoplasia than patients treated with laser photocoagulation.

It is important to look for signs of regression and reactivation following anti-VEGF for ROP patients. Regression of the ROP lesion is characterized by gradual thinning and whitening of neovascular tissue and decrease of plus disease. Vascular changes in ROP reactivation include recurrent vascular dilation and/or tortuosity, similar to acute phase “pre-plus” or plus disease or reappearance of neovascularization. Additional concerns for the use of anti-VEGF for ROP inlcude risks of ocular complications, such as cataract and endophthalmitis following injection; late reactivation; the need for long-term follow-up after injection; the risk of increased retinal traction (crunch syndrome); abnormal retinal vascularization after the acute phase; uncertainty of future neurodevelopmental outcomes; and persistent avascular retinal areas and other angiographic anomalies.

SYSTEMIC RISKS OF ANTI-VEGF

VEGF is an important neurodevelopmental growth factor in the early newborn period and is involved in organogenesis, especially that of the lungs and kidneys. In our previous study, we found that intravitreal bevacizumab or aflibercept could suppress serum VEGF levels for up to 2 months after treatment.10,11 On the other hand, serum VEGF suppression was only 1 week with ranibizumab.12 Among the 3 anti-VEGF agents, ranibizumab had the least systemic suppressive effect. This difference is presumably due to the larger molecular size of bevacizumab resulting in slower retinal clearance and therefore prolonged diffusion into the systemic circulation.

What about the impact of anti-VEGF on neurodevelopmental outcomes in these patients? More recently, our group conducted a prospective study to evaluate infants with type 1 ROP who underwent treatment with bevacizumab.13 Bayley III scores were determined at 1 to 3 years of age. Premature infants with a history of ROP treatment with bevacizumab had similar refractive, visual, and neurodevelopmental outcomes compared to premature patients with ROP who did not require treatment. On the contrary, some studies report negative neurodevelopmental outcome following anti-VEGF use.14,15 Although anti-VEGF may lead to better structural outcomes of eyes and less refractive errors, there is a lack of long-term studies, especially prospective randomized studies, to identify a lasting effect on systemic organs or neurodevelopment. Developmental deficits in cognition, emotional and behavioral development, and social adaptive functioning may emerge at older ages. Thus, studies involving longer follow-up of these anti-VEGF-treated infants are needed to fully assess any potential systemic adverse events resulting from intravitreal anti-VEGF treatment.

CONCLUSION

Anti-VEGF agents are increasingly being adopted over laser photocoagulation and cryotherapy due to the ease of administration, quick treatment response, and no need to purchase a laser machine. There are, however, concerns about anti-VEGF treatment for ROP, including possible ocular complications and long-term systemic effects. Further studies are needed on the optimal doses, long-term efficacy, and systemic effects using them in ROP treatment. Laser photocoagulation remains the gold standard for the treatment of ROP. Retina specialists must use both treatments carefully for children to achieve the best outcome. Knowing each treatment’s strengths and limitations is vital before we apply them to this vulnerable group of patients. RP

Xiao Chun Ling, MD, and Wei-Chi Wu, MD, PhD, are with the Department of Ophthalmology of the Chang Gung Memorial Hospital in New Taipei City, Taiwan. The authors report no related disclosures. Reach Dr. Wu at weichi666@gmail.com. Editor’s note: Hear discussion of this article on the Retina Podcast at www.retinapodcast.com .

REFERENCES

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  2. 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. Lancet. 2019;394(10208):1551-1559. doi:10.1016/S0140-6736(19)31344-333
  3. Aflibercept for retinopathy of prematurity - intravitreal injection versus laser therapy (FIREFLEYE). ClinicalTrials.gov identifier:NCT04004208. Updated December 17, 2020. Accessed December 31,2020. https://clinicaltrials.gov/ct2/show/NCT04004208 .
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