Use of anti-VEGFs in ROP still a concern for organogenesis, neurodevelopment

There may be a rationale for using anti-VEGFs in cases of severe retinopathy of prematurity to prevent neovascularization, but concerns exist about the possible detrimental effects of VEGF suppression on the organogenesis and neurodevelopment of preterm infants.

A study published earlier this year in JAMA Ophthalmology showed that Avastin (bevacizumab, Genentech) remained in the systemic circulation for as long as 8 weeks after intravitreal injection and that VEGF expression was inhibited for that time. And the same authors showed in a 2-year retrospective study, unpublished but presented at the American Society of Retina Specialists meeting in Vienna, that patients treated with intravitreal bevacizumab and laser had a higher incidence of significant mental (P = .028) and psychomotor (P = .002) impairment at 24 months than patients treated with laser alone.

“Though further and larger studies are needed, our findings highlight the need for caution,” Wei-Chi Wu, MD, PhD, professor of ophthalmology at Chang Gung Memorial Hospital, Taoyuan, Taiwan, said.

In the same study, a group of patients treated with anti-VEGF alone did not show a significant difference in neurodevelopment compared with patients treated with laser alone.

According to Wu and co-authors, destruction of the blood-retinal barrier by laser photocoagulation may result in a higher level of anti-VEGF leakage in the systemic circulation.

“We also had a higher incidence of zone 1 ROP in this group, and it is likely that patients with zone 1 ROP have a less mature avascular retina, which may also cause more anti-VEGF leakage into the systemic circulation,” he said. “On the other hand, these babies had worse systemic conditions prior to treatment, a lower birthweight and probably more immature systemic organs, which may be another explanation for the worse outcomes.”

Currently, Wu and his group are conducting a further follow-up study of these patients, testing vision outcomes and neurodevelopment up to the age of 3 years to 5 years. This information will be important to assess the long-term safety of anti-VEGFs in the treatment of ROP, he said.

Image: Chan RVP

A lack of scientific data

The absence of long-term data pertaining to adverse events, both locally and systemically, remains one of the biggest concerns that exists among physicians and neonatologists when considering anti-VEGF treatment in ROP.

“One major issue is that we have to follow these children more frequently and for longer periods of time in order to make sure that, one, if there is recurrence we treat it appropriately, and two, that the normal vascularization actually occurs,” OSN Pediatrics/Strabismus Board Member R.V. Paul Chan, MD, said. “We still don’t know how long it is going to take every child with ROP, who was treated with intravitreal anti-VEGF therapy, to have full vascular development of the retina.”

Regarding the study presented by Wu, Antonio Capone Jr., MD, professor of biomedical sciences at Oakland University, Michigan, and professor at the European School for Advanced Studies in Ophthalmology, Lugano, Switzerland, said that “short of any randomized prospective multicenter study, this is the best sort of data we have at present.” He said he trusts Wu, formerly his fellow, to produce even more interesting follow-up data.

“These patients are exquisitely susceptible given their profound prematurity and small size. We have evidence from animal models as well as in humans that even small doses of anti-VEGF drugs given into the eye have a profound effect with regard to suppressing systemic VEGF levels, and the systemic VEGF is very important for organogenesis and neurodevelopment,” Capone said.

The BEAT-ROP study was the only prospective, randomized, multicenter clinical trial to evaluate anti-VEGF therapy in comparison with conventional laser therapy in infants with stage 3+ ROP. A statistically significant greater efficacy of anti-VEGF therapy compared with laser was found for zone 1 disease, but the trial was “too small to assess safety,” the authors said.

“On one hand, the studies done to date have not demonstrated a prominent and profound impact of giving anti-VEGF agents to infants. On the other hand, the background noise — all the morbidities these children are vulnerable to at baseline because of their profound prematurity — makes it so that a systemic impact of an anti-VEGF may be hard to discern,” Capone said.

“These extremely premature children without being treated with an anti-VEGF agent are still at risk for developing neurological issues and other issues systemically simply because of the sequelae of profound prematurity, so to control for that in any study is very challenging. You would need a significant number of children in the study. You need good data, and you need a good study design,” Chan said.

Given the high morbidity of these infants, Birgit Lorenz, MD, PhD, professor and chair of the department of ophthalmology at Justus-Liebig-University, Giessen, Germany, estimated that a prospective study on at least 1,000 infants would be needed to really evaluate the impact.

“There are some preliminary data; some say there is no difference, others say there may be, but with small numbers, you cannot draw any precise conclusion,” she said.

Advantages of anti-VEGF treatment

The biggest advantage of anti-VEGF treatment is that, in contrast to laser photocoagulation, it preserves the peripheral retina.

“Laser destroys a large area of peripheral retina, leading to incomplete vascularization and complications such as high refractive error, decreased visual field, high incidence of strabismus and also poor development of the foveal depression. It has good treatment outcomes, but it is not optimal,” Wu said.

There is also a certain fail rate associated with laser treatment in very aggressive cases, according to Chan.

“For aggressive posterior ROP or for cases of zone 1 disease, it’s been reported that laser may not always be effective,” he said. “So, you’re not guaranteed 100% success, and therefore it’s important to have other treatment options.”

Anti-VEGF is a much easier and faster treatment, but this should not influence decision making if there is a higher risk for adverse effects that, at present, may still be undetected, Lorenz said.

One can also argue that the procedure does not require as much skill, “meaning that you don’t necessarily have to be an expert at indirect ophthalmoscopy or indirect laser to treat these children,” Chan said.

From the physician’s perspective, laser can be a difficult, stressful technique that may require up to 2,000 laser exposures per eye, performed by indirect ophthalmoscopy. In addition, it may require prolonged general anesthesia, for at least 1 hour but more likely 2 hours, and involves cooperation with the neonatologist and the anesthesiologist.

With that, considering the child’s well-being at the time is also essential in determining treatment.

“If you have a very unstable child who can’t tolerate a long laser procedure, being able to provide an effective treatment that won’t cause additional stress to the neonate would be a good option,” Chan said.

“The ease of application of an anti-VEGF injection is quite evident. It is fast and easy and is normally done under topical anesthesia. This should not be the reason to do the treatment, but it is, theoretically, the advantage,” Lorenz said.

“There are many complications that can occur with intravitreal injections. Nonetheless, it takes considerably less time and is less systemically distressful to the child from the procedure perspective. That’s one significant advantage,” Capone said.

A neonatologist’s perspective

Brian A. Darlow, MD, is a neonatologist and Cure Kids chair of pediatrics at the University of Otago, New Zealand. In his publications, as well as in an interview with Ocular Surgery News, he said that although laser might have drawbacks, his biggest concerns are with anti-VEGFs.

“There are many examples in neonatology of widely used therapies that seemed a good idea initially. The first was giving oxygen to healthy preterm babies. It caused retinopathy of prematurity, but it took 10 years to make that connection. A very common one is postnatal steroids. Not so long ago, every baby still on a ventilator at 2 weeks was given a dose of postnatal steroids. It seemed to be magic, they came off the ventilator, and it took us a very long time to prove that it also caused severe brain damage,” he said.

Proper studies are needed because the BEAT-ROP was “very poorly designed,” in his opinion.

“The real problem was that the editorial of the New England Journal of Medicine, which accompanied the publication of the study, suggested that anti-VEGF should be the standard of care. I objected to it; many of us wrote letters,” he said.

The International Network for Evaluation of Outcomes, an international cooperation of eight national neonatal networks, is currently producing a large database of both anti-VEGF-treated and laser-treated cases. This will provide some information, but not the scientific evidence that only a randomized, controlled trial can give, Darlow said.

He said there is concern about ophthalmologists injecting anti-VEGFs in infants.

“There is a wealth of evidence that it does escape the eye. VEGF has been described as the Swiss army knife of growth factors: It does everything. There’s a huge number of actions it takes around the body quite apart from what is going on in the eye, and if you reduce the level of it, it has the potential to cause problems,” he said.

When anti-VEGF drugs are used, patients should be followed for a long time, but this is not often the case, he said.

Personal choices

In the absence of guidelines and specific indications based on sound scientific evidence, the choice between laser and anti-VEGFs is largely personal.

“It would be better for the physicians to be able to use both treatment modalities for different scenarios of patients. Anyway, two weapons at hand are better than one,” Wu said.

He said that both treatments have drawbacks and advantages, and there are cases in which the benefits of anti-VEGF are worth the potential risks, such as posterior zone 1 or aggressive posterior ROP.

“In these cases, you allow the vessels to grow more naturally. I recommend a single injection, and in case of recurrence, you can use the laser. By that time, you’ll have more vascular retina,” Wu said.

“If my kid had zone 1 ROP, this is the treatment I would use,” he said. “If I were not prepared to use it on my own child, I would not do it in other kids either.”

According to Lorenz, anti-VEGF should not be used in cases in which laser is expected to be 99% successful.

“We use it in cases where we know that prognosis with laser is not good by experience, [such as] very severe cases like zone 1 ROP where success with laser in several studies is only about 60%. For me, also the speed of progression is important,” she said, noting that she may use anti-VEGF in posterior zone 2 when there is rapid progression, such as aggressive posterior ROP.

Capone said he considers anti-VEGF a meaningful option in children whose retinal vascular development is so immature that they have not truly vascularized the center of vision.

“If you stop the ROP with the laser, you would have taken away so much of the retina that you might win the battle against the ROP but lose the war to save vision,” he said.

Chan added that the decision between treatment options is not only patient-specific but, at large, a discussion to be held with the family. Typically, he recommends discussing laser treatment first but will consider anti-VEGF treatment under certain circumstances.

“In very posterior cases or cases that seem to be very aggressive, I will consider using anti-VEGF treatment,” he said. “And I say consider it because it’s always a discussion you have to have with the patient’s parents. I think that it’s always prudent to discuss laser as a first-line treatment and then talk about the advantages and so forth of anti-VEGF treatment with the family at that time.”

Dosage

In several ways, anti-VEGF treatment is still navigating uncharted waters in ROP. There is no clearly defined management protocol, the length of follow-up is undefined, recurrences are unpredictable, and the ideal dose has not yet been established. Dosage is a key issue, with obvious repercussions on safety.

“We don’t know what the ideal dose is for a child for ROP. We are empirically choosing doses based on the experience we have in adults,” Capone said.

“The most frequent dosage used is half of the dose injected unilaterally in adults with AMD or DME. Babies usually have bilateral disease, so they get the same dose of an adult and their weight is in the order of 1,200 g to 1,500 g,” Lorenz said.

Her study with a quarter of the dosage showed results comparable to those of the BEAT-ROP and other studies. However, aggressive posterior ROP may need a higher dosage.

“Further research is underway. We are comparing different dosages and other anti-VEGF molecules with different time of systemic VEGF suppression,” she said.

“There is evidence now that, while high doses of anti-VEGF inhibit both angiogenesis and vasculogenesis, lower doses might just target angiogenesis, the abnormal blood vessel formation,” Capone said. “This suggests that we could possibly get a positive therapeutic effect at much lower doses, overcoming most of the safety concerns in babies.”

Future studies

The upcoming RAINBOW study will compare Lucentis (ranibizumab, Genentech) with laser therapy for the treatment of infants with ROP. The phase 3 interventional study has not yet opened for participant recruitment, but it is estimated to enroll approximately 300 participants and be completed by July 2017.

“We would like to see a multicenter prospective study with a good study design looking at laser vs. anti-VEGF treatment for ROP. That still has to be done on a larger scale,” Chan said.

Chan also said that future studies should look at which anti-VEGF drug is safer and more effective as well as which dose works best for ROP treatment.

“All in all, looking at very clear, systemic outcomes with neonatologists and pediatricians involved in the study design,” he said.

Because laser and cryotherapy were historically the treatments of choice for ROP, Chan said he thinks the additional option of anti-VEGF treatment changes the way physicians have to think about managing premature infants with treatment-requiring ROP.

“I think that most people would agree that anti-VEGF treatment works in terms of causing active disease to regress,” he said. “And I think that having the option of anti-VEGF therapy adds to our ability to manage children with ROP. But again, we need to proceed with caution. We have to be thoughtful about which treatment option we choose and be very patient-selective.” – by Michela Cimberle and Kristie L. Kahl

• References:
• Darlow BA. J Paediatr Child Health. 2015;doi:10.1111/jpc.12860.
• Darlow BA, et al. Arch Dis Child Fetal Neonatal Ed. 2013;doi:10.1136/archdischild-2011-301148.
• Geloneck MM, et al. JAMA Ophthalmol. 2014;doi:10.1001/jamaophthalmol.2014.2772.
• Hong YR, et al. Retina. 2015;doi:10.1097/IAE.0000000000000535.
• Klufas MA, et al. J Pediatr Ophthalmol Strabismus. 2015;doi:10.3928/01913913-20150216-01.
• Lorenz B, et al. Expert Rev Ophthalmol. 2015;doi:10.1586/17469899.2015.1007128.
• Lutty GA, et al. Invest Ophthalmol Vis Sci. 2011;doi:10.1167/iovs.10-6798.
• 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.
• RAINBOW Study: Ranibizumab compared with laser therapy for the treatment of infants born prematurely with retinopathy of prematurity. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/study/NCT02375971. Updated June 2015.
• Sonmez K, et al. Ophthalmology. 2008;doi:10.1016/j.ophtha.2007.08.050.
• Wu WC, et al. Am J Ophthalmol. 2013;doi:10.1016/j.ajo.2012.06.010.
• Wu WC, et al. JAMA Ophthalmol. 2015;doi:10.1001/jamaophthalmol.2014.5373.

• For more information:
• Antonio Capone Jr., MD, can be reached at Associated Retinal Consultants, 344 William Beaumont Medical Building, 3535 W. Thirteen Mile Road, Suite 344, Royal Oak, MI 48073; email: acaponejr@yahoo.com.
• R.V. Paul Chan, MD, can be reached at Illinois Eye and Ear Infirmary, University of Illinois at Chicago, 1855 W. Taylor St., Chicago, IL 60612; email: rvpchan@uic.edu.
• Brian A. Darlow, MD, can be reached at Department of Paediatrics, University of Otago, Christchurch, P.O. Box 4345, Christchurch 8140, New Zealand; email: brian.darlow@otago.ac.nz.
• Birgit Lorenz, MD, PhD, can be reached at Department of Ophthalmology, Justus-Liebig-University Giessen, Friedrichstrasse 18, 35392 Giessen, Germany; email: birgit.lorenz@uniklinikum-giessen.de.
• Wei-Chi Wu, MD, PhD, can be reached at Department of Ophthalmology, Chang Gung Memorial Hospital. No. 5, Fu-Hsing Street, Kweishan, Taoyuan, 333, Taiwan; email: weichi666@gmail.com.

Disclosures: Capone, Chan, Darlow, Lorenz and Wu report no relevant financial disclosures.

How do you manage children who have persistent plus disease or progressive ROP after laser or anti-VEGF treatment?

More information needed on safety, dosage of anti-VEGFs before broad acceptance over laser

In infants with ROP and persistent plus disease, there are several factors to consider for management, including the post-gestational age of the infant, whether laser or anti-VEGF was used, and the presence of vascular (neovascularization) or fibrovascular (vitreous condensation, fibrovascular contraction or thickening of the ridge area) features.

Regarding anti-VEGF treatment, we are still learning from clinical trials, but weekly examinations of infants treated with anti-VEGF may be needed even a year after injection. I will focus my thoughts on laser until we have more information on dose, safety and follow-up from clinical trials with anti-VEGF agents. Of course, in eyes with zone 1, stage 3 and plus disease, anti-VEGF is considered based on the BEAT-ROP study.

In infants less than term (younger than 37 to 40 weeks post-gestational age) with persistent plus and neovascularization, fill in skipped areas and regions in between laser spots with laser and monitor. This is particularly true for infants who had laser at a young post-gestational age. Skipped areas in between laser spots can become more apparent as the infant’s eye grows. In older infants (older than 40 weeks post-gestational age), treat vascular activity with laser. Also be vigilant for fibrovascular activity and early stage 4 ROP, which may be present in the region where plus is present in eyes with asymmetric plus. Progressive stage 4 ROP has been associated with two or more of the following features: two or more quadrants of plus disease, 6 or more clock hours of fibrosis or thickening of the ridge, and fibrovascular condensation over the optic nerve or within the vitreous cavity. Also important are areas of fibrovascular proliferation or vitreous hemorrhage overlying the ridge, even if involving only a clock hour. It is not only important to monitor the ridge area, but also the lasered previous avascular zone where neovascularization can develop and lead to fibrovascular traction. Sometimes plus persists into adulthood and may be monitored in eyes in which laser appears complete or that never developed ROP.

Mary Elizabeth Hartnett, MD, FACS, FARVO, is the director of pediatric retina, University of Utah, John A. Moran Eye Center, Salt Lake City. Disclosure: Hartnett reports no relevant financial disclosures.

Anti-VEGF may be a good option in several cases

Various factors must be considered to decide the next step in the management of progression after treatment for type 1 ROP: type of primary treatment, zone and stage of disease. If there is persistent plus disease and no retinal detachment in an eye treated with laser for zone 2 ROP, treatment of skipped areas should be done. If adequate treatment was given (near confluent spots in all the avascular area), the use of an intravitreal anti-VEGF drug is advisable.

If the eye had zone 1 ROP and was initially treated with laser, the secondary treatment would depend on the zone where the vessels are located. If vessels are still in zone 1, the injection of an intravitreal anti-VEGF drug could be performed. If vessels are in zone 2, more laser should be applied if skipped areas are found.

If there is progression after primary treatment with an anti-VEGF and no retinal detachment is present, the zone where the vessels are located will determine the secondary treatment. If vessels are still in zone 1, a re-injection of anti-VEGF might be performed. If vessels are in zone 2, laser should be applied. It is worth noting that the patterns of regression after the use of anti-VEGFs are distinct and not well known. This should be considered to avoid unnecessary re-treatments.

If progression of the disease produces a retinal detachment, the eye’s vascular activity should be evaluated in order to define the subsequent therapeutic actions.

Vascular activity is a major problem when operating ROP retinal detachment. If there is vascular activity, then the injection of an anti-VEGF 1 week before vitreoretinal surgery is recommended. The vascular regression induced by the anti-VEGF will allow performing the intervention in a quiet eye without the drawback of waiting for the eye to become spontaneously vascularly inactive, which can lead to progression of the detachment.

Andres Kychenthal, MD, is from the Kydoft Foundation, Santiago, Chile. Disclosure: Kychenthal reports no relevant financial disclosures.