Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity

Abstract

Background: Retinopathy of prematurity is a leading cause of childhood blindness worldwide. Peripheral retinal ablation with conventional (confluent) laser therapy is destructive, causes complications, and does not prevent all vision loss, especially in cases of retinopathy of prematurity affecting zone I of the eye. Case series in which patients were treated with vascular endothelial growth factor inhibitors suggest that these agents may be useful in treating retinopathy of prematurity.

Methods: We conducted a prospective, controlled, randomized, stratified, multicenter trial to assess intravitreal bevacizumab monotherapy for zone I or zone II posterior stage 3+ (i.e., stage 3 with plus disease) retinopathy of prematurity. Infants were randomly assigned to receive intravitreal bevacizumab (0.625 mg in 0.025 ml of solution) or conventional laser therapy, bilaterally. The primary ocular outcome was recurrence of retinopathy of prematurity in one or both eyes requiring retreatment before 54 weeks' postmenstrual age.

Results: We enrolled 150 infants (total sample of 300 eyes); 143 infants survived to 54 weeks' postmenstrual age, and the 7 infants who died were not included in the primary-outcome analyses. Retinopathy of prematurity recurred in 4 infants in the bevacizumab group (6 of 140 eyes [4%]) and 19 infants in the laser-therapy group (32 of 146 eyes [22%], P=0.002). A significant treatment effect was found for zone I retinopathy of prematurity (P=0.003) but not for zone II disease (P=0.27).

Conclusions: Intravitreal bevacizumab monotherapy, as compared with conventional laser therapy, in infants with stage 3+ retinopathy of prematurity showed a significant benefit for zone I but not zone II disease. Development of peripheral retinal vessels continued after treatment with intravitreal bevacizumab, but conventional laser therapy led to permanent destruction of the peripheral retina. This trial was too small to assess safety. (Funded by Research to Prevent Blindness and others; ClinicalTrials.gov number, NCT00622726.).

Figure 1. Pathogenesis and Therapy of Retinopathy of Prematurity (ROP)

Phases 1 and 2 of ROP are associated with different levels of vascular endothelial growth factor (VEGF), oxygen, and neovascular activity. ROP stages 0 to 5 are shown, as are the outcomes, when therapy is successful, of cryotherapy (established in a clinical trial in 1988), laser therapy (established in clinical trial in 2003), and intravitreal bevacizumab (this study). Cryotherapy involves scarring of the full ocular thickness, laser therapy scarring of the retinal thickness, and intravitreal bevacizumab scarring with a needle near the limbus. Also shown are the postmenstrual ages at which infants are at high risk for ROP, the appropriate postmenstrual age for the first ocular screening examination for ROP, and the mean postmenstrual ages at the onset of aggressive posterior ROP (APROP) (type 2 ROP) and stages 1, 2, and 3 (type 1 ROP).

Figure 2

Enrollment, Randomization, and Follow-up of the 150 Study Infants.

Figure 3. Fundus Photographs and Fluorescein Angiograms of Retinas in Study Infants with Stage 3+ Retinopathy of Prematurity in Zone I, before and after Treatment

Panels A and B show the left retina of an infant before conventional laser therapy (at approximately 2 months of age, or 33.1 weeks’ postmenstrual age) and after therapy (at 13 months’ postmenstrual age), respectively. The infant was born at 24 weeks’ gestational age, with a birth weight of 760 g. The post-treatment photograph shows destruction of the full thickness of the peripheral retina, with only choroidal vessels (not retinal vessels) visible in the lasered area. Panels C and D show the left retina in another infant before intravitreal bevacizumab therapy (at approximately 3 months of age, or 35.6 weeks’ postmenstrual age) and after therapy (at 13 months’ postmenstrual age), respectively. The infant was born at 23 weeks’ gestational age, with a birth weight of 495 g. The post-treatment photograph shows continued vascularization of the peripheral retina. In all four panels, black arrows indicate identical retinal points for comparison before and after treatment, and thin white arrows indicate the extent of vascularization at each time point; the wide white arrows in Panel D indicate the extent of vascularization at the time of treatment with bevacizumab.