Emerging use of Bevacizumab in the Treatment of Posterior Retinopathy of Prematurity(ophthalmic hyperguides)

Pediatric Ophthalmology Emerging use of Bevacizumab in the Treatment of Posterior Retinopathy of Prematurity Rudolph S. Wagner, MD The Institute of Ophthalmology & Visual Science · University of Medicine and Dentistry of New Jersey · New Jersey Medical School · Newark, New Jersey  Aswin Chandrakantan The Institute of Ophthalmology & Visual Science · University of Medicine and Dentistry of New Jersey · New Jersey Medical School · Newark, New Jersey  Angiogenesis is the process by which new capillaries are formed from blood vessels. Physiologically, it is a normal process; however, it also can be a cause of significant pathology in retinopathy of prematurity (ROP), diabetic retinopathy and AMD. The process of angiogenesis is regulated by a multitude of both pro- and anti-angiogenic factors. Vascular endothelial growth factor (VEGF) is one of the most important pro-angiogenic factors in this interplay of regulation.1 VEGF is a category of proteins that increase capillary growth through the use of tyrosine kinase receptors. VEGF uses cascades to promote neovascularization, and pharmacological treatments can focus on inhibiting VEGF directly and indirectly via the modulation of VEGF, as well as its upstream receptors.2  Pharmacologic agents such as pegaptanib, ranibizumab, bevacizumab, VEGF-Trap and Sirna-027 have shown promise in treating pathological ocular neovascularization.3 Of particular interest in recent years is bevacizumab, which is a monoclonal antibody against VEGF-A, a particular subcategory of VEGF.  Retinopathy of Prematurity  ROP is a leading cause of blindness in children and is caused by an incomplete vascularization of the peripheral retina leading to a subsequent overcompensatory neovascularization. Risk factors include degree of prematurity, birth weight and use of oxygen supplementation in the postdelivery period.4 The Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) - Outcome Study of Cryotherapy for Retinopathy of Prematurity has shown that 44.4% of preterm infants with severe ROP subsequently treated with cryotherapy had a visual acuity of 20/200 at 10 years of age and, of the children whose treated eye had a visual acuity higher than 20/200, only 45.4% had a visual acuity 20/40 or better. In this trial, peripheral retinal ablation was performed when the risk for retinal detachment approached 50%.5 This cut-off deemed "threshold" is defined as at least 5 contiguous zones or 8 cumulative sectors of stage 3 ROP in zone I or I with plus disease. Plus disease is a measurement of dilation and tortuosity of posterior retinal vessels that exceed that of a normal eye. Results of the Early Treatment for Retinopathy of Prematurity (ETROP) study that was funded by the National Institutes of Health demonstrated that peripheral ablation should be considered for any eye with type I ROP defined as (1) zone I, any stage ROP with plus disease; (2) zone 1, stage 3 ROP with or without plus disease; or (3) zone II, stage 2 or 3 ROP with plus disease (Slide 1). Serial examinations are recommended in type II ROP, which is defined as (1) zone I, stage 1 or 2 ROP without plus disease or (2) zone II, stage 3 ROP without plus disease.6 Slide 1. Retinal image showing stage 3, zone II retinopathy of prematurity with plus disease. (Image courtesy of Rudolph S. Wagner, MD)  http://www.ophthalmic.hyperguides.com/images/content/tutorials/37514/slide1.jpg Active screening is required in at-risk neonates followed by monitoring of oxygen supplementation and ablating the peripheral retina once "threshold" disease has been reached. Zone I disease, in particular, has been shown to be associated with a poor prognosis as compared to zone II or zone III disease, even after the use of laser photocoagulation or cryotherapy. The CRYO-ROP study found a 77.8% unfavorable outcome rate using cryotherapy and the ETROP study found a 55.2% unfavorable outcome rate using laser photocoagulation in treating patients with zone I ROP disease.5,6 It has been suggested that the frequent failure of ablation therapy in the treatment of zone I ROP can be caused by neovascularization due to VEGF-165 secreted by vitreal macrophages.7 VEGF levels have been shown to be higher in patients with ROP stage III than those with lower stage of disease. Furthermore, it is has been established that patients with zone I ROP, especially aggressive proliferative ROP, have poor clinical outcomes despite proper screening and timely intervention using laser therapy. 8-13 Hence, there is increased attention toward the downregulation of VEGF in patients with ROP, and preliminary studies and case reports have shown the successful clinical use of bevacizumab.  Bevacizumab for Treatment of Retinopathy of Prematurity  The benefits of using anti-VEGF agents include the elimination of the numerous complications of laser therapy, prevention of retinal atrophy and consequent visual field loss, decreased myopia and reduced strabismus with or without amblyopia. The BLOCK-ROP study, a phase 1 trial that started in fourth quarter 2007, will evaluate the effectiveness of 0.75-mg intravitreal injections of bevacizumab in 22 patients in the potential treatment of ROP.  Case reports  In previous studies, injections have been performed with continuous cardiorespiratory monitoring under conscious sedation or intubated general anesthesia. The injections are delivered behind the lens by aiming the needle toward the optic nerve, entering the sclera through the conjunctiva 1 mm to 1.5 mm behind the limbus and advancing the needle two thirds of the way and delivering the injection into the central vitreous. Using an indirect ophthalmoscope, the neonate's eye is then examined for signs of lens injury and blood flow through the retinal artery and to identify tears or vitreous hemorrhage that may have inadvertently occurred during the procedure.14,15  There is no consensus on the dosing of bevacizumab in neonates; however, previous studies have reported no serious side effects in doses ranging from 0.75 mg to 2.5 mg. 15-19 The normal adult dose is 1.25 mg and, considering that neonates have smaller vitreous volume, it may be prudent to use lower doses. Four previous case reports have shown that dosages of 0.75 mg may be sufficient to inhibit the production of VEGF and consequently neovascular proliferation.4,14,18,19 These cases received 0.75 mg bevacizumab to successfully treat aggressive posterior ROP with no reported systemic complications. One case reported bilateral anterior segment ischemia, which may have been due to extensive laser ablation rather than the use of bevacizumab.18 A set of case reports from Portugal details how 3 neonates with aggressive posterior ROP were given a 0.75-mg intravitreal injection of bevacizumab and, within 24 hours, showed regression of both tunica vasculosa lentis and iris vessel engorgement with a concurrent disappearance of iris rigidity.19 The most recent trial performed on 11 neonates with severe stage 3 ROP in zone I or posterior zone II were treated bilaterally with 0.625 mg of bevacizumab and had no concurrent laser therapy. The treatment was successful in all eyes and no patients experienced complications.14  Potential risks of therapy  With the downregulation of VEGF, theoretically, there is a risk of downregulating both normal and pathological neovascularization, although such effects have not been demonstrated in any studies thus far. Hence, excessive doses of a VEGF-inhibiting pharmacological agent may risk inhibiting physiologically normal angiogenesis and hinder the normal development of the neonate eye. Further studies are warranted to investigate the optimal dosing for neonates and these case reports can serve as a platform for inquiry.  Intraocular risks of intravitreally administered bevacizumab in adults have included endophthalmitis, retinal detachment, cataract and uveitis. In adult patients given pegaptinib, endophthalmitis occurred at a rate of 0.16% per injection, retinal detachment occurred at a rate of 0.08% per injection and cataract occurred at 0.07% per injection.20 One case report details acute contraction of the proliferative membrane leading to partial tractional retinal detachment after the injection of 0.4 mg of bevacizumab.21 Studies on the use of bevacizumab in patients with severe proliferative diabetic retinopathy (PDR) also reported the possibility of tractional retinal detachment after the injection. Although these anti-VEGF drugs have not been extensively studied in neonates with ROP, it is important to study the safety profile of this drug within this population.  Bevacizumab is indicated for the treatment of patients with metastatic colon cancer. Ranibizumab is an anti-VEGF agent; however, with a molecule size of 48 kilodaltons (kD), it is considerably smaller than bevacizumab (148 kD).14 It has been hypothesized that smaller molecules may infiltrate the peripheral undifferentiated retina and cause local damage. Furthermore, potential exists for diffusion into systemic circulation in amounts that could cause side effects. Studies of the use of bevacizumab in rabbits have found bevacizumab levels of 1:1,000 in the untreated versus treated eye.22 In adults, the intravitreal half-life of bevacizumab is 5.6 days in contrast with a half-life of 3.2 days for ranibizumab, which is hypothesized to be considerably extended in preterm neonates' viscous vitreous fluid.14  Other Potential Treatments  Interest in the role of insulin-like growth factor-1(IGF-1) in the development of normal retinal vasculature has grown. Low levels of IGF-1 have been implicated in the development of ROP and hence it is believed that supplementation of IGF-1 in preterm infants could prevent the development of ROP.23 IGF-1 has been associated with gestational age and birth weight and therefore preterm infants have been found to have significant reductions in this important somatic growth factor.24 It is believed that preterm neonates may be unable to normally develop their retinal vasculature leading to retinal hypoxia and having a subsequent rebound in IGF-1 levels that triggers proliferative neovascularization. Further studies are warranted to identify the potential use of IGF-1 supplementation to prevent subsequent neovascular changes, especially in preterm infants.  Bevacizumab shows potential in the treatment of patients with ROP; however, no large-scale randomized study has proven its efficacy for the treatment of this condition and it is not yet approved by the FDA for this use. 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