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Management of ROP continues to evolve

Part 2 of a two-part series focuses on the use of bevacizumab in the treatment of retinopathy of prematurity.

With a better understanding of the pathophysiology of retinopathy of prematurity, management is evolving.

Premature birth results in a loss of access to maternal growth factors, which can deprive the infant of stimulation of important developmental pathways. One of the factors depressed in the infant after preterm birth is insulin-like growth factor 1 (IGF-1). IGF-1 regulates retinal neovascularization through control of VEGF activation; therefore, low levels of IGF-1 will inhibit vessel growth despite the presence of VEGF. Improving IGF-1 levels might improve early postnatal growth and reduce ROP and the comorbidities associated with premature birth. Therefore, a study of exogenous IGF-1/IGFBP-3 replacement therapy is underway, with reduction of ROP as the primary endpoint. Promoting postnatal weight gain, reducing comorbidities and risk factors, and suppressing VEGF are all considered treatment modalities to decrease the progression of ROP.

Use of bevacizumab

The first single interventional case using off-label intravitreal injections of Avastin (bevacizumab, Genentech) for ROP was published in January 2007. Since then, a number of cases have been reported using bevacizumab as both first-line treatment and salvage treatment for ROP. The BEAT-ROP study was the first randomized, multicenter, interventional trial investigating intravitreal bevacizumab vs. conventional laser for the treatment of stage 3 ROP in zone 1 and 2 with plus disease. The bevacizumab injection dose was 0.625 mg/0.025 mL. Bevacizumab was chosen due to its complete blockage of VEGF-A and less retinal penetration because it is a full antibody. The results revealed that the rate of recurrence with zone 1 disease was significantly higher with conventional laser than with bevacizumab, 42% vs. 6%. The rate of recurrence with zone 2 posterior disease did not differ significantly between the laser and bevacizumab groups, 12% vs. 5%.

Christin L. Sylvester

The precautions with bevacizumab use are the unknown systemic or local side effects. The retinal vessels will continue to advance to the point at which the vascular precursors have ceased migration. Thus, the far peripheral retina may never fully vascularize or differentiate. This can lead to late recurrences of ROP with bevacizumab, 16 ± 4.6 weeks vs. 6.2 ± 5.7 weeks with laser, as described in the BEAT-ROP study. A recent follow-up study from the BEAT-ROP Cooperative Group revealed very high myopia (≥ –8 D) occurred in zone 1 in two of 52 eyes (3.8%) that received intravitreal bevacizumab and in 18 of 35 eyes (51.4%) that received laser treatment. In posterior zone 2 disease, one of 58 eyes (1.7%) had very high myopia in the bevacizumab group vs. 24 of 66 eyes (36.4%) in the laser group.

Recent reports

Hu and colleagues reported late treatment-requiring recurrences of ROP and retinal detachments after bevacizumab injection, even up to 69 weeks’ postmenstrual age. There is no clear data supporting the best treatment for recurrence of ROP after bevacizumab therapy, but they hypothesize that laser may be preferable for treatment-requiring recurrences. They also stress that the anatomic location of recurrence may occur at or near the original posterior site of neovascularization vs. the more anterior site of the vascular and avascular junction.

Chen and colleagues recently reported a case of late recurrence of ROP despite both bevacizumab and laser, including atypical neovascularization within the previously lasered retina. With a variable recurrence site and delayed peripheral retinal vascularization, diligent surveillance is necessary for more prolonged periods of time after bevacizumab injection with or without laser. The aforementioned authors also stressed that successful treatment should only be considered with complete retinal vascularization to the ora serrata and no active ROP.

This statement raises questions as to the final outcome measure for successful ROP treatment with bevacizumab. Further studies are necessary to answer these questions about the optimal treatment for ROP. Long-term data are also necessary to establish the safety and dosage of bevacizumab in a developing infant, with unknown effects on structures such as the brain, heart, lungs and kidneys.

Visit UPMCPhysicianResources.com/Ocular to learn more about retinopathy of prematurity. You can also submit clinical questions or read the most recent questions asked of the UPMC Eye Center’s ophthalmology experts.

References:
Chen W, et al. J AAPOS. 2014;doi:10.1016/j.jaapos.2014.03.011.
Geloneck MM, et al. JAMA Ophthalmol. 2014;doi:10.1001/jamaophthalmol.2014.2772.
Hellström A, et al. Pediatrics. 2003;doi:10.1542/peds.112.5.1016.
Hellström A, et al. Lancet. 2013;doi:10.1016/S0140-6736(13)60178-6.
Hu J, et al. Arch Ophthalmol. 2012;doi:10.1001/archophthalmol.2012.592.
Mintz-Hittner HA, et al. N Engl J Med. 2011;doi:10.1056/NEJMoa1007374.
For more information:
Christin L. Sylvester, DO, is a clinical assistant professor of ophthalmology at UPMC and the University of Pittsburgh. She can be reached at Children’s Hospital of Pittsburgh of UPMC, Children’s Hospital Drive, 45th and Penn Ave., CHP Faculty Pavilion, Suite 5000, Pittsburgh, PA 15201; email: sylvestercl@upmc.edu.
Disclosure: Sylvester reports no relevant financial disclosures.

With a better understanding of the pathophysiology of retinopathy of prematurity, management is evolving.

Premature birth results in a loss of access to maternal growth factors, which can deprive the infant of stimulation of important developmental pathways. One of the factors depressed in the infant after preterm birth is insulin-like growth factor 1 (IGF-1). IGF-1 regulates retinal neovascularization through control of VEGF activation; therefore, low levels of IGF-1 will inhibit vessel growth despite the presence of VEGF. Improving IGF-1 levels might improve early postnatal growth and reduce ROP and the comorbidities associated with premature birth. Therefore, a study of exogenous IGF-1/IGFBP-3 replacement therapy is underway, with reduction of ROP as the primary endpoint. Promoting postnatal weight gain, reducing comorbidities and risk factors, and suppressing VEGF are all considered treatment modalities to decrease the progression of ROP.

Use of bevacizumab

The first single interventional case using off-label intravitreal injections of Avastin (bevacizumab, Genentech) for ROP was published in January 2007. Since then, a number of cases have been reported using bevacizumab as both first-line treatment and salvage treatment for ROP. The BEAT-ROP study was the first randomized, multicenter, interventional trial investigating intravitreal bevacizumab vs. conventional laser for the treatment of stage 3 ROP in zone 1 and 2 with plus disease. The bevacizumab injection dose was 0.625 mg/0.025 mL. Bevacizumab was chosen due to its complete blockage of VEGF-A and less retinal penetration because it is a full antibody. The results revealed that the rate of recurrence with zone 1 disease was significantly higher with conventional laser than with bevacizumab, 42% vs. 6%. The rate of recurrence with zone 2 posterior disease did not differ significantly between the laser and bevacizumab groups, 12% vs. 5%.

Christin L. Sylvester

The precautions with bevacizumab use are the unknown systemic or local side effects. The retinal vessels will continue to advance to the point at which the vascular precursors have ceased migration. Thus, the far peripheral retina may never fully vascularize or differentiate. This can lead to late recurrences of ROP with bevacizumab, 16 ± 4.6 weeks vs. 6.2 ± 5.7 weeks with laser, as described in the BEAT-ROP study. A recent follow-up study from the BEAT-ROP Cooperative Group revealed very high myopia (≥ –8 D) occurred in zone 1 in two of 52 eyes (3.8%) that received intravitreal bevacizumab and in 18 of 35 eyes (51.4%) that received laser treatment. In posterior zone 2 disease, one of 58 eyes (1.7%) had very high myopia in the bevacizumab group vs. 24 of 66 eyes (36.4%) in the laser group.

Recent reports

Hu and colleagues reported late treatment-requiring recurrences of ROP and retinal detachments after bevacizumab injection, even up to 69 weeks’ postmenstrual age. There is no clear data supporting the best treatment for recurrence of ROP after bevacizumab therapy, but they hypothesize that laser may be preferable for treatment-requiring recurrences. They also stress that the anatomic location of recurrence may occur at or near the original posterior site of neovascularization vs. the more anterior site of the vascular and avascular junction.

Chen and colleagues recently reported a case of late recurrence of ROP despite both bevacizumab and laser, including atypical neovascularization within the previously lasered retina. With a variable recurrence site and delayed peripheral retinal vascularization, diligent surveillance is necessary for more prolonged periods of time after bevacizumab injection with or without laser. The aforementioned authors also stressed that successful treatment should only be considered with complete retinal vascularization to the ora serrata and no active ROP.

This statement raises questions as to the final outcome measure for successful ROP treatment with bevacizumab. Further studies are necessary to answer these questions about the optimal treatment for ROP. Long-term data are also necessary to establish the safety and dosage of bevacizumab in a developing infant, with unknown effects on structures such as the brain, heart, lungs and kidneys.

Visit UPMCPhysicianResources.com/Ocular to learn more about retinopathy of prematurity. You can also submit clinical questions or read the most recent questions asked of the UPMC Eye Center’s ophthalmology experts.

References:
Chen W, et al. J AAPOS. 2014;doi:10.1016/j.jaapos.2014.03.011.
Geloneck MM, et al. JAMA Ophthalmol. 2014;doi:10.1001/jamaophthalmol.2014.2772.
Hellström A, et al. Pediatrics. 2003;doi:10.1542/peds.112.5.1016.
Hellström A, et al. Lancet. 2013;doi:10.1016/S0140-6736(13)60178-6.
Hu J, et al. Arch Ophthalmol. 2012;doi:10.1001/archophthalmol.2012.592.
Mintz-Hittner HA, et al. N Engl J Med. 2011;doi:10.1056/NEJMoa1007374.
For more information:
Christin L. Sylvester, DO, is a clinical assistant professor of ophthalmology at UPMC and the University of Pittsburgh. She can be reached at Children’s Hospital of Pittsburgh of UPMC, Children’s Hospital Drive, 45th and Penn Ave., CHP Faculty Pavilion, Suite 5000, Pittsburgh, PA 15201; email: sylvestercl@upmc.edu.
Disclosure: Sylvester reports no relevant financial disclosures.