Round table: Pediatric ophthalmologists tackle question of when and how to use anti-VEGF in ROP

In this round table conducted at the 2012 AAPOS meeting, members of the OSN Pediatrics/Strabismus Section consider treatment with bevacizumab in retinopathy of prematurity.

Issue: October 25, 2012

Robert S. Gold, MD: Let’s talk about the hot topic of Avastin (bevacizumab, Genentech) for retinopathy of prematurity. The key question is, when to use it and how often?

Robert S. Gold

R.V. Paul Chan, MD: Helen Mintz-Hittner’s BEAT-ROP study stimulated a lot of conversation. Now many people view intravitreal anti-VEGF as an added treatment modality, but I think it is going to be some time until there is a consensus agreement considering it standard of care.

I think that anti-VEGF therapy does have a role. We know historically over the past 6 to 8 years that it works. We just do not have all the information regarding adverse events; we do not have the large prospective controlled trial.

Although there is a significant amount of controversy regarding its use, in my opinion, intravitreal anti-VEGF has a place for the treatment of ROP. I would consider using Avastin for cases of treatment requiring ROP in zone 1, when the laser fails, when there is significant progression or recurrence, or when there is a poor view because of neovascularization. What we do know is that when you inject Avastin, the neovascularization goes away very quickly — in many cases, within a day.

R.V. Paul Chan

For the retina surgeon, it is also an adjunct for surgery. But we have to be very careful about when we time the surgery after injection because the complication that can occur is ROP “crunch,” where the retina detachment progresses rapidly.

Kenneth P. Cheng, MD: A paper presented by a group in Italy that did fluorescein angiography in these patients showed quite strikingly that patients injected with Avastin had seemingly permanent changes to the choroid and the choroid was not developing appropriately within the presumed macular region. In contrast, patients who had laser ended up doing OK. Clearly the need for a randomized clinical trial is huge. Are we just kicking the ball down the road with a future development of familial exudative vitreoretinopathy type patients? I do not think anybody can answer that question until there is a clinical trial.

Kenneth P. Cheng

M. Edward Wilson, MD: We had an announcement from one of our private commercial payers in our area that they would no longer pay for Avastin in ROP because it was “unproven.” Is that becoming an issue in your area?

M. Edward Wilson

Chan: I have not run across that. I have injected a number of patients, and we have not had an issue with commercial payers even if the Avastin is being used off label.

The payer and the cost issues are interesting. I think many of us feel that Avastin would cost less than laser, but does it really? If you have a global period after laser treatment, every exam after that laser is not billable for a period of time. For an intravitreal injection, however, there is not a global period. And in cases of ROP post-treatment with Avastin, when you are uptight and worried about normal vascularization or recurrence, you may potentially be following these children weekly. If you use fluorescein angiography to assess the peripheral avascular area, that also incurs a cost. The number of follow-up exams can be substantial after Avastin injection for ROP.

Wilson: We need them to recognize that the physician has to have some discretion here. This is a new treatment that may, in the long run, save costs.

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Roberto Warman, MD: What we need to look into now is whether Avastin is the right anti-VEGF treatment. It has a bigger molecule. It lasts much longer than not only Lucentis (ranibizumab, Genentech) but also Eylea (aflibercept, Regeneron), which is probably the shortest lasting. We need to evaluate. Yes, Avastin is cheaper and it was good that we started with that, but this is just a new avenue. We also need to clarify the systemic effects. Even so, in posterior zone 1, thank goodness we have it.

Roberto Warman

Chan: We now have all of these different anti-VEGF agents for intraocular use. Pegaptanib (Macugen, Valeant Pharmaceuticals), ranibizumab, bevacizumab — all of these have been used and reported on for the treatment of ROP. We also now use aflibercept in wet age-related macular degeneration. However, all of these options raise the question of what drug is best for ROP. And is intravitreal injection the best method for delivery of anti-VEGF therapy in these children?

Gold: I am glad to see that there is more of a delineation as to when to use it. There are people around the country who would use this in any case instead of laser. The discussion that has gone on over the past year has more delineated that this treatment would be used in zone 1 disease. I do not want every child with zone 3 or zone 2 disease to have that kind of a medication when we still do not know what is going to happen with it.

Cheng: There is no established standard of care for zone 1 disease other than early laser. But to expect that Avastin at this point in time should strongly be considered for any individual child is outside of the box. These are heroic measures at this point still.

Rudolph S. Wagner, MD: One major concern has been with the systemic absorption and the possibility of side effects. In the American Journal of Ophthalmology, a study from Osaka, Japan, found systemic absorption and depression of VEGF in the systemic circulation. What that means, no one really knows. You have to follow the child for a long time to monitor renal and pulmonary development. That is one of the concerns. Perhaps one of these other molecules will not have the systemic absorption issue. Many people will not use Avastin for that reason.

Rudolph Wagner

The other thing I want to mention is that I have had the opportunity to follow a few patients who have been treated with Avastin, and the impression that I have is that they remain hyperopic or do not become as myopic as is expected. So if medication was ideal and safe, that could be a consideration in the future with regard to management. The development of significant myopia is a major concern in children treated with laser for ROP.

Chan: There is 5- or 6-year data on a cohort from Dr. Maria Ana Martinez-Castellanos and Dr. Hugo Quiroz-Mercado in Mexico. It is a small cohort and the infants there may actually be heavier and a little older when they get an injection, but we do have that information.

The reality for us is that pharmacotherapy for treatment of ROP is here, and I do not think it is going away. The question now is: What is going to be standard of care?

References:

Martinez-Castellanos MA, Schwartz S, Hernandez-Rojas M, et al. Long term effect of antiangiogenic therapy for retinopathy of prematurity: Up to 5 years of follow-up. Retina. In press.
Mintz-Hittner, Kennedy KA, Chuang AZ; BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011;364(7):603-615
Quiram PA, Drenser KA, Lai MM, Capone A Jr, Trese MT. Treatment of vascularly active familial exudative vitreoretinopathy with pegaptanib sodium (Macugen). Retina. 2008;28(3 Suppl):S8-S12
Sato T, Wada K, Arahori H, et al. Serum concentrations of bevacizumab (Avastin) and vascular endothelial growth factor in infants with retinopathy of prematurity. Am J Ophthalmol. 2012;153(2):327-333.

For more information:

R.V. Paul Chan, MD, can be reached at New York-Presbyterian Hospital, Weill Cornell Medical College, 1305 York Ave., 11th Floor, New York, NY 10021; 646-962-2540; fax: 646-962-0609; email: roc9013@med.cornell.edu.
Kenneth P. Cheng, MD, can be reached at 1000 Stonewood Drive, Suite 310, Wexford, PA 15090; 724-934-3333; email: kpchengmd@me.com.
Robert S. Gold, MD, can be reached at 790 Concourse Parkway South, Suite 200, Maitland, FL 32751; 407-767-6411; fax: 407- 767-8160; email: rsgeye@gmail.com.
Rudolph S. Wagner, MD, can be reached at Doctors Office Center, Suite 6100, P.O. Box 1709, Newark, NJ 07101; 973-972-2065; email: wagdoc@comcast.net.
Roberto Warman, MD, can be reached at Miami Children’s Hospital, 3200 SW 60th Court, Suite 103, Miami, FL 33155-4072; 305-662-8390; fax: 305-661-7862; email: rwarman@eyes4kids.com.
M. Edward Wilson, MD, can be reached at Albert Florens Storm Eye Institute, 167 Ashley Ave., Charleston, SC 29425; 843-792-1414; email: wilsonme@musc.edu.

Disclosures: Chan, Cheng, Gold, Wagner, Warman and Wilson have no relevant financial disclosures.