Caroline Helwick

November 19, 2012

CHICAGO, Illinois — Intravitreal bevacizumab is effective for severe or threshold retinopathy of prematurity (ROP) and ocular complications, and consequences are rare, according to a 6-year follow-up of infants treated at a center in India.

The findings from a study of intravitreal bevacizumab in 137 eyes were presented by Alay S. Banker, MD, from Banker's Retina Clinic and Laser Centre in Ahmedabad, India, here at the American Academy of Ophthalmology 2012 Annual Meeting.

"Ever since the landmark study by the BEAT-ROP [Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity] Cooperative Group (N Engl J Med. 2011;364:603-615), there has been a lot of interest in anti-VEGF [vascular endothelial growth-factor] treatment for ROP; however, there are many unanswered questions with regard to indications, dose, timing of treatment, and long-term ocular and systemic adverse effects," Dr. Banker explained.

A recent study demonstrated that after a single injection of bevacizumab, serum levels of the drug increased and were maintained for 2 weeks or longer; this corresponded to a reduction in serum VEGF (Am J Ophthalmol. 2012153:327-333.e1), Dr. Banker reported.

"The concern is that we don't know the implications of this, especially on the development of the heart, lungs, and brains of infants," he said.

Dr. Banker and colleagues, therefore, conducted a 6-year follow-up of their patients treated with bevacizumab 0.625 mg without laser. The mean birth weight was 1533 g (range, 820 - 1900 g), indicating that the population was considerably larger than infants treated for ROP in Western countries. Mean gestational age was 29.2 weeks and mean age at injection was 1.6 months.

The purpose was to evaluate anatomic outcomes (regression of ROP), functional outcomes (using electroretinography and visual evoked potential), systemic and ocular adverse effects, effect on neurodevelopment (pediatric-neurologist assessed developmental-quotient score), and structural changes in the macula on optical coherence tomography.

Follow-up was rigorous, he noted. Patients were seen weekly for the first month, monthly for 1 year, every 3 months for 2 years, and then every 6 months out to 6 years.

Excellent Outcomes Reported

Neovascular and plus disease completely resolved after 1 injection in all but 2 eyes, which needed 1 more injection. Functional evaluation (electroretinography with dark and light adaptation) was completely normal for all subjects, and no macular structural changes were observed on optical coherence tomography.

On neurodevelopmental analysis, there were no differences between the study population and the norms for the domains of personal social age, motor adaptive skills, gross motor skills, and language. "Compared with normal babies, all scores were within normal values for 163 different neurodevelopmental aspects," Dr. Banker reported.

Ocular and Systemic Adverse Effects

No concerning ocular or systemic adverse effects were observed with intravitreal bevacizumab injections.

Among the 137 eyes, 17 (12.4%) had local adverse events, 8 (5.8%) had self-resolving subconjunctival hemorrhage, 6 (4.4%) had persistent peripheral avascular retina, 2 (1.46%) had transient vitreous hemorrhage, 2 (1.46%) had peripheral fibrous avascular membrane, and 2 (1.46%) had late recurrences (which resolved after a second injection).

Patients with ongoing issues are being closely followed, he noted.

"We feel that intravitreal bevacizumab has a role in threshold ROP, particularly for more aggressive posterior disease, and particularly in our part of the world where ROP develops in larger babies," he said.

"Ocular complications are rare but they are very important, especially late recurrences. Since the long-term systemic effects are still unknown, close follow-up is absolutely critical. If you can't follow these babies, we do not recommend this treatment," he emphasized. "Until more research is done, laser remains the gold standard."

Remaining Questions and Concerns

Michael F. Chiang, MD, professor of pediatrics and ophthalmology at the Oregon Health and Science University in Portland, explained that it is "useful to have studies like this with such long follow-up."

He indicated that although the effectiveness of bevacizumab for ROP has been established, the possibility of late recurrences remains a concern. "I think it's interesting that you are barely seeing any of these," he told Dr. Banker.

The other concern, he added, is the possibility of systemic adverse effects. He was pleased to see there were no neurodevelopmental issues with the children in the study, but pointed out that "this does not answer what is happening to the heart, lungs, and so forth."

"Because this is not a randomized trial, we can't say whether bevacizumab works better than laser.... [However], published studies suggest the laser complication rate is higher, since you essentially saw close to zero here." Dr. Chiang explained.

Finally, he questioned whether the disease that Dr. Banker's team studied "is the same disease as I see" (i.e., which may be more oxygen-induced and occurs in infants 600 to 700 g and 24 to 25 weeks of gestational age). "Do your findings extrapolate to my population? We don't know yet," he said. "More work is needed."

Dr. Banker and Dr. Chiang have disclosed no relevant financial relationships.

American Academy of Ophthalmology (AAO) 2012 Annual Meeting: Abstract PA084. Presented November 13, 2012.