Bevacizumab as First-Line Therapy for Retinopathy of Prematurity

Systemic Effects Reduced by Limiting Use to a Single Dose

Ron Zimmerman

April 27, 2012

April 27, 2012 (San Antonio, Texas) — Bevacizumab (Avastin), an angiogenesis inhibitor, is being used as an alternative therapy for retinopathy of prematurity (ROP) in some children's hospitals for premature babies.

Results from a study of this off-label use were reported here at the American Association for Pediatric Ophthalmology and Strabismus 38th Annual Meeting.

Helen Mintz-Hittner, MD, from the University of Texas Health Science Center, Houston Medical School, reported that her team found long-term effectiveness and safety with bevacizumab as long as strict protocols were followed, including written parental consent (the drug is not approved for this use by the US Food and Drug Administration), completely sterile conditions, and administration by trained ophthalmologists.

"There's basically cryotherapy, an aggressive treatment that destroys the anterior portion of the retina. There's laser therapy, which is much less destructive but still destructive. And then there's bevacizumab, where you inject the antibody to VEGF [vascular endothelial growth factor] and you actually get growth of the vessels forward," explained Dr. Mintz-Hittner.

She displayed a timeline of the pathogenesis of ROP, which progressively develops after an infant's premature birth. "You have to recognize the stages of ROP," she said. "In the embryologic state, oxygen and VEGF are in great balance. When premature birth occurs and too much oxygen is supplied to the retina, VEGF goes down. As the eye grows, the retina grows and the edge portion becomes hypoxic. In phase 2, the oxygen in the retina goes down and VEGF rises; that's what causes neovascularization and leads to stage 2 or stage 3 disease. That's our 'go' point [for injecting bevacizumab], where oxygen is not a factor and disease is already here."

At Dr. Mintz-Hittner's hospital, they perform a single injection of one half the adult dose of bevacizumab, using a 0.3 mL diabetic syringe with a 31-gauge, 5/16-inch long needle, about 2 mm back from the limbus, angled toward the optic nerve to avoid hitting the lens.

She presented preliminary results from the Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) trial of 150 infants (143 survivors). In patients with zone 1 ROP, 64 received treatment; 31 were treated with bevacizumab and 33 with laser therapy.

Ocular outcomes were compared at 6 months. Recurrence of ROP was seen in only 2 patients in the bevacizumab group (6%) and in 23 in the laser group (42%; P = .003).

According to Dr. Mintz-Hittner, timing is critical. "We recommend that you not even consider using this drug as a prophylactic.... It's a therapeutic drug."

"A lot of what you're reading in the literature about bad results is treating too early — where you don't have stage 3 disease or if VEGF is actually down and you're decreasing it further, leading to severe retinal dystrophy. If you give it too late, you get accelerated retinal detachment," she noted.

"You should not be giving it before 31 weeks...[and] you shouldn't give it once there are significant tractional elements indicating that you're going to get accelerated retinal detachment."

There are advantages to bevacizumab therapy: reintubation is prevented, exposure to anesthesia is reduced, hospital stay is shorter, the risk for destruction of the peripheral retina is reduced, loss of the visual field is prevented, there are fewer effects on other parts of the eye (such as anterior segment complications and myopia), the advance of ROP is immediately stopped with a single dose, and the risk for progression to stage 3 ROP is reduced.

"It's best to treat type 1 ROP, because that's your ideal standard-of-care time to treat," Dr. Mintz-Hittner said. "But if someone sends you a late case, or if you have [a premature infant] with terrible complications, you can treat very advanced stage 3 until extensive membranes form and still expect good results."

One possible disadvantage is the late recurrence of ROP. "Recurrence occurs 10 weeks later than it appears in laser patients," noted Dr. Mintz-Hittner. However, "you have time to watch and treat it."

Meeting attendee Greg Lear, MD, from St. Louis, Missouri, expressed concern about long-term systemic effects, particularly on the nervous system. Bevacizumab is absorbed into the systemic circulation when the brains of these babies are developing. "How are you going to determine systemic effects in a group of 500 g babies who have a lot of developmental problems to begin with?" he asked.

Dr. Mintz-Hittner acknowledged the controversy, but explained that a single dose limits the systemic effects. "People have been using it all over the world for more than 6 years. In India and Mexico, they have developed mental outcomes but not in randomized trials.... I have one family in which one child got lasered 5 years ago and another child got [bevacizumab] 2 years ago; the parents said: 'I wish my other child could have had this [drug].' The outcome of the laser was not good: one eye is prosthetic and the other eye sees 20/200. One child has thick glasses and a poor field, whereas the other has nothing. They are our testimonial about the 2 techniques and the different outcomes."

David K. Wallace, MD, professor of ophthalmology at Duke University School of Medicine in Durham, North Carolina, raised another issue related to bevacizumab: "Our success rate is really good with laser," he said. "While I think [bevacizumab] is promising, there's still a lot we need to know. We just want to know more of the systemic side effects, the ocular effects, in terms of vascularization, function of the macula, and long-term effects, particularly visual acuity and visual fields and neurodevelopment."

Nils Mungan, MD, from the University of Mississippi Medical Center in Jackson, noted that although he currently only uses laser therapy for his ROP patients, he would use bevacizumab if he had a case with vitreous hemorrhage or poor dilation, or where the vascular zone of the retina included the fovea. But Dr. Mungan is wary about the length of follow-up required. "For conventional laser therapy, after the laser has had a good effect, we follow them for a few weeks. But with [bevacizumab], it's worrisome that neovascularization could reoccur much later — in one case at 22 months of age."

Attendee Ahmed Fahmi, MD, from Khartoum, Sudan, has a unique view of bevacizumab because of his hospital's extremely limited resources and distance from other hospitals. "I'm very much inclined to not use [bevacizumab] because of the controversy over it," he told Medscape Medical News. "It's a difficult choice for me.... I cannot send my patients away to Egypt because I know they do not have the financial capacity, but at the same time I find it very difficult as a doctor to give something that is questionable. What I am doing now is screening patients and sending the high-risk ones to Egypt. Many of them tell me they don't have the money to go, so I am trying to get money for an indirect laser and training for the laser. I think I will use [bevacizumab] in only the most aggressive, most serious ROP as a stopgap before the patients go to Egypt."

"In some foreign countries where they don't have enough ophthalmologists, this could be a godsend," said Dr. Mintz-Hittner. "I don't think it's right — when you have a zone 1 that's aggressive and not going to do well — for you to not to even offer this. No one has ever shown any effect systemically at all.... So we have a known beneficial effect and a proposed — a "maybe" — systemic side effect. In really significant diseases with the really significant morbidity of total blindness, you need to weigh the risk/benefit. If I was going to have a totally blind child," she emphasized, "it would have to be some awful complication before I would turn this drug down."

Dr. Mintz-Hittner, Dr. Lear, Dr. Mungan, and Dr. Fahmi have disclosed no relevant financial relationships. Dr. Wallace reports being a consultant for Allergan, receiving honoraria from Alcon, and receiving grant support from the National Eye Institute and Research to Prevent Blindness.

American Association for Pediatric Ophthalmology and Strabismus (AAPOS) 38th Annual Meeting: Abstract 127. Presented March 26, 2012.

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