Retinopathy of prematurity: optimising prognosis

Intravitreal monotherapy with bevacizumab (Avastin, Roche) has significantly improved outcomes for children with retinopathy of prematurity (ROP). Careful monitoring for recurrence is important, however, because of the potential for unfavourable outcomes with late reactivation of ROP, said Helen Mintz-Hittner MD.

Delivering the inaugural Kanski Medal Lecture at the 3rd World Congress of Pediatric Ophthalmology and Strabismus in Barcelona, Spain, Dr Mintz-Hittner reviewed the benefits and risks of bevacizumab monotherapy for ROP. In addition, she reviewed findings from analyses conducted to characterise post-bevacizumab recurrences, and outlined a tentative follow-up schedule targeting better clinical management for the treated infants.

“Treatment of ROP with bevacizumab makes children more functional, especially those with zone I disease, but it also alters the natural history of ROP. We know that outcomes can be adversely affected by recurrence, but we have not known when, where or how to look for recurrence,” said Dr Mintz-Hittner, Alfred W Lasher III Professor of Ophthalmology and Visual Science, John P and Kathrine G McGovern Medical School at Houston, USA.

BENEFITS AND RISKS OF BEVACIZUMAB

The benefits of anti-vascular endothelial growth factor (anti-VEGF) treatment versus conventional laser therapy (CLT) include better visual field, less myopia (especially high myopia), and better optical coherence tomography (OCT) appearance of the macula corresponding to better visual acuity. Destruction of the peripheral retina with CLT accounts for the difference in visual field, but also for the reduced risk of myopia since growth factors released from the peripheral retina are responsible for the normal development of the anterior segment.

Discussing safety, Dr Mintz-Hittner said that the systemic toxicity of intravitreal Avastin is still an open question, since there has not been a trial large enough to adequately assess this issue. While the Bevacizumab Eliminates the Angiogenic Threat for ROP (BEAT-ROP) trial was not powered to evaluate the safety of intravitreal bevacizumab, the initial publication raised some concerns about systemic risks as it reported two deaths in the CLT group versus five deaths among bevacizumab-treated infants with follow-up to 54 weeks’ adjusted age (N Engl J Med. 2011;364(7):603-615). During continued follow-up, however, there was just one additional death in the bevacizumab group while the total number of deaths in the CLT group reached seven (JAMA Ophthalmol. 2014;132(11):1327-1333).

Dr. Mintz-Hittner acknowledged local adverse events can occur with bevacizumab injection, including infection or trauma to the lens or retina. However, the risk can be mitigated with attention to proper injection technique. She added that children treated with both bevacizumab and laser are at risk for all of the adverse consequences associated with laser treatment, including visual field loss, high myopia, and more frequent ROP recurrence.

“The risk of these events is especially high in children treated in zone I, and the risk occurs because the drug leaks out of the defects created by the laser,” she said.

MONITORING FOR RECURRENCE

Dr Mintz-Hittner conducted analyses to understand the incidence, risk factors, risk period, and anatomic characteristics of ROP recurrence after bevacizumab monotherapy, using data collected from March 2008 to December 2014. The children included initially had Type 1 ROP in zone I or zone II posterior as stage 3+ ROP or aggressive posterior ROP (APROP), and were followed to at least 65 weeks adjusted age. Mean follow-up for the analysed cohort was to 132 weeks.

A total of 471 eyes of 241 infants were eligible for the analyses that found recurrence, defined as return of both intravitreal neovascularisation and plus disease, developed in 20 infants (eight per cent) and 34 eyes (seven per cent). Taking into account data on mean time of first treatment and the mean time to recurrence, Dr Mintz-Hittner suggested the period between 45 to 55 weeks adjusted age represents the window during which more vigilant follow-up with examinations every one or two weeks is needed.

Based on characterisation of the recurrence pattern after the first bevacizumab injection, Dr Mintz-Hittner proposed this more frequent examination schedule is particularly needed if the advancing edge grows slowly, reaching just one to three disc diameters beyond the site of the first injection. According to findings of a multivariate analysis conducted to determine risk factors for recurrence, she said it is also recommended if the infant had APROP (vs stage 3+), an extended hospital stay, and/or a low birth weight.

“Before and after this critical period, examinations can be performed less frequently, every two to three weeks, and especially if the advancing edge advanced many disc diameters after the first bevacizumab treatment,” said Dr Mintz-Hittner.

She noted that most infants treated with bevacizumab demonstrate progression of retinal vessels rapidly toward the ora serrata by about 44 weeks adjusted age. She proposed that when that occurs and the infant has none of the three risk factors for recurrence, the follow-up examinations can be suspended at 55 weeks.

However, if the progression of retinal vessels was very slow and the infant had APROP initially, she advised continuing the examinations to look for recurrence until retinal vascularisation is complete or up to 65 weeks adjusted age.

Helen Mintz-Hittner: helen.a.mintz-hittner@uth.tmc.edu