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More study needed regarding use of anti-VEGF in ROP
The use of intravitreal anti-VEGFs as monotherapy for retinopathy of prematurity in the last few years, although shown to be effective from an ocular standpoint, has raised several serious questions pertaining to its safety, especially from the systemic standpoint. The indications for anti-VEGF in ROP have been recently better agreed upon by those who recommend it, but there is still no universal consensus regarding several aspects, including the dosage, the risk for ROP recurrence and the extent of follow-up required. There is neither an established protocol nor a clear understanding of its adverse effects.
Laser photocoagulation
Laser photocoagulation currently is the standard treatment for proliferative ROP. However, it has its limitations. Laser photocoagulation, especially for zone 1 disease, almost ablates most of the retina permanently, resulting in severe constriction of visual fields. Laser photocoagulation also increases the risk of inducing myopia. Regarding the practical aspects of the procedure, it may be very stressful for the preterm infant, especially when prolonged treatment periods and extensive ablation are required, with risks of apneic episodes, requiring continuous monitoring by anesthetists and neonatologists.
VEGF and its role in organogenesis and neurodevelopment
VEGF plays a critical role at multiple levels in the development of several organ systems. In the neurological system, VEGF plays an important role in neuronal events such as axonal guidance, neuronal migration and neuronal protection through its interactions with several other regulatory factors. VEGF has a neurotrophic effect. It enhances survival of Schwann cells, protects hippocampal neurons from ischemic injury and enhances cerebellar granule neurons survival after hypoxia. Suppression of systemic VEGF can have profound effects in an already compromised preterm child.
Anti-VEGF in ROP
Anti-VEGF initially was used by experts as an adjutant to laser photocoagulation or in an attempt to limit disease progression after recurrence after laser photocoagulation. However, more recently, some ROP experts who are in favor of anti-VEGF monotherapy (when it may not be possible to salvage the eye with extensive laser) feel that the application of laser might actually increase the disruption of the blood-retinal barrier, resulting in more systemic dissemination of the anti-VEGF and its consequences. There has been clear-cut evidence for spread of the anti-VEGF into systemic circulation as evidenced by persistent elevated blood anti-VEGF levels for several weeks after intravitreal injection and also by reports of a therapeutic effect on the contralateral uninjected eye. Despite these reports, those who favor anti-VEGF argue that there has been no definitive evidence to indicate systemic consequences. They also further defend that the mortality that has been reported so far in literature cannot be attributed to anti-VEGF alone because these preterm infants have a higher baseline risk for increased mortality in general.
BEAT-ROP study
The BEAT-ROP study has been the only prospective, randomized, multicenter clinical trial to compare anti-VEGF therapy with conventional laser therapy in infants with stage 3+ ROP. The study suggested greater efficacy of anti-VEGF for zone 1 threshold disease. The authors reported completion of retinal vascularization, lesser recurrence rate and preservation of peripheral retina. However, several major concerns have been raised about the study design and the treatment recommendations by both ROP specialists and neonatologists. Many ROP experts have questioned several aspects of the study, including the protocols used for laser in the BEAT-ROP study.
Dosage and complications
Although the U.S. Food and Drug Administration has approved the use of anti-VEGF intravitreal injections for many adult ocular conditions with suspected neovascular etiology, it has not yet approved its use in treating ROP. Currently, physicians may use it “off label.” However, this requires that physicians are well-informed about the medication and base its use on firm scientific rationale and sound medical evidence, and maintain thorough records of its use and effect. A thorough explanation and consent are required. Most ROP specialists who use anti-VEGF agree at least regarding the timing of the injection. There are currently no standard dosage recommendations for ensuring safety. Avastin (bevacizumab, Genetech/Roche) has been used in varying doses in different studies, and 0.625 mg appears to be the most often used. The ocular complications that have been reported include retinal hemorrhage, cataract, macular traction and exotropia. Recurrence, persistent plus disease, and partial or total retinal detachment have also been reported. Currently, there is consensus regarding the timing of injection (during phase 2: 31 weeks to 45 weeks). Physicians also agree that it is contraindicated when a tractional element is present.
Conclusion
The use of a medication with yet unknown systemic adverse effects raises several important ethical questions. A well-designed larger prospective randomized controlled study addressing all major concerns is the need of the hour.
References:
Azad R. Indian J Ophthalmol. 2011;doi:10.4103/0301-4738.86305.
Duffy AM, et al. Madame Curie Bioscience Database. Landes Bioscience. http://www.ncbi.nlm.nih.gov/books/NBK6482/#A22372.
Mintz-Hittner HA, et al. N Engl J Med. 2011;doi:10.1056/NEJMoa1007374.
Pertl L, et al. PLoS One. 2015;doi:10.1371/journal.pone.0129383.
For more information:
Dennis S.C. Lam, MD, FRCOphth, can be reached at State Key Laboratory in Ophthalmology, Sun Yat-Yen University, 54 South Xianlie Road, Guangzhou 510060, People’s Republic of China; email: dennislam.gm@gmail.com.
Disclosure: Karthikeyan and Lam report no relevant financial disclosures.