Introduction
The role of vascular endothelial growth factor (VEGF) in the pathogenesis of retinopathy of prematurity (ROP) has been well described, and destruction of the cellular elements that release VEGF in the peripheral retina has proven to be an effective treatment. Current recommendations include less-destructive therapies (laser therapy in place of cryotherapy) administered earlier in the acute phase of ROP,1 with an emphasis on a careful screening process that identifies ROP at the appropriate time for therapeutic intervention.2 Zone I cases, especially aggressive posterior retinopathy of prematurity (AP-ROP),3 often have bad outcomes despite appropriate screening and timing of intervention. With the development of anti-VEGF drugs for intravenous use in advanced cancer therapy and for intravitreal use in neovascular ocular disease, interest by researchers and clinicians has led to the study of intravitreal anti-VEGF drugs for ROP, and articles documenting the successful clinical use of bevacizumab have recently been published.4-7
This article reviews problems with conventional laser therapy, defines specific potential advantages of bevacizumab usage for ROP, discusses the concerns of local or systemic complications following the use of bevacizumab, and emphasizes the potential of bevacizumab as a first-line treatment for stage 3 ROP in zone I and posterior zone II.
Problems with Conventional Laser Therapy
Re-intubation of a fragile premature infant often is necessary to accomplish extensive retinal ablation for AP-ROP in zone I or for stage 3 ROP in zone I or posterior zone II. Multiple additional procedures in the operating room may be necessary in cases where laser therapy is unsuccessful. The complications of laser therapy are many and include (but are not limited to) cataracts, lens dislocation, anterior segment or intravitreal hemorrhage, glaucoma, phthisis, recurrence, and retinal detachment. Even successful outcomes following laser surgery may include (but are not limited to) substantial visual field loss due to retinal ablation, significant myopia (although this is usually less severe following laser therapy than following cryotherapy), strabismus without amblyopia (associated with a smaller area of overlapping fields), and strabismus with amblyopia (due to asymmetrical macular pathology or deprivation from unequal media opacities (related to an unequal inflammatory response to laser or to unilateral anterior segment or intravitreal hemorrhage). Another problem following laser therapy is the continuation of the neovascular process of ROP until the VEGF already present in the vitreous is gone; in contrast, there is an immediate cessation of this process in the vitreous when intravitreal bevacizumab injections are given.
Specific Potential Advantages of Bevacizumab
Bevacizumab (Avastin) is chosen so as to try to minimize the possibility of systemic complications. The molecular weight of bevacizumab is 149 kilodaltons (kD), of VEGF-Trap (investigational) is 110 kD, and of ranibizumab (Lucentis) is 48 kD. In adults, the half-life of bevacizumab is 5.6 days, of VEGF-Trap is 4.4 days, and of ranibizumab is 3.2 days. Injection of substances into the viscous, preterm vitreous compared to that of the watery, aging vitreous likely increases this half-life considerably.
Concerns Regarding Intravitreal Bevacizumab Injections for ROP
There is considerable concern regarding the choice of this drug, its dosage, the timing of injections, the necessity of multiple injections, and the possibility that acute and long-term local and systemic complications may be caused by anti-VEGF therapy. There are many potential local complications when any intravitreal injection is given.8 However, if these complications can be avoided, several lines of evidence encourage clinicians to continue with caution. First, a pathological case demonstrate no retinal toxicity in the retina of an infant (350 grams birth weight, 22 weeks gestational age) who received 1 intravitreal injection in each eye for AP-ROP in very small zone I eyes at age 9 weeks and another intravitreal injection in each eye when ROP recurred as stage 3 ROP in posterior zone II at age 20 weeks. The infant expired 9 weeks later of other causes. (Submitted as 2008 ARVO abstract.) Second, the pharmacokinetics of intravitreal bevacizumab suggest that bevacizumab levels in the blood or in the fellow eye compared to the bevacizumab level in the injected eye are 1:1000.9 Third, the possibility of bevacizumab escaping from the vitreous is lessened without the inflammatory reaction that accompanies laser therapy and without retinal atrophy due to laser therapy concurrent or antecedent to intravitreal bevacizumab injections.
The Promise of Anti-VEGF Therapy
As with conventional laser therapy, perhaps anti-VEGF therapy should be considered earlier in the course of acute ROP and not in combination with or following laser therapy. Currently anti-VEGF therapy is being considered only as salvage therapy for stages 4a, 4b, and 5 ROP, when laser therapy for stage 3 ROP fails. Existing pilot data support cautious consideration of broadening the use of anti-VEGF therapy to include stage 3 ROP. We suggest using it at a later stage than ET-ROP but earlier than CRYO-ROP.
One noncomparative, prospective, interventional case series involving 13 infants (18 eyes) using bevacizumab (1.25 mg in 0.05 ml) as a first-line therapy has been reported. These clinicians used bevacizumab at the onset of threshold stage 3 ROP, in both zones I and II, with or without clear visualization, and they also used anti-VEGF therapy after conventional laser therapy had failed.
We also have experience with a noncomparative, retrospective, interventional, consecutive case series of 11 infants (22 eyes) using intravitreal bevacizumab (0.625 mg in 0.025 ml) as a first-line therapy when stage 3 ROP occurred, in both zone I and posterior zone II, without (Figure 1A and B; before and after injection of bevacizumab) and with (Figure 2A and B; before and after injection of bevacizumab) clear visualization. These 11 infants (22 eyes) were treated successfully. However, length of follow up in this small case series is a mean of only 27.0 weeks (approximately 6 months, with a range from 3 to 14 months) following injection of bevacizumab at a mean of 11.0 weeks postnatal age. Thus, the mean postnatal age at the last visit is only 38.0 weeks (until approximately 9 months postnatal age). We chose to refrain from laser therapy to minimize the possibility of systemic complications with the egress of bevacizumab from the vitreous via the larger choroidal vessels into the blood. Similarly, we decided to give bilateral intravitreal injections to avoid creating a case series of amblyopic eyes related to the inflammatory response that accompanies unilateral laser therapy.
Conclusion
As with all new therapies, extreme caution must be advised, especially when neonates are involved. The results of 2 small case series without any early local or systemic complications may be promising; however, they should not be interpreted to imply that bevacizumab can now be considered "standard of care." A prospective, randomized, controlled, multicenter clinical trial with a larger patient population must be performed to compare intravitreal injections of bevacizumab with conventional laser therapy. Evidence-based studies are necessary when a potentially dangerous growth hormone is being considered for neonates. Many examples of serious late complications in neonates of other "promising therapies" have been reported when carefully planned clinical trials have not been performed.
References
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2. Section on Ophthalmology American Academy of Pediatrics, American Academy of Ophthalmology, American Association for Pediatric Ophthalmology and Strabismus. Screening examination of premature infants for retinopathy of prematurity [published correction appears in Pediatrics 2006;118(3):1324] Pediatrics. 2006;117(2):572-576.
3. International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity Revisited [published correction appears in: Arch Ophthalmol. 2006;124(11):1669-1670]. Arch Ophthalmol. 2005;123(7):991-999.
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9. Bakri SJ, Snyder MR, Reid JM, et al. Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology. 2007;114(5):855-859.
Author Disclosure
The author states that she has no financial relationship with the manufacturer or provider of any product or service discussed in this article or with the manufacturer or provider of any competing product or service.