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Figure 1. Photographs of the right (A) and left (B) eyes demonstrating fibrovascular tissue and retinal detachment in the retrolental location.

Figure 1. Photographs of the right (A) and left (B) eyes demonstrating fibrovascular tissue and retinal detachment in the retrolental location.

Figure 2. Ultrasonographic images (12 MHz) demonstrating tight funnel-shaped retinal detachment in the right (A) and left (B) eyes.

Figure 2. Ultrasonographic images (12 MHz) demonstrating tight funnel-shaped retinal detachment in the right (A) and left (B) eyes.

1.
Cryotherapy for Retinopathy of Prematurity Cooperative Group.  Multicenter trial of cryotherapy for retinopathy of prematurity: preliminary results.  Arch Ophthalmol. 1988;106(4):471-479PubMedArticle
2.
Early Treatment for Retinopathy of Prematurity Cooperative Group.  Revised indications for the treatment of retinopathy of prematurity: results of the Early Treatment for Retinopathy of Prematurity randomized trial.  Arch Ophthalmol. 2003;121(12):1684-1694PubMedArticle
3.
Mintz-Hittner HA, Kennedy KA, Chuang AZ.BEAT-ROP Cooperative Group.  Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity.  N Engl J Med. 2011;364(7):603-615PubMedArticle
4.
Moshfeghi DM, Berrocal AM. Retinopathy of prematurity in the time of bevacizumab: incorporating the BEAT-ROP results into clinical practice.  Ophthalmology. 2011;118(7):1227-1228PubMed
5.
Lalwani GA, Berrocal AM, Murray TG,  et al.  Off-label use of intravitreal bevacizumab (Avastin) for salvage treatment in progressive threshold retinopathy of prematurity [published correction appears in Retina. 2009;29(1):127].  Retina. 2008;28(3):(suppl)  S13-S18PubMedArticle
Research Letters
June 2012

Significant Treatment Failure With Intravitreous Bevacizumab for Retinopathy of Prematurity

Author Affiliations

Author Affiliations: Section of Ophthalmology and Visual Science, Department of Surgery, University of Chicago (Drs Patel and Blair) and Departments of Ophthalmology (Drs Blair and Shapiro) and Surgery and Pediatrics, College of Medicine (Dr Lichtenstein), University of Illinois at Chicago, Chicago, Retina Consultants, Ltd, Des Plaines (Drs Blair and Shapiro), and Departments of Surgery and Pediatrics, University of Illinois College of Medicine at Peoria, Pediatric Ophthalmology Service, Children's Hospital of Illinois, and Illinois Eye Center, Peoria (Dr Lichtenstein).

Arch Ophthalmol. 2012;130(6):801-802. doi:10.1001/archophthalmol.2011.1802

The mainstay of treatment for retinopathy of prematurity (ROP) with risk of retinal detachment has been ablation of peripheral avascular retina through cryotherapy or laser.1,2 Because ablative treatments are destructive and treatment often requires intubation and anesthesia in neonates with comorbid conditions, there has been interest in alternative treatments. Intravitreous bevacizumab injection is an emerging treatment that can be performed with minimal sedation. The BEAT-ROP study3 demonstrated a significant benefit of bevacizumab over laser in reducing treatment-requiring recurrence by 54 weeks. Given that recurrence in eyes treated with bevacizumab occurred later, at a mean (SD) of 16.0 (4.6) weeks after treatment, than in eyes treated with laser, at a mean (SD) of 6.2 (5.7) weeks after treatment, the time course of recurrence and progression of ROP is likely altered. Thus, late recurrences may not have been detected by the study.4 Herein, we report a case of significant treatment failure after bevacizumab monotherapy.

Report of a Case

A 560-g neonate, born prematurely at 23 weeks' postmenstrual age, was noted was noted to have stage 3 ROP in zone 1 at postmenstrual age 34 weeks. Following informed consent, off-label intravitreous bevacizumab (0.625 mg) was injected into each eye. The patient was then examined every 1 to 2 weeks. Posterior fibrotic tissue was noted first at 48 weeks, and fine vascularity appeared at 50 weeks. Retinal detachment (stage 4a ROP) in the right eye was present at 52 weeks, and the patient was referred by the original treater to our service for surgical intervention. Unfortunately, the patient did not appear for treatment and state department of family services intervention was required to bring the patient to our service, which occurred at 57 weeks. At that time, both retinas were completely detached (stage 5) with fibrovascular tissue immediately posterior to the lens (Figure 1 and Figure 2).

Comment

Retinopathy of prematurity is a proliferative retinal vascular disorder associated with local ischemia and subsequent extraretinal fibrovascular proliferation and tractional retinal detachment. Current standard treatment involves ablation of avascular retina,1,2 but recent studies3,5 have shown intravitreous bevacizumab monotherapy to be an effective treatment for ROP.

Despite promising results with intravitreous bevacizumab monotherapy, we believe this case demonstrates that caution must be taken when using bevacizumab. Clearly the progression of ROP is altered, with initial regression but possible recurrence as the effect declines over time. Unfortunately, the timing and rapidity of onset are not well characterized. Moreover, the location and pattern of recurrence may also be altered. Our patient displayed a posterior rather than anterior recurrence that progressed rapidly to retinal detachment.

Although not strictly medical failure, lapses in parental compliance with an extended burden of follow-up may play an important role in outcome and therefore the treatment choice. It is our belief that laser, despite causing less rapid regression of disease, induces a more permanent response because it destroys the source of vascular endothelial growth factor. Additionally, laser induces some retinal adhesion that may slow the effect of contracting fibrovascular tissue, and the recurrence pattern is more clearly defined and thus easier to detect. Clearly laser has its deficiencies, but we are concerned that the dramatic early effects of bevacizumab may lead to an underappreciation of its own limitations. We believe treatment success can be considered final not after the early response but only after there is complete retinal vascularization. This case and others that will likely follow should allow a more complete and balanced perspective. In our experience, laser after bevacizumab treatment seems to reduce severe complications, but further study is required to evaluate combined treatment.

This case serves as a warning to clinicians that extensive, long-term, careful follow-up and prompt subsequent intervention are needed in infants treated with intravitreous bevacizumab.

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Article Information

Correspondence: Dr Blair, Retina Consultants, Ltd, 2454 E Dempster St, Ste 400, Des Plaines, IL 60016 (michaelblairmd@gmail.com).

Financial Disclosure: None reported.

References
1.
Cryotherapy for Retinopathy of Prematurity Cooperative Group.  Multicenter trial of cryotherapy for retinopathy of prematurity: preliminary results.  Arch Ophthalmol. 1988;106(4):471-479PubMedArticle
2.
Early Treatment for Retinopathy of Prematurity Cooperative Group.  Revised indications for the treatment of retinopathy of prematurity: results of the Early Treatment for Retinopathy of Prematurity randomized trial.  Arch Ophthalmol. 2003;121(12):1684-1694PubMedArticle
3.
Mintz-Hittner HA, Kennedy KA, Chuang AZ.BEAT-ROP Cooperative Group.  Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity.  N Engl J Med. 2011;364(7):603-615PubMedArticle
4.
Moshfeghi DM, Berrocal AM. Retinopathy of prematurity in the time of bevacizumab: incorporating the BEAT-ROP results into clinical practice.  Ophthalmology. 2011;118(7):1227-1228PubMed
5.
Lalwani GA, Berrocal AM, Murray TG,  et al.  Off-label use of intravitreal bevacizumab (Avastin) for salvage treatment in progressive threshold retinopathy of prematurity [published correction appears in Retina. 2009;29(1):127].  Retina. 2008;28(3):(suppl)  S13-S18PubMedArticle
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