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Recurrence of Retinopathy of Prematurity Following Bevacizumab Monotherapy: Is It Only the Tip of the Iceberg?

Recurrence of Retinopathy of Prematurity Following Bevacizumab Monotherapy: Is It Only the Tip of... In 2011, a landmark article was published that could change the way retinopathy of prematurity (ROP) is treated.1 The Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) trial concluded that intravitreal injection of bevacizumab, 0.625 mg in 0.025 mL, had a beneficial effect compared with laser photocoagulation for zone 1, stage 3+ ROP.1However, their end point for recurrence of disease was only 54 weeks' postmenstrual age (PMA). Previously, Moshfeghi and Berrocal2 estimated that 47.7% of recurrences would have occurred after the 54 weeks' PMA reported in the BEAT-ROP study as the primary end point for treatment success. In this journal, Hu et al3 described their clinical experience with recurrence of ROP following intravitreal injection of bevacizumab, adding further evidence that 54 weeks' PMA is not a sufficient end point for observation. Hu and colleagues reported 17 eyes of 9 patients who had recurrence of ROP requiring treatment on average 14.4 weeks after bevacizumab injection (range, 4-35 weeks). Notably, 5 eyes that progressed to having retinal detachment (RD) did so at a median age of 55 weeks' PMA (range, 49-69 weeks). They mentioned the shortfalls of their study as retrospective, uncontrolled, and small in number. Also, the period in which their patients were seen in relation to recent publications on bevacizumab was not described, and patients were seen and managed by different ophthalmologists without prior examination by authors of the study in some cases. Thus, this retrospective study raises concerns about nonstandardized use of a new treatment modality. Most importantly, 2 patients had repeated intravitreal injections of bevacizumab within a relatively short period. One patient (patient 3) had 6 doses of bevacizumab, 0.625 mg (total, 3.75 mg), in a 7-week period, and another patient (patient 9) had 5 doses in the same period (total, 3.125 mg). Sato et al4 showed that a total dose injection of only 0.5 mg of bevacizumab causes a 6-fold reduction in serum vascular endothelial growth factor 2 weeks after injection in neonates. There are no data for repeated injections, but by implication, patients 3 and 9 in the article by Hu and colleagues were likely to have been subjected to even lower serum vascular endothelial growth factor levels. Systemic adverse effects remain the biggest concern among ROP experts in both the short and long term.5-7 We therefore welcome the recommendation that recurrences of ROP should be treated with laser, not just because of a reduced RD rate3 but also for protecting the patient from systemic complications. We are in uncharted waters with regard to patterns of recurrence following bevacizumab treatment. Hu and colleagues defined recurrence as “arrest of anterior progression of retinal vasculature associated with a new demarcation line, ridge, or extraretinal fibrovascular proliferation (EFP) or leakage on fluorescein angiography, with or without recurrence of plus disease.”3 Recurrence did not require EFP. They also observed anatomical recurrence as anterior and/or posterior. This is different from the definitions in the BEAT-ROP study.1 There is a need for the larger ROP community to standardize the definition and re-treatment criteria for recurrence after bevacizumab injection. In the study by Hu and colleagues, both recurrence criteria and treatment were at the discretion of the treating ophthalmologist. Again, questions can be raised regarding some patients with the information provided in the article. For example, patient 9 was born at 32 weeks' PMA, weighed 1843 g at birth, and reportedly developed aggressive posterior ROP in zone 1 with atypical stage 3 and plus disease at 35 weeks.3 Aggressive posterior ROP is usually considered to occur in the tiniest and most premature babies8; in our combined experience, we have not seen such a scenario in a developed country and we find the case surprising. It is unusual for such a case to even be eligible for screening, let alone to have such severe disease warranting treatment 3 weeks after birth (the first screening examination is normally 4 weeks after birth).9 Again, without further information and independent verification, it is difficult to draw conclusions from this case as the figures attributed to the case (unlabeled as to the PMA they represent) do not match the severity described.3 This study also demonstrates the problems relating to unknown follow-up protocol for patients with ROP after bevacizumab injection.3 It is not reported whether the high proportion of RDs was due to loss to follow-up and hence preventable in some cases. For example, patient 2 was described as having stage 4A RD in the right eye at 50 weeks' PMA, progressing to stage 5 RD at 54 weeks' PMA. The patient's left eye was reported as having stage 5 RD at 55 weeks' PMA without any indication of what happened in this eye during the preceding 5 weeks while the fellow eye was being observed. It is difficult to deduce the speed and pattern of complications with the information available. The authors could not comment on whether the RDs were rhegmatogenous or tractional. Stage 5 RDs (3 patients) were categorized as anterior recurrence of ROP even though in the table of results the diagnosis was made at presentation.3 However, if injections were carried out at 2.5 mm behind the limbus as described in the BEAT-ROP study,1 a rhegmatogenous cause may be the culprit as this distance lies in full-thickness retina in a neonate.10 Nevertheless, it is appropriate to conclude that with bevacizumab, regular long-term observation is vital to identify potentially preventable RDs. How often follow-up should be performed is not known, and loss to follow-up is of greater concern than laser-treated eyes, which on average have a more predictable course within 12 weeks.2 The study demonstrates the need for long-term follow-up requiring skilled ophthalmological observation and emphasizes that while bevacizumab injection treatment may be less time-consuming than laser as initial therapy, it has significant long-term follow-up issues. This has implications in terms of workforce commitment for ophthalmologists and the necessity to ensure that the patients are brought for outpatient assessment. Despite the shortfalls of the study by Hu and colleagues, the study demonstrates that late recurrence after bevacizumab injection is a major cause for concern. Recurrence with resulting RD has a very poor prognosis; therefore, missed recurrence can severely affect the child's vision. The authors conclude that “only with complete vascularization to the ora serrata and no active disease can treatment [with bevacizumab] be considered successful.”3 Parents should be alerted of the need for prolonged regular follow-up visits and the potential need for a general anesthetic for indented examination of the peripheral retina and possibly a fluorescein angiogram in some of the older children (≥50 weeks' PMA). Further standardized and controlled studies with longer follow-up are required so that the late recurrence of ROP can be assessed, and they should also aim to establish a safe end point for ROP screening examinations following bevacizumab monotherapy. Finally, it is important to note that laser photocoagulation for ROP does not have the problem of recurrence. There may be a failure to adequately respond to laser, but once ROP has regressed it does not recur weeks to months later.11 The concluding paragraph of the Early Treatment of ROP (ETROP) randomized trial states, “Even with the addition of early [laser] treatment for selected eyes with prethreshold ROP, some eyes will still progress to an unfavorable visual and/or structural outcome. Thus, additional research is needed to identify better methods for the prevention and treatment of severe ROP.”11 Hence, no treatment is perfect for ROP at present and the search must continue for better outcomes. Bevacizumab may not be the ideal treatment if the problems of recurrence and suboptimal local and systemic long-term safety profiles prove to be only the tip of the iceberg. Back to top Article Information Correspondence: Dr Mireskandari, Department of Ophthalmology and Visual Sciences, The Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8, Canada (kamiar.mireskandari@sickkids.ca). Conflict of Interest Disclosures: None reported. References 1. 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):603-61521323540PubMedGoogle ScholarCrossref 2. Moshfeghi DM, Berrocal AM. Retinopathy of prematurity in the time of bevacizumab: incorporating the BEAT-ROP results into clinical practice. Ophthalmology. 2011;118(7):1227-122821724044PubMedGoogle Scholar 3. Hu J, Blair MP, Shapiro MJ, Lichtenstein SJ, Galasso JM, Kapur R. Reactivation of retinopathy of prematurity after bevacizumab injection. Arch Ophthalmol. 2012;130(8):1000-100622491394PubMedGoogle ScholarCrossref 4. Sato T, Wada K, Arahori H, et al. Serum concentrations of bevacizumab (Avastin) and vascular endothelial growth factor in infants with retinopathy of prematurity. Am J Ophthalmol. 2012;153(2):327-333, e121930258PubMedGoogle ScholarCrossref 5. Gilbert CE, Zin A, Darlow B. Bevacizumab for retinopathy of prematurity. N Engl J Med. 2011;364(24):2359-2360, author reply 2361-236221675898PubMedGoogle ScholarCrossref 6. Gole GA, Camuglia JE, Ells AL. Bevacizumab for retinopathy of prematurity. N Engl J Med. 2011;364(24):2360-2361, author reply 236221675896PubMedGoogle Scholar 7. Lim LS, Cheung CM, Mitchell P, Wong TY. Emerging evidence concerning systemic safety of anti-VEGF agents: should ophthalmologists be concerned? Am J Ophthalmol. 2011;152(3):329-33121855670PubMedGoogle ScholarCrossref 8. International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005;123(7):991-99916009843PubMedGoogle ScholarCrossref 9. Section on Ophthalmology, American Academy of Pediatrics; American Academy of Ophthalmology; American Association for Pediatric Ophthalmology and Strabismus. Screening examination of premature infants for retinopathy of prematurity [published corrections appear in Pediatrics. 2006;117(4):1468 and Pediatrics. 2006;118(3):1324]. Pediatrics. 2006;117(2):572-57616452383PubMedGoogle ScholarCrossref 10. Hairston RJ, Maguire AM, Vitale S, Green WR. Morphometric analysis of pars plana development in humans. Retina. 1997;17(2):135-1389143042PubMedGoogle ScholarCrossref 11. 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):1684-169414662586PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Ophthalmology American Medical Association

Recurrence of Retinopathy of Prematurity Following Bevacizumab Monotherapy: Is It Only the Tip of the Iceberg?

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Publisher
American Medical Association
Copyright
Copyright © 2013 American Medical Association. All Rights Reserved.
ISSN
2168-6165
eISSN
2168-6173
DOI
10.1001/jamaophthalmol.2013.711
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Abstract

In 2011, a landmark article was published that could change the way retinopathy of prematurity (ROP) is treated.1 The Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) trial concluded that intravitreal injection of bevacizumab, 0.625 mg in 0.025 mL, had a beneficial effect compared with laser photocoagulation for zone 1, stage 3+ ROP.1However, their end point for recurrence of disease was only 54 weeks' postmenstrual age (PMA). Previously, Moshfeghi and Berrocal2 estimated that 47.7% of recurrences would have occurred after the 54 weeks' PMA reported in the BEAT-ROP study as the primary end point for treatment success. In this journal, Hu et al3 described their clinical experience with recurrence of ROP following intravitreal injection of bevacizumab, adding further evidence that 54 weeks' PMA is not a sufficient end point for observation. Hu and colleagues reported 17 eyes of 9 patients who had recurrence of ROP requiring treatment on average 14.4 weeks after bevacizumab injection (range, 4-35 weeks). Notably, 5 eyes that progressed to having retinal detachment (RD) did so at a median age of 55 weeks' PMA (range, 49-69 weeks). They mentioned the shortfalls of their study as retrospective, uncontrolled, and small in number. Also, the period in which their patients were seen in relation to recent publications on bevacizumab was not described, and patients were seen and managed by different ophthalmologists without prior examination by authors of the study in some cases. Thus, this retrospective study raises concerns about nonstandardized use of a new treatment modality. Most importantly, 2 patients had repeated intravitreal injections of bevacizumab within a relatively short period. One patient (patient 3) had 6 doses of bevacizumab, 0.625 mg (total, 3.75 mg), in a 7-week period, and another patient (patient 9) had 5 doses in the same period (total, 3.125 mg). Sato et al4 showed that a total dose injection of only 0.5 mg of bevacizumab causes a 6-fold reduction in serum vascular endothelial growth factor 2 weeks after injection in neonates. There are no data for repeated injections, but by implication, patients 3 and 9 in the article by Hu and colleagues were likely to have been subjected to even lower serum vascular endothelial growth factor levels. Systemic adverse effects remain the biggest concern among ROP experts in both the short and long term.5-7 We therefore welcome the recommendation that recurrences of ROP should be treated with laser, not just because of a reduced RD rate3 but also for protecting the patient from systemic complications. We are in uncharted waters with regard to patterns of recurrence following bevacizumab treatment. Hu and colleagues defined recurrence as “arrest of anterior progression of retinal vasculature associated with a new demarcation line, ridge, or extraretinal fibrovascular proliferation (EFP) or leakage on fluorescein angiography, with or without recurrence of plus disease.”3 Recurrence did not require EFP. They also observed anatomical recurrence as anterior and/or posterior. This is different from the definitions in the BEAT-ROP study.1 There is a need for the larger ROP community to standardize the definition and re-treatment criteria for recurrence after bevacizumab injection. In the study by Hu and colleagues, both recurrence criteria and treatment were at the discretion of the treating ophthalmologist. Again, questions can be raised regarding some patients with the information provided in the article. For example, patient 9 was born at 32 weeks' PMA, weighed 1843 g at birth, and reportedly developed aggressive posterior ROP in zone 1 with atypical stage 3 and plus disease at 35 weeks.3 Aggressive posterior ROP is usually considered to occur in the tiniest and most premature babies8; in our combined experience, we have not seen such a scenario in a developed country and we find the case surprising. It is unusual for such a case to even be eligible for screening, let alone to have such severe disease warranting treatment 3 weeks after birth (the first screening examination is normally 4 weeks after birth).9 Again, without further information and independent verification, it is difficult to draw conclusions from this case as the figures attributed to the case (unlabeled as to the PMA they represent) do not match the severity described.3 This study also demonstrates the problems relating to unknown follow-up protocol for patients with ROP after bevacizumab injection.3 It is not reported whether the high proportion of RDs was due to loss to follow-up and hence preventable in some cases. For example, patient 2 was described as having stage 4A RD in the right eye at 50 weeks' PMA, progressing to stage 5 RD at 54 weeks' PMA. The patient's left eye was reported as having stage 5 RD at 55 weeks' PMA without any indication of what happened in this eye during the preceding 5 weeks while the fellow eye was being observed. It is difficult to deduce the speed and pattern of complications with the information available. The authors could not comment on whether the RDs were rhegmatogenous or tractional. Stage 5 RDs (3 patients) were categorized as anterior recurrence of ROP even though in the table of results the diagnosis was made at presentation.3 However, if injections were carried out at 2.5 mm behind the limbus as described in the BEAT-ROP study,1 a rhegmatogenous cause may be the culprit as this distance lies in full-thickness retina in a neonate.10 Nevertheless, it is appropriate to conclude that with bevacizumab, regular long-term observation is vital to identify potentially preventable RDs. How often follow-up should be performed is not known, and loss to follow-up is of greater concern than laser-treated eyes, which on average have a more predictable course within 12 weeks.2 The study demonstrates the need for long-term follow-up requiring skilled ophthalmological observation and emphasizes that while bevacizumab injection treatment may be less time-consuming than laser as initial therapy, it has significant long-term follow-up issues. This has implications in terms of workforce commitment for ophthalmologists and the necessity to ensure that the patients are brought for outpatient assessment. Despite the shortfalls of the study by Hu and colleagues, the study demonstrates that late recurrence after bevacizumab injection is a major cause for concern. Recurrence with resulting RD has a very poor prognosis; therefore, missed recurrence can severely affect the child's vision. The authors conclude that “only with complete vascularization to the ora serrata and no active disease can treatment [with bevacizumab] be considered successful.”3 Parents should be alerted of the need for prolonged regular follow-up visits and the potential need for a general anesthetic for indented examination of the peripheral retina and possibly a fluorescein angiogram in some of the older children (≥50 weeks' PMA). Further standardized and controlled studies with longer follow-up are required so that the late recurrence of ROP can be assessed, and they should also aim to establish a safe end point for ROP screening examinations following bevacizumab monotherapy. Finally, it is important to note that laser photocoagulation for ROP does not have the problem of recurrence. There may be a failure to adequately respond to laser, but once ROP has regressed it does not recur weeks to months later.11 The concluding paragraph of the Early Treatment of ROP (ETROP) randomized trial states, “Even with the addition of early [laser] treatment for selected eyes with prethreshold ROP, some eyes will still progress to an unfavorable visual and/or structural outcome. Thus, additional research is needed to identify better methods for the prevention and treatment of severe ROP.”11 Hence, no treatment is perfect for ROP at present and the search must continue for better outcomes. Bevacizumab may not be the ideal treatment if the problems of recurrence and suboptimal local and systemic long-term safety profiles prove to be only the tip of the iceberg. Back to top Article Information Correspondence: Dr Mireskandari, Department of Ophthalmology and Visual Sciences, The Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8, Canada (kamiar.mireskandari@sickkids.ca). Conflict of Interest Disclosures: None reported. References 1. 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):603-61521323540PubMedGoogle ScholarCrossref 2. Moshfeghi DM, Berrocal AM. Retinopathy of prematurity in the time of bevacizumab: incorporating the BEAT-ROP results into clinical practice. Ophthalmology. 2011;118(7):1227-122821724044PubMedGoogle Scholar 3. Hu J, Blair MP, Shapiro MJ, Lichtenstein SJ, Galasso JM, Kapur R. Reactivation of retinopathy of prematurity after bevacizumab injection. Arch Ophthalmol. 2012;130(8):1000-100622491394PubMedGoogle ScholarCrossref 4. Sato T, Wada K, Arahori H, et al. Serum concentrations of bevacizumab (Avastin) and vascular endothelial growth factor in infants with retinopathy of prematurity. Am J Ophthalmol. 2012;153(2):327-333, e121930258PubMedGoogle ScholarCrossref 5. Gilbert CE, Zin A, Darlow B. Bevacizumab for retinopathy of prematurity. N Engl J Med. 2011;364(24):2359-2360, author reply 2361-236221675898PubMedGoogle ScholarCrossref 6. Gole GA, Camuglia JE, Ells AL. Bevacizumab for retinopathy of prematurity. N Engl J Med. 2011;364(24):2360-2361, author reply 236221675896PubMedGoogle Scholar 7. Lim LS, Cheung CM, Mitchell P, Wong TY. Emerging evidence concerning systemic safety of anti-VEGF agents: should ophthalmologists be concerned? Am J Ophthalmol. 2011;152(3):329-33121855670PubMedGoogle ScholarCrossref 8. International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005;123(7):991-99916009843PubMedGoogle ScholarCrossref 9. Section on Ophthalmology, American Academy of Pediatrics; American Academy of Ophthalmology; American Association for Pediatric Ophthalmology and Strabismus. Screening examination of premature infants for retinopathy of prematurity [published corrections appear in Pediatrics. 2006;117(4):1468 and Pediatrics. 2006;118(3):1324]. Pediatrics. 2006;117(2):572-57616452383PubMedGoogle ScholarCrossref 10. Hairston RJ, Maguire AM, Vitale S, Green WR. Morphometric analysis of pars plana development in humans. Retina. 1997;17(2):135-1389143042PubMedGoogle ScholarCrossref 11. 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):1684-169414662586PubMedGoogle ScholarCrossref

Journal

JAMA OphthalmologyAmerican Medical Association

Published: Apr 1, 2013

References

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