Intravitreal anti-VEGF yields significant benefit in treatment of stage 3+ ROP

Intravitreal bevacizumab provided appreciable benefits in treating acute retinopathy of prematurity, a study found.

Drug therapy resulted in a lower recurrence rate than conventional laser treatment. Treatment effect was decidedly superior for zone 1 ROP compared with zone 2 disease, the study authors said.

“The single most significant outcome was that bevacizumab did not allow the disease to recur as frequently as laser,” lead author Helen A. Mintz-Hittner, MD, FACS, told Ocular Surgery News.

Intravitreal Avastin (bevacizumab, Genentech) treatment enabled investigators to avoid damage to the peripheral retina, a risk associated with laser treatment.

“Laser is basically a destructive technique and it destroys the anterior portions of the eye, which is the peripheral field,” Dr. Mintz-Hittner said. “It destroys, especially in the zone 1 cases, the peripheral field and it often induces high myopia.”

The study was published in the New England Journal of Medicine.

Patients and protocol

The prospective, randomized clinical trial included 286 eyes of 143 premature infants with acute ROP stage 3 with plus disease in zone 1 or posterior zone 2. Patients with stages 1 or 2 and 4 or 5 ROP in either eye were excluded. The study was too small to assess safety, the authors said.

Dr. Mintz-Hittner said that intravitreal injection of bevacizumab offers optimal results when administered during stage 3+ ROP, which typically occurs at postconceptual age 31 to 44 weeks and is associated with extra retinal fibrovascular proliferation.

“If you do it in stage 1 or 2, when there really is no neovascularization, it stops the normal development of the retina and you have retinal dystrophy,” she said. “If you do it in stage 4 or 5, when there are already membranes formed and retinal detachment is occurring, it actually accelerates the retinal detachment.”

Investigators randomly assigned 140 eyes to receive intravitreal injections of 0.625 mg bevacizumab in 0.025 mL of solution and 146 eyes to undergo peripheral retinal laser ablation.

Results and conclusions

The recurrence rate for zones 1 and 2 combined was 4% of eyes in the bevacizumab group and 22% of eyes in the laser therapy group (P = 0.002). In the zone 1 group alone, the recurrence rate was 6% of eyes treated with bevacizumab and 42% of eyes treated with laser therapy (P = 0.003).

The treatment effect for zone 2 disease was statistically not significant. Dr. Mintz-Hittner attributed the difference to the low number of recurrences in zone 2 cases included in the study rather than a deficiency in treatment.

“It turns out that because zone 2 cases recur so infrequently, we did not have a large enough sample size to show statistical significance between the two treatment groups in zone 2. The tendency was still in the right direction,” she said.

Future study of a large number of patients with zone 2 ROP may show a statistically significant treatment effect, Dr. Mintz-Hittner said.

Mean time to recurrence of ROP was about 6 weeks after laser therapy but about 16 weeks after intravitreal bevacizumab therapy.

“You have to be watching them closely for a longer time to make sure that if the neovascularization comes back, you’re there to give another injection,” Dr. Mintz-Hittner said.

Conventional laser therapy caused permanent destruction of vessels in the peripheral retina, while intravitreal bevacizumab allowed further vessel growth into the peripheral retina.

Additional benefits

Intravitreal bevacizumab is less expensive than laser treatment and can be performed at the bedside in 2 or 3 minutes, whereas laser treatment takes up to 2 hours, requires expensive equipment and must be performed in an operating room specially equipped for laser surgery, Dr. Mintz-Hittner said.

Bevacizumab, which is approved by the U.S. Food and Drug Administration for the treatment of metastatic colon cancer, currently is used off-label for ophthalmic indications such as age-related macular degeneration and diabetic retinopathy. Use in ROP is just beginning.

At about $40 per treatment, bevacizumab is more cost-effective than Lucentis (ranibizumab, Genentech), which costs about $2,000 per treatment, Dr. Mintz-Hittner said.

In addition, the bevacizumab molecule escapes the eye less by virtue of being three times larger than the ranibizumab molecule, she said.

“We don’t want to use Lucentis, not only because of expense but because we don’t want the smaller molecule being injected,” she said.

Parents should be asked to sign consent forms acknowledging that bevacizumab is not approved by the FDA for ROP and that long-term safety has not been established in preterm infants, Dr. Mintz-Hittner said.

“Physicians should put protocols for compassionate use of bevacizumab for ROP through their hospital institutional review board,” she said. – by Matt Hasson

Reference:

• Mintz-Hittner HA, Kennedy KA, Chuang AZ. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011;364(7):603-615.

• Helen A. Mintz-Hittner, MD, FACS, can be reached at Robert Cizik Eye Clinic, 6400 Fannin St., Suite 1800, Houston, TX 77030; 713-559-5277; fax: 713-559-5290; email: helen.a.mintz-hittner@uth.tmc.edu.
• Disclosure: Dr. Mintz-Hittner receives honoraria from the Bascom Palmer Eye Institute and Clarity Medical Systems, and has travel expenses paid by Pediatrix.

Through previous reports and now in this study (designed as a prospective, randomized, controlled clinical trial) by Mintz-Hittner and colleagues, intravitreal bevacizumab has been shown to be effective in promoting regression of treatment-requiring ROP. Although the results of this study are promising, more questions arise. As noted by the study authors, long-term safety has not yet been determined. The ROP population is a sensitive one. In a developing child, what effect will intravitreal anti-VEGF therapy have on overall development and will it affect the natural history of the developing eye? (With regard to this specific study, there is no mention of a visual function outcome measure.) In addition, it is still unclear what the appropriate dosage of anti-VEGF therapy should be for the treatment of ROP. Therefore, with these questions still present, we must continue to include laser in our treatment paradigm because historically laser has been shown to work well for most cases. However, we should consider intravitreal bevacizumab in our armamentarium for treatment-requiring ROP in zone 1 and in the most aggressive forms of the disease.

– R.V. Paul Chan, MD, FACS
OSN Pediatrics/Strabismus Board Member
Disclosure: Dr. Chan has no relevant financial disclosures.