Anti-VEGF for ROP may still be in its infancy

Take-home

Laser remains the standard treatment for infants with retinopathy of prematurity. The safety and efficacy of anti-vascular endothelial growth factor drugs for treating the disease have not been investigated.

By Lynda Charters; Reviewed by Michael T. Trese, MD

Royal Oak, MI-Use of anti-vascular endothelial growth factor (VEGF) drugs may not be ready for prime time in the treatment of retinopathy of prematurity (ROP), related one ophthalmologist.

Laser remains the standard treatment for infants with ROP because the safety and efficacy of anti-VEGF drugs for treating the disease have not been investigated, said Michael T. Trese, MD, chief, pediatric and adult vitreoretinal surgery, Beaumont Eye Institute, William Beaumont Hospital, Royal Oak, MI.

Dr. Trese discussed the current status of the use of anti-VEGF drugs in this patient population.

BEAT-ROP

The results from the Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) study (N Engl J Med. 2011;364:603-615) showed that there was no difference between laser and anti-VEGF drugs for treating zone 2 disease. However, the results showed a significant difference between laser and bevacizumab (Avastin, Genentech) for treating zone 1 ROP, with bevacizumab having greater efficacy.

The difference in efficacy stemmed from the fact that two-thirds of study patients were Hispanic with a more difficult type of ROP to treat. The laser failure rate for zone 1 disease was 42%, as defined by the study. This raised a question about the significance of the results if other treatment failure rates were used, Dr. Trese noted.

The results of three other studies of laser for treating zone 1 ROP, according to Dr. Trese, would not have shown statistical significance between laser and anti-VEGF therapy.

Another question concerns the safety of anti-VEGF drugs for ROP. Seven infants in the BEAT-ROP study died: five in the bevacizumab group and two in the laser group. While the difference between the two did not reach significance, it raises some concern, according to Dr. Trese.

The editorial that accompanied the BEAT-ROP study in the New England Journal of Medicine noted that bevacizumab could reasonably be presumed to be safe.

However, there have been other instances in which therapies were adopted based on only short-term results without appropriate studies, Dr. Trese noted. For example, uncontrolled oxygen administration that resulted in the first ROP epidemic; interferon therapy for capillary hemangiomas that resulted in spastic diplegia; and post-natal steroids to wean infants off the ventilator that 10 years later resulted in cerebral palsy.

Intravitreally administered bevacizumab escapes into the systemic circulation. While the vitreous half-life of ranibizumab (Lucentis, Genentech) and bevacizumab are very similar, the peak plasma concentration of bevacizumab is much higher than that of ranibizumab (20 to 687 ng/ml versus 0.79 to 2.9 ng/ml, respectively), and it remains in the circulation for significantly longer (half-life, 20 days versus 0.09 days, respectively).

Another factor is that VEGF is necessary to normal infant development.

“VEGF regulates normal angiogenesis in many organs,” Dr. Trese said. “In the central nervous system, it is neurotropic, neuroprotective, and maintains the blood-brain barrier. In the lungs, VEGF has an important role in alveolization, and it has key roles in bone growth and cardiac and kidney development.”

Other safety issues include the absence of safety studies to determine the lowest effective dose of anti-VEGF drugs in ROP. Ranibizumab also remains in the general circulation but for a much shorter time than bevacizumab.

“All use of anti-VEGF drugs for ROP or in infants and children is off-label and requires appropriate documentation and consent,” he said. “The FDA is currently looking at more rigorous testing of drugs for use in neonates and children.”

A problem is that in future studies, assessing the real risk involved in treating premature infants with anti-VEGF drugs may be impossible.

BLOCK-ROP

However, using a low dose of a drug with a shorter half-life may be a better choice. Genentech and the Pan-VEGF Blockade for the Treatment of Retinopathy of Prematurity (BLOCK-ROP) study group are investigating the potential for a cooperative study group to determine the lowest dose and the safest drug to use in these children.

An anti-VEGF drug does have value for treating children with ROP when no laser is available, Dr. Trese noted.

“If a laser is available-and the doctor knows how to perform the appropriate laser treatment, and the population includes fewer children who are Hispanic-I believe that laser is unquestionably safer for the infants,” he said.

In addition, Dr. Trese explained, use of anti-VEGF therapy negatively affects ROP by changing it from a disease with a predictable course and a finite follow-up period to one with an indefinite follow-up period that can lead to very late retinal detachment. This makes the physician examination and the parental cooperation difficult when follow-up is need for 6 months or longer.

“Anti-VEGF therapy . . . will most likely have a role in ROP management, but until convincing safety data are available, the right drug and the right dose remain in question,” Dr. Trese said. “In my opinion, laser is still the standard primary therapy for ROP in most populations.”

Michael T. Trese, MD

E: mgjt46@aol.com

Dr. Trese is a consultant for Genentech. This article is adapted from Dr. Trese’s presentation during Retina 2012 at the annual meeting of the American Academy of Ophthalmology.