OFF-LABEL USE OF INTRAVITREAL BEVACIZUMAB (AVASTIN) FOR SALVAGE TREATMENT IN PROGRESSIVE THRESHOLD RETINOPATHY OF PREMATURITY

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1 OFF-LABEL USE OF INTRAVITREAL BEVACIZUMAB (AVASTIN) FOR SALVAGE TREATMENT IN PROGRESSIVE THRESHOLD RETINOPATHY OF PREMATURITY GEETA A. LALWANI, MD, AUDINA M. BERROCAL, MD, TIMOTHY G. MURRAY, MD, MBA, MARIA BUCH, MD, SCOTT CARDONE, MD, DITTE HESS, CRA, ROSE A. JOHNSON, RN, CARMEN A. PULIAFITO, MD, MBA Purpose: To report the short term anatomic response of intravitreal bevacizumab (Avastin, Genentech) as salvage treatment in progressive retinopathy of prematurity (ROP) in a small series of patients. Methods: The study included five eyes of three patients with progressive ROP despite peripheral laser ablation. Patients received intravitreal injections of bevacizumab (Avastin, Genentech). RetCam (Clarity Medical Systems, Inc., Pleasanton, CA) photography and ultrasonography were used to document effect. Results: Three patients were transferred to the Bascom Palmer Eye Institute/Jackson Memorial Hospital for management of progressive ROP despite laser therapy at an outside facility. RetCam fundus photography and ultrasonography were used to document all cases. After informed consent was obtained from the parents, the patients received off-label intravitreal bevacizumab as salvage treatment. Repeat intravitreal injections of bevacizumab were utilized in several cases. The ROP stabilized allowing laser supplementation. There was varying development of tractional retinal detachments in several of the eyes but the ROP component quieted in all cases. Conclusions: Off-label use of bevacizumab appears to be useful as a salvage treatment for ROP when laser treatment is precluded. It improves dilation, quiets the disease when visibility is difficult, and temporizes the disease until laser can be supplemented. RETINA 28:S13 S18, 2008 From the Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Florida. None of the authors has any proprietary interest in the materials presented in this study. Reprint requests: Audina Berrocal, MD, 900 NW 17th Street, Miami, FL 33136; aberrocal@med.miami.edu Retinopathy of prematurity (ROP) is a disease affecting the retina of premature infants. Of the babies born weighing less than 1,251 g, 4 6% reportedly go on to develop threshold ROP requiring treatment. 1 In our experience at a busy, inner-city neonatology unit, of babies born weighing less than 1,000 g, 19% develop threshold ROP requiring laser. Despite advances in treatment, ROP continues to be a major cause of blindness in the developed world. As the incidence of ROP increases (associated with an increase in survival rate of premature infants), interest in the pathogenesis of ROP has become renewed. S13

2 S14 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2008 VOLUME 28 NUMBER 3 The pathophysiology of ROP is similar to other proliferative retinopathies such as proliferative diabetic retinopathy and sickle cell retinopathy, in that there is a hypoxic phase followed by a neovascular response. In ROP, the first phase involves the premature termination of normal retinal vascular growth after premature birth producing an avascular peripheral retina. In the second phase, the hypoxic state of the peripheral retina leads to a retinal neovascularization response in the second phase. The same factors that are crucial to normal development of the retina are likely involved with the pathologic process of ROP. In one hypothesis of normal development, vascular endothelial growth factor (VEGF) serves as a stimulus for angiogenesis of the advancing peripheral retina. 2 As the capillary plexus develops, the signal to produce VEGF is reduced, and angiogenesis slows. A mouse model of the disease aided in the elucidation of VEGF as a crucial player in both phase 1 and phase 2 of the disease. 3 Alon et al demonstrated that supplemental oxygen leads to the downregulation of VEGF and death of endothelial cells, potentially leading to closure of the vasculature in phase 1 of the disease. 4 The resulting hypoxia drives the upregulation of VEGF expression, inducing neovascularization. Sampling of the subretinal fluid in patients with stage 4 and 5 ROP demonstrated significantly elevated levels of VEGF. 5 Interestingly, in animal models, complete inhibition of VEGF does not lead to complete inhibition of retinal neovascularization, suggesting that other factors are involved. Flynn and Chan-Ling postulated that in the development of Zone 1 ROP there is a vasculogenic drive independent of VEGF whereas in Zone 2 ROP there is an angiogenic stimulus. 6 Based on this reasoning and the inability to use conventional treatments in these cases of ROP, an anti-vegf agent was used as a salvage treatment to enable laser supplementation in three cases. Methods The clinical records of five eyes of three patients with the diagnosis of progressive ROP despite laser therapy that were treated with intravitreal bevacizumab (Avastin, Genentech, Inc.) at the Bascom Palmer Eye Institute/Jackson Memorial Hospital were reviewed. After obtaining parental consent, off-label intravitreal injections of bevacizumab (Avastin) as salvage therapy were administered at the discretion of the treating physician. RetCam (Clarity Medical Systems, Inc., Pleasanton, CA) photography and ultrasonography were used to document all the cases at baseline, preinjection, postinjection, and post supplemental laser. Results A standard preparation protocol with topical anesthesia and 5% topical povidone-iodine and lid speculum was employed before an injection of bevacizumab 1.25 mg/0.05 cc for the first injection in Case 1 and 0.63 mg/0.3 cc for the subsequent injection and all other cases. The procedures were tolerated without complication in all cases. No alterations in blood pressure or systemic condition were observed in any of the patients. Case 1 A former 23-week premature, 600 g neonate was transferred at a gestational age of 42 weeks to the Bascom Palmer Eye Institute/Jackson Memorial Hospital for evaluation and management of threshold ROP after laser treatment was aborted due to miosis, hyphemas, and vitreous hemorrhages. RetCam photography and ultrasonography documented limited fundus visibility and anterior elevation of the temporal retina in both eyes. Following a lengthy discussion with the parents after transfer, a decision was made to use off-label intravitreal bevacizumab as salvage therapy in both eyes. The procedures were tolerated without complication. Serial RetCam photography and ultrasonography documented the increased dilation (Figure 1), clearing of the hemorrhages, allowing increasing visibility of the retina (Figure 2) and the resolution of the anterior retinal elevation. The retina had a significant decrease in plus disease, which seemed to diminish on a daily basis as observed by serial clinical examinations and photography. At 6 weeks post injection (gestational age 48 weeks), vein engorgement was noted with vitreous traction and reactivation of the temporal neovascularization in both eyes. Peripheral laser ablation was applied to both eyes. The right eye was reinjected with bevacizumab at gestational age 49 weeks. Both eyes continue to remain stable at gestational age 53 weeks. Case 2 A former 24-week premature, 760 g neonate was transferred at gestational age of 35 weeks to the Bascom Palmer Eye Institute/Jackson Memorial Hospital for management of treated Zone 1 ROP with persistent plus disease (Figure 3A). RetCam photography and ultrasonography documented the fundus findings. Following a lengthy discussion with the parents after transfer, a decision was made to use off-label intravitreal bevacizumab as sal-

3 AVASTIN FOR PROGRESSIVE THRESHOLD ROP LALWANI ET AL S15 Fig. 1. Case 1, RetCam digital photographs: right and left eyes at (A) baseline, intravitreal bevacizumab bilaterally, (B) week 1, observation, and (C) week 3, observation. vage therapy in the right eye in combination with laser supplementation and isolated laser supplementation in the left eye. The procedures were tolerated without complication. Serial RetCam photography and ultrasonography documented a decrease in plus disease 2 days after treatment and evidence of subretinal fluid which resolved resolution with subretinal fluid 1 week following treatment. At gestational age 41 weeks (6 weeks s/p treatment) both eyes remain stable without plus disease or subretinal fluid (Figure 3B). Case 3 A former 25-week premature, 835 g neonate was transferred at gestational age 41 weeks to the Bascom Palmer Eye Institute/Jackson Memorial Hospital for management of bilateral exudative retinal detachments. The patient had received laser therapy at gestational age 38 weeks at an outside facility. Photography and ultrasonography confirmed the bilateral exudative retinal detachments (Figures 4 and 5). Following a lengthy discussion with the parents after transfer, a decision was made to use off-label intravitreal bevacizumab as salvage therapy in the left eye initially. A week later, the right eye was also injected with bevacizumab due to persistent exudation which prevented laser application. At this point, laser was supplemented in both eyes. The left eye was reinjected at gestational age 43 weeks to reduce vascular engorgement (Figures 4 and 5). The left eye remains stable. The right eye developed a rhegmatogenous component from the tractional retinal detachment at 45 weeks gestational age.

4 S16 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2008 VOLUME 28 NUMBER 3 Fig. 2. Case 1, RetCam digital fundus photographs: right and left eyes at (A) baseline, intravitreal bevacizumab bilaterally, (B) week 1, observation, and (C) week 6, laser bilaterally. Discussion The current treatment for ROP is retinal ablation, similar to other vasculoproliferative diseases. This treatment strategy was achieved through the Cryotherapy for Retinopathy of Prematurity and Early Treatment for Retinopathy of Prematurity studies, which validated retinal ablation for threshold ROP. Retinal ablation is thought to diminish the production of VEGF and/or other vascular signals and lead to regression of the neovascularization. The use of retinal ablation is mimicked in other vascular diseases presumably through modulation of growth factors. A role for VEGF is suggested in other ocular neovascular pathologies including proliferative diabetic retinopathy (PDR), retinal vein occlusion, iris neovascularization, and neovascular age-related macular degeneration (AMD). 7 9 In an effort to improve visual outcomes in neovascular degeneration, various anti-vegf pharmacotherapies have been developed including pegaptanib sodium (Macugen, Eyetech), ranibizumab (Lucentis, Genentech), and bevacizumab (Avastin, Genentech). Phase III clinical trials of ranibizumab for wet AMD have clearly demonstrated the regression of choroidal neovascular membranes. Given the overwhelming evidence for the role of VEGF and the reported efficacy of the anti-vegf therapies, bevacizumab has been used for the treatment of PDR. 10 Furthermore, Spaide and Fisher reported a case series of patients with PDR complicated by vitreous hemorrhage treated with bevacizumab to induce cessation of bleeding. 11 In this series, the

vitreous hemorrhage rapidly resorbed revealing regressing retinal neovascularization.

5 AVASTIN FOR PROGRESSIVE THRESHOLD ROP LALWANI ET AL S17 Fig. 3. Case 2, RetCam digital fundus photographs: right eye at (A) baseline, intravitreal bevacizumab and laser supplementation, and (B) week 2, observation. vitreous hemorrhage rapidly resorbed revealing regressing retinal neovascularization. Natural history suggests that a presentation of vitreous hemorrhages associated with ROP (Case 1) would progress to bilateral retinal detachment without laser supplementation. 12 In Case 1, the neovascularization secondary to ROP regressed similar to cases of PDR or AMD complicated by vitreous hemorrhages. It is unclear how long this regression will be maintained, but ROP is unique in that it is a self-limited condition. At the current gestational age of 52 weeks, perhaps the window of disease is passed and the eyes will remain stable. In Case 2, bevacizumab modulated the VEGF levels that drive the ROP activity. Laser supplementation of the avascular retina after improved dilation further reduced the VEGF drive. A small exudative detachment was noted 2 days after the laser which resolved a week after the injection. This type of exudative component seemed to be more inflammatory than a result of the injection or disease process. Fig. 4. Case 3, RetCam digital fundus photographs: left eye at (A) baseline, intravitreal bevacizumab, (B) week 1, laser, and (C) week 2, reinjection of intravitreal bevacizumab. In Case 3, laser supplementation was precluded by massive exudation. Intravitreal bevacizumab caused the regression of neovascularization and reduction in the permeability of capillaries, significantly reducing the subretinal fluid accumulation. Laser supplementation was applied without difficulty. In several of these eyes, repeat injections of bevacizumab were required due to the flare in disease activity. This observation correlates with the previously stated find-

S18 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2008 VOLUME 28 NUMBER 3 It is unclear how long the regression of ROP will remain in these cases, but in the setting of media opacity, poor

6 S18 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2008 VOLUME 28 NUMBER 3 It is unclear how long the regression of ROP will remain in these cases, but in the setting of media opacity, poor dilation, exudative retinal detachment, or medical instability, anti-vegf therapies could provide an adjuvant treatment until laser therapy can be applied. Repeat injections may be necessary to temporize the disease, especially in advanced cases of ROP. Furthermore, the tractional retinal detachments may worsen with injection if the vascular component of the ROP is still active. In contrast to other ocular pathologic angiogenesis conditions, ROP is a selflimited condition. This raises the question as to whether intravitreal injections of anti-vegf agents at the appropriate time window could abort the need for laser entirely. Further study of the safety and efficacy of intravitreal bevacizumab in the treatment of ROP is warranted. Key Words: anti-vegf therapy, bevacizumab, retinopathy of prematurity, salvage treatment. References Fig. 5. Case 3, RetCam digital fundus photographs: right eye at (A) baseline, observation, (B) week 1, intravitreal bevacizumab and laser, and (C) week 2, observation. ing of increased VEGF levels in the subretinal fluid of eyes with stage 4 or 5 ROP. Until further studies are done, it is unknown what the frequency of dosing should be. Both of the eyes in Case 3 developed a tractional retinal component similar to that seen in diabetes. Although the tractional effect worsened with injection, the endovascular component of the detachment quieted and eventually stabilized. 1. Hussain N, Clive J, Bhandari V. Current incidence of retinopathy of prematurity, Pediatrics 1999;104: Smith LEH. Pathogenesis of retinopathy of prematurity. Acta Paediatr 2002;437:S26 S Penn JS, Tolman BL, Henry MM. Oxygen-induced retinopathy in the rat: relationship of retinal perfusion to subsequent neovascularization. Invest Ophthalmol Vis Sci 1994;35: Alon T, Hemo I, Itin A, et al. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nature Medicine 1995;1: Lashkari K, Hirose T, Yazdany J, et al. Vascular endothelial growth factor and hepatocyte growth factor levels are differentially elevated in patients with advanced retinopathy of prematurity. Am J Pathol 2000;156: Flynn JT, Chan-Ling T. Retinopathy of prematurity: two distinct mechanisms that underlie zone 1 and zone 2 disease. AJO 2006;142: Adamis AP, Miller JW, Bernal MT, et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. AJO 1994;118: Tripathi RC, Li J, Tripathi BJ, et al. Increased level of vascular endothelial growth factor in aqueous humor of patients with neovascular glaucoma. Ophthal 1998;105: Kliffen M, Sharma HS, Mooy CM, et al. Levels of vascular endothelial growth factor are elevated in the vitreous of patients with subretinal neovascularization. BJO 1996;80: Avery RL, Perlman J, Pieramici DJ, et al. Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology 2006;113:1695.e Spaide RF, Fisher YL. Intravitreal bevacizumab (Avastin) treatment of proliferative diabetic retinopathy complicated by vitreous hemorrhage. Retina 2006;26: Coats DK. Retinopathy of prematurity: involution, factors predisposing to retinal detachment, and expected utility of preemptive surgical reintervention. Trans Am Ophthalmol Soc 2005;103:

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