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QUESTION
WHEN SHOULD I CONSIDER ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR TREATMENT FOR RETINOPATHY OF PREMATURITY?
Yoshihiro Yonekawa, MD
Kimberly A. Drenser, MD, PhD
Retinopathy of prematurity (ROP) is a vascular endothelial growth factor (VEGF)–driven disease, so why not treat all infants using anti-VEGF agents? It makes sense physiologically, and it fits into the current drift of treating seemingly every retinal or choroidal vasculopathy with local VEGF suppression. Unfortunately, it’s much more complex for ROP, and there are several key factors to consider that we will outline. But first, we will preface by mentioning that there is no consensus on laser vs anti-VEGF treatment for ROP. Some practitioners use only laser, some use only anti-VEGF, while most use a thoughtfully titrated combination of the 2, and end up somewhere along the spectrum based on patient population, neonatal intensive care unit capabilities, access to resources, and surgeon preference. The following are our personal preferences at the time of writing, which may also evolve as we accumulate more evidence.
ROP occurs in 2 phases. In the vaso-obliterative phase, high oxygen tension attenuates the retinal vasculature and halts its growth from the optic disc towards the peripheral retina. In the subsequent vasoproliferative phase, arteriovenous shunting occurs at the vascular-avascular junction where retinal fibrovascular proliferation occurs in response to the ischemic peripheral retina. One of the key cytokines during this vasoproliferative phase is indeed VEGF, and suppressing VEGF during this phase does promote ROP regression.
Off-label use of anti-VEGF agents for ROP is increasing throughout the world since its first descriptions a decade ago.1 Avastin (bevacizumab) is currently the most commonly used, and most practitioners use half of the adult dose (0.625 mg), although the optimal dose has not yet been determined. We prefer using Lucentis (ranibizumab) if possible, because it does not suppress systemic circulating VEGF as much (though it is unknown if this is a clinically meaningful benefit). The main drawbacks of ranibizumab are that it is difficult to access for ROP because it is not a US Food and Drug Administration–approved indication, and that recurrence of plus disease and neovascularization are more common than with bevacizumab, and the recurrences tend to occur sooner.
There are many benefits of anti-VEGF monotherapy. First, it’s easy to administer from a logistic, technical, and economic (if using bevacizumab) standpoint. A bedside injection under local anesthesia takes only a few moments; the infant does not have to undergo general anesthesia that may have associated systemic risk (as a cohort, these are arguably the highest risk patients in our field). Additionally, bevacizumab is widely available and cheap; an intravitreal injection is technically much easier to perform than thorough laser, and injections are possible, even through media opacities. Studies have also shown that the rates of pathologic myopia are less compared to eyes that have been lasered, and most intriguingly, the retinal vasculature can continue to grow into the periphery after anti-VEGF treatment.2,3 Visual fields are therefore more preserved compared to ablative laser treatment.
There are, however, potential drawbacks of anti-VEGF treatment. Organogenesis is still occurring in premature infants, and VEGF is known to play a key role in development of the lungs, kidneys, brain, etc. Intravitreally injected anti-VEGF agents, especially bevacizumab, have been shown to enter the systemic circulation and suppress VEGF levels throughout the body. Thankfully no studies to date have shown whether this temporary suppression of systemic VEGF has any clinical effects. Two small retrospective studies placed the issue on the radar by suggesting an effect on neurodevelopment, but the studies are far from being definitive.4 This issue will be very hard to tease out because these infants often have severe systemic comorbidities that cause multiple chronic diseases including those that affect neurodevelopment.
Another downside of anti-VEGF treatment is the unpredictable recurrences that may sometimes occur many months after the injection.5 This unpredictability makes the follow-up schedule challenging. The children also become more difficult to examine in clinic as they get older. It has been suggested that infants be followed weekly until a postmenstrual age of 72 weeks. With laser treatment, the course of disease is very predictable, and we have a defined endpoint of when to stop screening, and late recurrences are not an issue. Therefore, if an infant does not fully vascularize with anti-VEGF treatment, many practitioners will laser the residual avascular retina.
The last downside of anti-VEGF treatment is the higher potential for crunching of the fibrotic component of the fibrovascular membranes, which can lead to progressive tractional retinal detachment. We have recently shown that these retinal detachments can have unique configurations that can be relatively difficult to operate on.6 As the infants approach term, the VEGF levels decrease in the eye, and there is an endogenous rise in transforming growth factor-beta (TGF-β). When VEGF is artificially suppressed pharmacologically, TGF-β rises also. As TGF-β is a profibrotic cytokine, the surges from both endogenous and pharmacologic routes may lead to crunching of the fibrovascular membranes and associated posterior hyaloid. This appears to occur more commonly in eyes with aggressive posterior-ROP, or if the injection takes place relatively later. If injected timely at the first signs of Type I ROP, we feel that this phenomenon may be avoidable.
As there are benefits and downsides to both laser and anti-VEGF treatment, the risks and benefits need to be weighed carefully for each individual patient. We do not recommend a one-size-fits-all paradigm for ROP treatment, because there are many variables at play as outlined previously. Please note that every ROP-treating physician has a management algorithm that works best for them and their patients. That being said, this is how the authors’ groups currently recommend using anti-VEGF agents given the presently available data (again, every patient is different, so this is a flexible guideline).
First, anti-VEGF treatment is recommended if laser photocoagulation is not available. Most of the ROP burden is now occurring in middle-income nations, and many hospitals still do not have access to indirect laser systems. Anti-VEGF treatment is certainly better than no treatment.
Second, we consider anti-VEGF treatment if the fovea is not vascularized, and laser treatment would require lasering the fovea. Anti-VEGF treatment usually allows the vasculature to grow through the macula. However, we have shown that the macula does develop to a surprising degree after laser treatment, so you should not be faulted if the presumed area of the fovea needs to be lasered.
Third, anti-VEGF agents work well if there are media opacities that prevent adequate laser application. This includes an intensely dilated tunica vasculosa lentis and neovascularization, and vitreous hemorrhage. However, if there is any suspicion for tractional membranes or retinal detachment, or if the vitreous hemorrhage is too dense for an accurate examination, we would proceed with pars plicata vitrectomy.
Fourth, anti-VEGF is indicated if the infant cannot medically tolerate laser photocoagulation. The sickest infants may not be able to tolerate general anesthesia and/or may become hemodynamically unstable with laser application. In these instances, which are not rare in this patient population, the quick intravitreal injection may be the best option. The least stable infants may be a poor choice for anti-VEGF treatment, however, as they theoretically have the greatest risk from systemic suppression of circulating VEGF. In particular, the risk of worsening their bronchopulmonary dysplasia should be discussed with the neonatologist and parents prior to any treatment.
Fifth, we consider anti-VEGF treatment only if reliable follow-up is possible. If the family cannot commit to close observation for any reason, laser photocoagulation is preferred.
Finally, we always present the option of laser vs anti-VEGF to the parents, and if the parents prefer anti-VEGF treatment after a balanced informed consent process that discusses all of the points aforementioned, we would offer anti-VEGF monotherapy as a starting point. It is important to discuss what off-label means and check with your malpractice insurance to ensure coverage for anti-VEGF use in infants.
For all other patients, which are the majority, we prefer to treat with laser photocoagulation, due to its proven efficacy, predictable response, and lack of effect on systemic VEGF. Having the peripheral retina lasered makes vitrectomy easier should it become necessary and treats avascular retina which presents a risk for future retinal tears and detachment. Again, these are our personal preferences, and there is no one correct answer at the current time.
There is a lot to learn about anti-VEGF treatment for infants with ROP, and we hope that ongoing clinical trials will provide better evidence.7 For the time being, both laser photocoagulation and anti-VEGF agents play important roles in the treatment of infants with ROP, and it is up to the practitioner to carefully evaluate individual infants to determine the best management plan to maximize outcomes and minimize complications for this vulnerable patient population.
References
1. Quiroz-Mercado H, Martinez-Castellanos MA, Hernandez-Rojas ML, et al. Antiangiogenic therapy with intravitreal bevacizumab for retinopathy of prematurity. Retina. 2008;28(Suppl):S19-25.
2. Lepore D, Quinn GE, Molle F, et al. Intravitreal bevacizumab versus laser treatment in type 1 retinopathy of prematurity: report on fluorescein angiographic findings. Ophthalmology. 2014;121(11):2212-2219.
3. Geloneck MM, Chuang AZ, Clark WL, et al. Refractive outcomes following bevacizumab monotherapy compared with conventional laser treatment: a randomized clinical trial. JAMA Ophthalmol. 2014:132(11):1327-1333.
4. Morin J, Luu TM, Superstein R, et al. Neurodevelopmental outcomes following bevacizumab injections for retinopathy of prematurity. Pediatrics. 2016;137(4):e20153218.
5. Wong RK, Hubschman S, Tsui I. Reactivation of retinopathy of prematurity after ranibizumab treatment. Retina. 2015:35(4):675-680.
6. Yonekawa Y, Wu WC, Nitulescu CE, et al. Progressive retinal detachment in infants with retinopathy of prematurity treated with intravitreal bevacizumab or ranibizumab. Retina. 2018;38(6):1079-1083.
7. ClinicalTrials.gov. RAINBOW study: ranibizumab compared with laser therapy for the treatment of infants born prematurely with retinopathy of prematurity. https://clinicaltrials.gov/ct2/show/NCT02375971. Updated March 6, 2018. Accessed April 30, 2018.
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