Peripheral retinal ablation has been the mainstay of therapy for vasoproliferative retinopathy of prematurity dating back to the Cryo-ROP Study. Though highly effective, laser photoablation—the current treatment standard²—is not a perfect treatment modality. Effective application of laser is often quite challenging. Timely treatment requires a thorough familiarity with the nuances of the clinical features of ROP, particularly posterior disease. Clinicians wellversed in the ROP diagnosis and laser application are not available worldwide.Infants afflicted with aggressive ROP may fare poorly despite timely and appropriate treatment. Though the advantages of peripheral retinal ablation far outweigh the consequences of untreated ROP, ocular and systemic morbidities are not so trivial as to be dismissed.

ROP is a biphasic disease characterized by oxygen-induced attenuation of normal retinal vascularization followed by hypoxia-induced vasoproliferation.³ Both phases are mitigated by growth factors, including the proangiogenic cytokine vascular endothelial growth factor. A growing body of laboratory and clinical evidence supports the rationale of targeted pharmacologic inhibition of VEGF as a treatment for acute phase ROP.^4,5

What follows is a brief review of the evidence available regarding antiVEGF pharmacotherapy of ROP, either adjunctive to peripheral retinal ablation or as monotherapy.


Literature: Case Reports/Series
The clinical literature speaking to the off-label use of the monoclonal anti-VEGF antibody bevacizumab (Avastin) given by intravitreal injection for infants with advanced ROP consists of case reports/case series and one clinical trial. Both lines of evidence provide clinical information of interest to the management of ROP.

The case series and case report literature on anti-VEGF therapy for ROP is highly variable as to treatment indications, dosage, treatment timing, treatment frequency, outcome measures, follow-up and more. Three main indications for treatment have emerged:

1. treatment-naïve eyes with vascular congestion of the anterior segment precluding adequate visualization for laser treatment (See Figure 1).^7,11,13-15
2. previously treated eyes with persistent plus disease, exudation, evolving vitreoretinal traction, or tractional retinal detachment.^6,9-14,18
3. primary monotherapy (without adjuvant retinal ablation) for eyes with posterior or aggressive disease (See Figure 2).^8,11,16,19 

Literature: Clinical Trials 
Two prospective randomized trials have been designed to investigate the effi cacy of intravitreal bevacizumab.

• BLOCK-ROP. The BLOCK-ROP study (Pan-VEGF Blockade for the Treatment of Retinopathy of Prematurity, clinical trials identifier NCT00702819) was designed to assess the safety and tolerability of bevacizumab in infants with aggressive posterior ROP (APROP) who had failed conventional laser therapy. Eleven premiere clinical centers with stateof- the-art neonatal intensive care units and clinicians highly experienced in the diagnosis and treatment of ROP were involved in the trial. This phase of BLOCK-ROP was terminated due to insufficient enrollment—ROP progression with timely and effective laser for APROP was rare at BLOCK-ROP study centers: Two infants were enrolled over the course of a year (unpublished data).

A second phase of the BLOCK-ROP study (NCT01232777) targets all treatment- eligible infants (Type-1 threshold ROP),³ with an internal control for more rigorous comparison of treatment efficacy. This dose-ranging Phase II study will aim to demonstrate noninferiority of intravitreal bevacizumab compared with standard-of-care laser.In this randomized three-armed trial, one group of infants will receive 0.75 mg intravitreal bevacizumab in one eye and laser treatment in the fellow eye; a second group will receive 0.625 mg intravitreal bevacizumab in one eye and laser treatment in the fellow eye; and a third group of infants will receive laser photocoagulation in both eyes. It is hoped that, by this study design, the relative risk of increased myopia, amblyopia, and functional outcomes can be assessed, since the eye treated with bevacizumab can be compared with the fellow, laser-treated eye of the same infant. Additionally, a lower effective dose of bevacizumab may be established.

• BEAT-ROP. In the BEAT-ROP study,¹ 150 infants with bilateral Stage 3+ ROP in zone I or posterior zone II were randomized to receive either intravitreal bevacizumab monotherapy (0. 625 mg in 0.025 cc) or laser photocoagulation in each eye. The primary outcome measure was recurrence of retinal neovascularization between 50 and 70 weeks post-conceptional age, ascertained in 143 surviving infants. In eyes with zone I ROP treated with bevacizumab, recurrence was significantly less than in eyes treated with standard laser photocoagulation (6 percent compared with 42 percent, p=0.003). In eyes with posterior zone II ROP, recurrence was lower in eyes treated with bevacizumab (5 percent Compared with 12 percent, p=0.27), but not to a statistically signifi cant degree. The timing of recurrence was much later in eyes treated with bevacizumab (16 weeks compared with six weeks).

Macular dragging was seen more commonly in laser-treated eyes (16 of 66 eyes with zone I ROP and six of 80 eyes with zone II ROP). Vitrectomy was performed in 13 of 66 eyes treated with laser for zone I ROP and in two of 78 eyes treated with bevacizumab for zone II ROP. Seven infants died (five treated with bevacizumab and two treated with laser). No systemic safety signals were raised, but no systemic adverse events were defined a priori as outcome measures.


Encouraging Data
Case reports/case series have provided some interesting and thoughtprovoking information. They have demonstrated the utility of bevacizumab in eyes with anterior segment features precluding clear visualization of the posterior segment. In such eyes, regression of ROP (either with or without accompanying laser photocoagulation) has been reported to occur in nearly 90 percent of cases.^7,11,13-15 Conversely, among previously treated eyes with persistent disease activity despite peripheral retinal ablation, the best response appears to be in eyes with persistent plus disease or exudation without significant fi brovascular proliferation.^6,9-14,18

The most encouraging and provocative data come from reports of bevacizumab monotherapy for posterior ROP. Regression, usually with a single injection, has been reported in over 90 percent of cases in this group.^8,11,16,19 Most striking is the observation that retinal vascularization may occur, often to the far retinal periphery,⁶ suggesting that either physiologic VEGF levels recover following acute inhibition, or that retinal vascularization may proceed by VEGF-independent mechanisms. However, complete peripheral retinal vascularization does not occur uniformly (See Figures 3 & 4).

Phase 1 of the BLOCK-ROP study is of interest as it demonstrated that laser peripheral ablation is a highly effective therapy for ROP in this patient population—as this was the reason for non-recruitment.

The BEAT-ROP study provided proof, in the context of a clinical trial, of the prevailing concept that appropriately timed intraocular VEGF inhibition can eliminate most cases of acute ROP. Yet in many respects the BEAT-ROP study data raise more questions than they answer:

• Ten of the 15 BEAT-ROP study centers were located in south and west Texas and more than half of enrolled infants were Hispanic. As a result, the study outcomes may be confounded by population bias, and the results potentially not generalizable. 
• The failure rate for ROP following laser in BEAT-ROP is unusually high compared to outcomes in the ETROP study.² Again, Phase 1 of the BLOCK-ROP study was terminated for precisely the opposite reason—laser failure was a rare event. In a recent study of infants with AP-ROP, laser treatment alone was successful in more than 80 percent of eyes.³² A study of zone 1 ROP from 20 years ago yielded similar results.³³ It is reasonable to ask why BEAT-ROP laser outcomes were so inferior to those in the peer-reviewed literature. If similar laser success rates had been achieved in BEAT-ROP, it is less likely that the results would be statistically significant for zone 1 disease. 
• The tendency to persistent broad areas of avascular peripheral retina (See Figures 3 & 4) and late recurrence of ROP in eyes treated with bevacizumab alone means that these infants will require extended follow-up. The mean time of recurrence was 16 weeks post-treatment, which is well beyond the time frame within which most infants are discharged. In the real-world, post-NICU setting, follow-up visits to the ophthalmologist may be missed among the myriad other specialist visits. Older infants are more challenging to examine. Given the necessity of these visits, as well as the medicolegal concerns regarding missed visits (the leading underlying cause for litigation), significantly more efforts for patient tracking, follow-up and documentation may be required. There are no data available to provide guidance as to whether eyes with persistent avascular retina are best observed or treated. 

Despite the statement of the BEAT-ROP investigators that “… bevacizumab … can be rapidly administered at the bedside by any ophthalmologist,” intravitreal injection is not trivial, requires detailed understanding of the relevant anatomy and technique, and carries risk (endophthalmitis, retinal detachment, significant intraocular pressure elevation and cataract, to name a few). Cataracts in this population are associated with severe developmental vision loss that may be irreversible. Injection through the peripheral retina may lead to an inoperable retinal detachment and blindness. The systemic impact of pharmacologic therapy may be difficult to ascertain but should not be completely ignored: Of the infant deaths in this study, 71 percent (five of seven) occurred in infants who received bevacizumab. The effectiveness of the treatment should not be determined by the perceived facility of acquisition of the medicine or speed of the procedure.

The prospect of eradicating a blinding disease with a single injection is an exciting one. It is likely that there will be an important role for anti-VEGF therapy in the management of ROP. However, important unanswered questions remain regarding the role of anti-VEGF therapy for ROP. In contrast to peripheral retinal ablation, for which standard of care parameters have been derived from high-quality prospective multicenter studies, there is no standard approach as to when and how bevacizumab is to be used. Similarly, none of the published literature to date provides adequate guidance as to the intervals or duration of post-treatment follow-up when bevacizumab is the treatment administered.

The conceptualization of ROP as a “window disease” is overly simplistic, as ROP treatment requires more than suppression of the acute phase of disease. Available evidence to date does not yet support broad adoption of anti-VEGF as primary or adjunctive treatment for ROP. For the moment, peripheral retinal ablation remains the treatment of choice. Well-designed clinical trials of anti-VEGF therapy for ROP are needed in order to provide information as to the balance of risk vs. benefit, as well as practical guidance regarding optimal treatment parameters and follow-up.