Use and abuse of anti-angiogenic drugs for ROP treatment

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Graham E. Quinn, MD MSCE,1 Brian A. Darlow MD FRACP FRCPCH,2 Andrea A. Zin, MD, MSC3

1 Division of Ophthalmology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States

2 Department of Paediatrics, University of Otago, Christchurch, New Zealand

3 Department of Neonatology, Fernandes Figueira Institute, Rio de Janeiro, Brazil

Peripheral retinal ablation for serious (Type 1) retinopathy of prematurity (ROP) is successful in preventing blindness in the vast majority of eyes and this therapy has been examined in large randomized trials with 5-15 year outcomes over the last 25 years.(1-3) At present, laser photocoagulation of the peripheral avascular retina is the gold standard treatment for severe ROP. However, there is now increased understanding of the cascade of vasoproliferative factors that are integral to the normal and abnormal development of the retinal vasculature and an increased interest in use of the promising anti-angiogenic drugs to treat serious ROP.(4,5) Such drugs as pegaptanib, ranibizumab and bevacizumab has proven useful in treatment of neovascular ocular diseases such as macular degeneration and diabetic retinopathy.(6-11)

Over the last few years, several case studies and case series from around the world have reported the use of vascular endothelial growth factor inhibitors (anti-VEGF – usually bevacizumab) to treat eyes with severe ROP. Micelli (12) summarized the reports of off-label use of bevacizumab from 2007 to 2009 and found that most treatment was for zone I disease or AP-ROP (aggressive posterior ROP). In 77 eyes of 48 babies, most bevacizumab treatment was administered after laser had failed or combined with laser as primary treatment. He noted concerns about the dosage, timing, frequency of treatment, as well as possible ocular and systemic long term effects.

In February 2011, Dr Mintz-Hittner and colleagues (13) reported a multicenter, randomized trial (BEAT-ROP) in which 150 babies with serious ROP (actually a subset of Type 1 ROP eyes, i.e. those eyes with plus disease and stage 3 ROP in zone I or posterior zone II). Babies were assigned to receive intravitreal bevacizumab (0.625 mg) or to undergo laser photocoagulation. The primary outcome measure was nonblinded and consisted of the proportion of eyes that required retreatment by 54 weeks postmenstrual age. Retreatment was done in 4/70 (6%) eyes in the bevacizumab group and 19/73 (26%) eyes in the laser group (p=0.002). When zone of disease was considered, the treatment was significant only in patients with zone I disease (P=0.003). The timing of recurrences in the bevacizumab was much delayed compared to the laser group (19.2±8.6 weeks vs 6.4±6.7 weeks). Dr. Mintz-Hittner and colleagues concluded that the treatment may result in better outcomes and an accompanying editorial by James Reynolds, MD stated that bevacizumab should be considered the treatment of choice for severe zone I disease.(14)

The study by Dr. Mintz-Hittner et al opens the exciting possibility of using a biopharmacologic treatment for severe ROP rather than conventional laser photocoagulation. However, there are concerns about methodology and data interpretation in this study.(15-16) In addition to using non-standard treatment criteria and using an unmasked primary outcome measure, ROP may have recurred after the outcome was measured since there is some evidence suggesting that anti-VEGF drugs might damp down the acute disease with recurrence happening months later—in essence creating an iatrogenic and chronic familial exudative vitreoretinopathy type picture. This would require longer, frequent retinal examinations to detect late recurrences. Further, the observed rate of 26% for needing retreatment after laser photocoagulation was much higher than in published series of less than 15%.(3)

Perhaps most importantly, the BEAT-ROP study was not designed to examine longer term ocular and systemic side effects. As noted by A.L. Hard and A. Hellstrom in Acta Paediatrica (17), the postmenstrual age when serious ROP develops is a period of rapid new vessel growth in lungs, kidney and brain, and interruption with anti-VEGF medication may have serious unintended consequences. There is good evidence in animal models that higher serum concentrations of bevacizumab are noted after intravitreal injection at an earlier age and studies in humans have found VEGF levels significantly reduced at 1 month after a single intravitreal injection of bevacizumab. (18-21) A recent report of 11 infants with ROP treated with intravitreal bevacizumab after failed laser therapy showed that serum drug levels reached a peak after 2 weeks while VEGF concentrations were low at 1 and 2 weeks after injection.(22)

At this point, circumspection is recommended when considering the use of intravitreal injection of bevacizumab for severe ROP.(23) This is especially true in middle-income countries where many infants who develop severe ROP are bigger and more mature than those in countries with well established NICU systems.(24) Few of these babies have zone I disease in contrast to the babies treated in the BEAT-ROP trial.

It is premature to conclude that bevacizumab injection is superior to conventional laser photocoagulation.(25) However, compassionate use of bevacizumab may be considered in cases that fail with conventional treatment after carefully informing parents of possible detrimental effects. In addition, adequately powered, masked, randomized clinical trials to evaluate the long-term ocular and systemic safety of this drug are essential at this time. We must be alert and design systems to detect possible ocular and systemic harm in our most vulnerable patients. At our present state of understanding of this exciting potential treatment, caution is required.

References

1. Cryotherapy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity: preliminary results. Arch Ophthalmol 1988;106:471-479.

2. Palmer EA, Hardy RJ, Dobson V, et al. 15-year outcomes following threshold retinopathy of prematurity: final results from the multicenter trial of cryotherapy for retinopathy of prematurity. Arch Ophthalmol 2005;123:311-318.

3. Early Treatment for Retinopathy of Prematurity Cooperative Group. Revised Indications for treatment of retinopathy of prematurity. Results of the Early Treatment for Retinopathy of Prematurity randomized trial. Arch Ophthalmol 2003;121:1684-1696.

4. Smith LEH. Through the eyes of a child: understanding retinopathy through ROP. The Friedenwald Lecture. Invest Ophthalmol Vis Sci 2008;19:5177-82

5. Heidary G, Löfqvist C, Mantagos IS, et al. Retinopathy of prematurity: clinical insights from molecular studies. NeoReviews 2009;10:e550-557.

6. Aiello LP, Pierce EA, Foley ED, et al. Suppression of retinal neovascularization in vivo by inhibition of vascular endotelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci USA. 1995;92:10457-10461.

7. van Wijngaarden P, Coster DJ, Williams KA. Inhibitors of ocular neovascularisation: promises and potential problems. JAMA 2005;293:1509-1513.

8. Rosenfeld J, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419-1431.

9. Fung AE, Rosenfeld PJ, Reichel E. The international intravitreal bevacizumab safety survey: using the internet to assess drug safety worldwide. Br J Ophthalmol 2006;90:1344-1349.

10. The CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364:1897-19

11. Quiroz-Mercado H, Ustariz-González O, Martinez-Castellanos MA, et al. our experience after 1765 intravitreal injections of bevacizumab: the importance of being part of a developing story. Semin Ophthalmol 2007;22:109-125.

12. Micelli JA, Surkont M, Smith AF. A systematic analysis of the off-label use of bevacizumab for severe retinopathy of prematurity. Am J Ophthalmol 2009;148:536-543.

13. Mintz-Hittner HA, Kennedy KA, Chuang AZ. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. New Engl J Med 2011;364:603-615.

14. Reynolds JD. Bevacizumab for retinopathy of prematurity. New Engl J Med 2011;364:677-678

15. Moshfeghi DM, Berrocal AM. Retinopathy of prematurity in the time of bevacizumab: incorporating the BEAT-ROP results into clinical practice. Ophthalmology 2011;118:1227-1228.

16. Correspondance. Bevacizumab for retinopathy of prematurity. New Engl J Med 2011;364:2359-2361.

17. Hård A-L, Hellström A. On the use of antiangiogenetic medications for retinopathy of prematurity. Acta Paediatrica 2011;100:1063-1065.

18. Wu WC, Lai CC, Chen KJ, et al. Long-term tolerability and serum concentration of bevacizumab (avastin) when injected in newborn rabbit eyes. Invest Ophthalmol Vis Sci 2010;51:3701-3708.

19. Rice D, Barone S. critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect 2000;108(suppl 3):511-533.

20. Heiduschka P, Fietz H, Hofmeister S, et al. Penetration of bevacizumab through the retina after intravitreal injection in the monkey. Invest Ophthalmol Vis Sci 2007;48:2814-2823.

21. Matsuyama K, Ogata N, Matsuoka M, et al. Plasma levels of vascular endothelial growth factor and pigment epithelium-derived factor before and after intravitreal injection of bevacizumab. Br J Ophthalmol 2010;94:1215-1218.

22. 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 2011 Sep 17 [Epub ahead of print]

23. Lim LS, Cheung CMG, Mitchell P, Wong TY. Emerging evidence concerning systemic safety of anti-VEGF agents – should ophthalmologists be concerned? Am J Ophthalmol 2011;152:329-331

24. Gilbert C, Fielder A, Gordillo L, et al. Characteristics of infants with severe retinopathy of prematurity in countries with low, moderate, and high levels of development: implications for screening programs. Pediatrics 2005;115:e518-e525.

25. Harder BC, von Baltz S, Jonas JB, Schlichtenbrede FC. Intravitreal bevacizumab for retinopathy of prematurity. J Ocul Pharmacol Ther 2011 Aug 8. [Epub ahead of print]

Brian Darlow

MA MB BChir MD FRCP FRACP FRCPCH was born in London and attended Cambridge University, where he undertook an initial degree in basic sciences before completing his medical degree in 1973. His post-graduate training was in the UK, Papua New Guinea and New Zealand. He completed his MD in 1989 with a thesis entitled “The epidemiology of retinopathy of prematurity in New Zealand”.

Professor Darlow holds the CureKids Chair of Paediatric Research at the University of Otago, Christchurch where he completed a ten year term as Head of the Department of Paediatrics in 2010. His clinical work has been predominantly as a neonatologist and his main research interests have focussed on free-radical disease in the newborn including retinopathy or prematurity, longer term outcome following preterm birth, and neonatal networking and unit variations in outcome. He has been principal investigator on over 12 project grants from the NZ Health Research Council, together with other grants from various funding bodies and is the author of over 140 original publications. Professor Darlow has been a member of the Australia and New Zealand Neonatal Network (ANZNN) Executive since its foundation in1994 and is now Chair of the Network Management Committee. For the past few years he has contributed to workshops aimed at improving care of the newborn and the prevention and treatment of retinopathy of prematurity in several developing and middle-income countries.

Graham Quinn

MD, MSCE, is an Attending Surgeon in the Division of Pediatric Ophthalmology at The Children’s Hospital of Philadelphia and director of research for the Division. He is also a Professor of Ophthalmology at the University of Pennsylvania. Dr. Quinn received his medical degree from Duke University School of Medicine in 1973. He completed an internship in internal medicine and a year of pathology residency at Case Western Reserve University in Cleveland before moving to Philadelphia to complete his residency in ophthalmology at Penn. He did his fellowship training at The Children’s Hospital of Philadelphia and stayed on as a member of the faculty in the Department of Ophthalmology at the University of Pennsylvania. Dr. Quinn completed the master’s of science degree in Clinical Epidemiology and Biostatistics at the University of Pennsylvania.

Dr. Quinn’s interest areas are retinopathy of prematurity (ROP) and visual and ocular development in children. He was a principal investigator and member of the executive and editorial committees of the landmark CRYO-ROP study and PI of the Philadelphia center and worked with Velma Dobson, PhD in the Vision Testing center for ETROP. He served as a member of the original group that developed the International Classification of ROP and recently chaired a “revisiting” of the classification. He has participated in a large number of international conferences and workshops on ROP prevention and treatment in countries with rapidly developing neonatal care systems. Recent work has concentrated on early markers identifying at risk babies and also telemedicine in ROP.

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