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Bevacizumab (Avastin) for retinopathy of prematurity: Wrong dose, wrong drug, or both?

2012; Elsevier BV; Volume: 16; Issue: 1 Linguagem: Inglês

10.1016/j.jaapos.2011.11.002

1528-3933

Robert L. Avery,

Retinal and Optic Conditions

Interest in and controversy over the use of bevacizumab (Avastin; Genentech/Roche, South San Francisco, CA) for the treatment of retinopathy of prematurity (ROP) have increased dramatically after the Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) study.1Mintz-Hittner H.A. Kennedy K.A. Chuang A.Z. BEAT-ROP Cooperative GroupEfficacy of intravitreal bevacizumab for stage 3 retinopathy of prematurity.N Engl J Med. 2011; 364: 603-615Crossref PubMed Scopus (999) Google Scholar, 2Moshfeghi D.M. Berrocal A.M. Retinopathy of prematurity in the time of bevacizumab: Incorporating the BEAT-ROP results into clinical practice.Ophthalmology. 2011; 118: 1227-1228Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 3Darlow BA, Ells AL, Gilbert CE, Gole GA, Quinn GE. Are we there yet? Bevacizumab therapy for retinopathy of prematurity. Epub ahead of print Dec 30 2011. Arch Dis Child Fetal Neonatal Ed.Google Scholar Off-label bevacizumab has been used extensively for age-related macular degeneration (AMD) for more than 6 years, and recently the Comparison of AMD Treatments Trials showed it to have similar safety and efficacy to ranibizumab (Lucentis; Genentech/Roche, South San Francisco, CA) in this population.4Martin D.F. Maguire M.G. et al.CATT Research GroupRanibizumab and bevacizumab for neovascular age-related macular degeneration.N Engl J Med. 2011; 364: 1897-1908Crossref PubMed Scopus (25) Google Scholar There was, however, an increased incidence of systemic adverse events scattered across many organ systems in the bevacizumab arm of this study, the significance of which remains unclear.4Martin D.F. Maguire M.G. et al.CATT Research GroupRanibizumab and bevacizumab for neovascular age-related macular degeneration.N Engl J Med. 2011; 364: 1897-1908Crossref PubMed Scopus (25) Google Scholar There are pharmacokinetic differences between these two vascular endothelial growth factor (VEGF) inhibitors that may be important in at-risk populations such as infants with ROP undergoing organogenesis.5Tolentino M. Systemic and ocular safety of intravitreal anti-VEGF therapies for ocular neovascular disease.Surv Ophthalmol. 2011; 56: 95-113Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 6Meyer C.H. Holz F.G. Preclinical aspects of anti-VEGF agents for the treatment of wet AMD: Ranibizumab and bevacizumab.Eye (Lond). 2011; 25: 661-672Crossref PubMed Scopus (101) Google Scholar In adults the intrinsic serum elimination half-life of ranibizumab is approximately 2 hours, whereas that of bevacizumab is approximately 20 days because it is a full-length antibody with an Fc domain that binds Fc receptors on endothelial cells and reduces systemic clearance.5Tolentino M. Systemic and ocular safety of intravitreal anti-VEGF therapies for ocular neovascular disease.Surv Ophthalmol. 2011; 56: 95-113Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar The systemic pharmacokinetics of both ranibizumab and bevacizumab in children is unknown but could be longer. Early in the use of bevacizumab for proliferative diabetic retinopathy (DR), we noted a reduction in leakage of neovascularization in the contralateral, uninjected fellow eye, a finding that raised concern about systemic levels capable of therapeutic effects.7Avery R.L. Pearlman J. Pieramici D.J. et al.Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy.Ophthalmology. 2006; 113 (e1-15): 1695Abstract Full Text Full Text PDF PubMed Scopus (711) Google Scholar This observation prompted us to evaluate lower doses of intravitreal bevacizumab, and we showed reduction in neovascularization even when injecting a dose 200-fold below the typical dose (6.25 μg instead of 1.25 mg).7Avery R.L. Pearlman J. Pieramici D.J. et al.Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy.Ophthalmology. 2006; 113 (e1-15): 1695Abstract Full Text Full Text PDF PubMed Scopus (711) Google Scholar There was initial skepticism as to the causality of fellow eye effects, but these effects have now been observed after bevacizumab injection in DR, vein occlusion, and uveitic cystoid macular edema (CME).5Tolentino M. Systemic and ocular safety of intravitreal anti-VEGF therapies for ocular neovascular disease.Surv Ophthalmol. 2011; 56: 95-113Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 8Al-Dhibi H. Khan A.O. Bilateral response following unilateral intravitreal bevacizumab injection in a child with uveitic cystoid macular edema.J AAPOS. 2009; 13: 400-402Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar One recent report even demonstrated the resolution of CME and retinal neovascularization in the fellow eye of a patient treated with ranibizumab in a prospective trial for uveitic CME.9Acharya N.R. Sittivarakul W. Qian Y. Hong K.C. Lee S.M. Bilateral effect of unilateral ranibizumab in patients with uveitis-related macular edema.Retina. 2011; 31: 1871-1876Crossref PubMed Scopus (32) Google Scholar In several studies authors have not demonstrated fellow eye effects in the setting of AMD, but systemic effects may be most notable when there is significant breakdown of the blood–retina barrier, as in uveitis or rubeosis; furthermore, preretinal neovascularization seems to be much more sensitive to anti-VEGF agents than the more commonly treated choroidal neovascularization.7Avery R.L. Pearlman J. Pieramici D.J. et al.Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy.Ophthalmology. 2006; 113 (e1-15): 1695Abstract Full Text Full Text PDF PubMed Scopus (711) Google Scholar, 10Barbazetto I.A. Saroj N. Shapiro H. Wong P. Ho A.C. Freund K.B. Incidence of new choroidal neovascularization in fellow eyes of patients treated in the MARINA and ANCHOR trials.Am J Ophthalmol. 2010; 149 (e931): 939-946Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar Other evidence for systemic effects comes from pharmacology studies in rabbits and monkeys that have demonstrated detectable levels of bevacizumab in fellow eyes after intravitreal injection.11Bakri S.J. Snyder M.R. Reid J.M. Pulido J.S. Singh R.J. Pharmacokinetics of intravitreal bevacizumab (Avastin).Ophthalmology. 2007; 114: 855-859Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar, 12Miyake T. Sawada O. Kakinoki M. et al.Pharmacokinetics of bevacizumab and its effect on vascular endothelial growth factor after intravitreal injection of bevacizumab in macaque eyes.Invest Ophthalmol Vis Sci. 2010; 51: 1606-1608Crossref PubMed Scopus (103) Google Scholar After observing fellow eye effects and the sensitivity of preretinal neovascularization to anti-VEGF agents, I proposed the use of lower doses of bevacizumab or changing to ranibizumab when treating ROP to lower the systemic risk in this susceptible population.13Avery R.L. Extrapolating anti-vascular endothelial growth factor therapy into pediatric ophthalmology: Promise and concern.J AAPOS. 2009; 13: 329-331Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Subsequently, several investigators14Ziemssen F. Zhu Q. Peters S. et al.Intensified monitoring of circadian blood pressure and heart rate before and after intravitreous injection of bevacizumab: Preliminary findings of a pilot study.Int Ophthalmol. 2009; 29: 213-224Crossref PubMed Scopus (21) Google Scholar, 15Sato T, Wada K, Arahori H, et al. Serum concentrations of bevacizumab (Avastin) and vascular endothelial growth factor in infants with retinopathy of prematurity. Epub ahead of print Sep 17, 2011. Am J Ophthalmol.Google Scholar have confirmed the presence of bevacizumab in the serum after intravitreal injection; however, the assays for bevacizumab in human serum are technically challenging because of the presence of other human IgG. Decreased VEGF levels in human plasma or serum have also been reported after the injection of intravitreal bevacizumab. Ziemssen and colleagues14Ziemssen F. Zhu Q. Peters S. et al.Intensified monitoring of circadian blood pressure and heart rate before and after intravitreous injection of bevacizumab: Preliminary findings of a pilot study.Int Ophthalmol. 2009; 29: 213-224Crossref PubMed Scopus (21) Google Scholar showed a reduction in serum VEGF 1 day and 1 week after treatment of AMD in several patients. This finding was consistent with the increased serum bevacizumab levels they detected at these times. Matsuyama and colleagues16Matsuyama K. Ogata N. Matsuoka M. Wada M. Takahashi K. Nishimura T. Plasma levels of vascular endothelial growth factor and pigment epithelium-derived factor before and after intravitreal injection of bevacizumab.Br J Ophthalmol. 2010; 94: 1215-1218Crossref PubMed Scopus (125) Google Scholar noted a dramatic reduction in plasma VEGF levels 1 day, 1 week, and 1 month after a single injection of intravitreal bevacizumab in 11 patients with proliferative DR. Qian and colleagues17Qian J. Lu Q. Tao Y. et al.Vitreous and plasma concentrations of apelin and vascular endothelial growth factor after intravitreal bevacizumab in eyes with proliferative diabetic retinopathy.Retina. 2011; 31: 161-168PubMed Google Scholar showed a significant reduction in plasma VEGF after preoperative bevacizumab injections in patients with diabetes. Ma and colleagues18Ma Y, Zhang Y, Zhao T, Jiang YR. Vascular endothelial growth factor in plasma and vitreous fluid of patients with proliferative diabetic retinopathy patients after intravitreal injection of bevacizumab. Epub ahead of print Oct 7, 2011. Am J Ophthalmol.Google Scholar have recently confirmed this finding in patients with diabetes injected more than 1 month before the plasma VEGF level was measured. The authors of a large, prospective, randomized, controlled clinical trial in the United Kingdom, the Inhibit VEGF in Age-related choroidal Neovascularization (IVAN) trial, are comparing bevacizumab to ranibizumab for the treatment of AMD. Although this trial is ongoing and individual patients remain masked for treatment received, the authors recently reported a reduction in serum VEGF levels of the pooled samples from both treatment arms (Glenn JV et al. Fluctuating levels of circulating VEGF in a subset of patients as part of the multicentre IVAN study. IOVS 2011;52: ARVO E-abstract 5930). There was a statistically significant reduction in serum VEGF at 1 and 11 months into the trial, but the difference did not reach statistical significance at 12 months. Further results from IVAN are expected in 2012, but there is already published evidence that systemic effects may differ between bevacizumab and ranibizumab.19Carneiro AM, Costa R, Falcão MS, et al. Vascular endothelial growth factor plasma levels before and after treatment of neovascular age-related macular degeneration with bevacizumab or ranibizumab. Epub ahead of print Sep 29, 2011. Acta Ophthalmol.Google Scholar Carneiro and colleagues19Carneiro AM, Costa R, Falcão MS, et al. Vascular endothelial growth factor plasma levels before and after treatment of neovascular age-related macular degeneration with bevacizumab or ranibizumab. Epub ahead of print Sep 29, 2011. Acta Ophthalmol.Google Scholar have recently reported the plasma VEGF levels in a prospective study of patients receiving these drugs for AMD. One month after 3 monthly intravitreal injections, there was no statistically significant reduction in the plasma VEGF levels in ranibizumab-injected eyes, but the bevacizumab-injected eyes had a reduction from 190 pg/ml to 110 pg/ml (P = 0.0002).19Carneiro AM, Costa R, Falcão MS, et al. Vascular endothelial growth factor plasma levels before and after treatment of neovascular age-related macular degeneration with bevacizumab or ranibizumab. Epub ahead of print Sep 29, 2011. Acta Ophthalmol.Google Scholar There is additional evidence of the difference in systemic effects of bevacizumab and ranibizumab from two transgenic mice models of over expression of VEGF.20Miki K. Miki A. Matsuoka M. Muramatsu D. Hackett S.F. Campochiaro P.A. Effects of intraocular ranibizumab and bevacizumab in transgenic mice expressing human vascular endothelial growth factor.Ophthalmology. 2009; 116: 1748-1754Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar In both models, there was a marked systemic effect with bevacizumab, but not with ranibizumab. In fact, in one model, the uninjected, fellow eyes of mice treated with bevacizumab demonstrated the same treatment effect as eyes that were directly treated with ranibizumab, and in the more severe model, the treatment effect in the bevacizumab fellow eyes was significantly greater than that of the eyes directly treated with ranibizumab.20Miki K. Miki A. Matsuoka M. Muramatsu D. Hackett S.F. Campochiaro P.A. Effects of intraocular ranibizumab and bevacizumab in transgenic mice expressing human vascular endothelial growth factor.Ophthalmology. 2009; 116: 1748-1754Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar There is evidence that Fc receptors facilitate the movement of intravitreal IgG such as bevacizumab across the blood–ocular barrier into the bloodstream.21Kim H. Robinson S.B. Csaky K.G. FcRn receptor-mediated pharmacokinetics of therapeutic IgG in the eye.Mol Vis. 2009; 15: 2803-2812PubMed Google Scholar One potential explanation of these systemic effects is that a prolonged, elevated serum bevacizumab level developed due to its half-life and diffused into the fellow eye. In infants with ROP, two groups have reported dramatic reductions in the systemic VEGF levels following intravitreal bevacizumab.15Sato T, Wada K, Arahori H, et al. Serum concentrations of bevacizumab (Avastin) and vascular endothelial growth factor in infants with retinopathy of prematurity. Epub ahead of print Sep 17, 2011. Am J Ophthalmol.Google Scholar Sato and colleagues15Sato T, Wada K, Arahori H, et al. Serum concentrations of bevacizumab (Avastin) and vascular endothelial growth factor in infants with retinopathy of prematurity. Epub ahead of print Sep 17, 2011. Am J Ophthalmol.Google Scholar measured not only VEGF levels but also serum bevacizumab levels, which continued to increase from 1 day to 1 week to 2 weeks after injection. The serum VEGF levels dropped from 1628 pg/ml to 269 pg/ml 2 weeks after injection of a total of 0.5 mg of bevacizumab.15Sato T, Wada K, Arahori H, et al. Serum concentrations of bevacizumab (Avastin) and vascular endothelial growth factor in infants with retinopathy of prematurity. Epub ahead of print Sep 17, 2011. Am J Ophthalmol.Google Scholar Lee and colleagues reported the reduction of plasma VEGF levels from 2050 pg/ml pre-injection to 170 pg/ml at 1week after injection, and a continued weekly decrease to 50 pg/ml at 7 weeks, the last time tested (Lee S-J et al. Plasma level of vascular endothelial growth factor in retinopathy of prematurity after intravitreal injection of bevacizumab. IOVS 2011;52:ARVO E-abstract 3165). These VEGF levels are well below reported plasma levels measured in premature infants with and without ROP.22Pieh C. Agostini H. Buschbeck C. et al.VEGF-A, VEGFR-1, VEGFR-2 and Tie2 levels in plasma of premature infants: relationship to retinopathy of prematurity.Br J Ophthalmol. 2008; 92: 689-693Crossref PubMed Scopus (65) Google Scholar The bevacizumab dose used in this study was 0.625 mg/eye, one half of the normal adult dose, and most of the babies received bilateral injections. In a canine model that closely resembles ROP in eyes of approximately the same size, 3 doses of VEGF trap (Regeneron Pharmaceuticals, Tarrytown, NY), 5 μg, 25 μg, and 250 μg, were evaluated.23Lutty G.A. McLeod D.S. Bhutto I. Wiegand S.J. Effect of VEGF trap on normal retinal vascular development and oxygen-induced retinopathy in the dog.Invest Ophthalmol Vis Sci. 2011; 52: 4039-4047Crossref PubMed Scopus (67) Google Scholar All doses markedly inhibited intravitreal neovascularization, but the two higher doses also inhibited retinal revascularization as well as normal retinal vasculogenesis. These higher doses reduced the total retinal vascular area and the capillary density, whereas, the lowest dose inhibited the abnormal neovascularization, but not retinal revascularization or vasculogenesis.23Lutty G.A. McLeod D.S. Bhutto I. Wiegand S.J. Effect of VEGF trap on normal retinal vascular development and oxygen-induced retinopathy in the dog.Invest Ophthalmol Vis Sci. 2011; 52: 4039-4047Crossref PubMed Scopus (67) Google Scholar Lower doses of VEGF trap were not tested, and could have shown a beneficial effect, but the 5 μg dose is in the range of the 6.25 μg dose of bevacizumab, which was shown to reduce diabetic neovascularization in larger, adult eyes.7Avery R.L. Pearlman J. Pieramici D.J. et al.Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy.Ophthalmology. 2006; 113 (e1-15): 1695Abstract Full Text Full Text PDF PubMed Scopus (711) Google Scholar Injection of these doses should produce initial intravitreal concentrations greater than those which have been shown to inhibit VEGF in vitro.24Yu L. Liang X.H. Ferrara N. Comparing protein VEGF inhibitors: In vitro biological studies.Biochem Biophys Res Commun. 2011; 408: 276-281Crossref PubMed Scopus (83) Google Scholar However, VEGF trap has a greater affinity for VEGF than does bevacizumab and has been recently been reported to have potency similar to ranibizumab.24Yu L. Liang X.H. Ferrara N. Comparing protein VEGF inhibitors: In vitro biological studies.Biochem Biophys Res Commun. 2011; 408: 276-281Crossref PubMed Scopus (83) Google Scholar Nevertheless, these observations imply that the dose of bevacizumab (625 μg) commonly used for ROP may be an order of magnitude or two greater than what is required to have a beneficial effect. Furthermore, these high doses could potentially interfere with normal retinal vasculogenesis and revascularization.23Lutty G.A. McLeod D.S. Bhutto I. Wiegand S.J. Effect of VEGF trap on normal retinal vascular development and oxygen-induced retinopathy in the dog.Invest Ophthalmol Vis Sci. 2011; 52: 4039-4047Crossref PubMed Scopus (67) Google Scholar More importantly, unlike patients with AMD, infants with ROP are still in the processes of organogenesis, and VEGF plays a role in the development of most organs.5Tolentino M. Systemic and ocular safety of intravitreal anti-VEGF therapies for ocular neovascular disease.Surv Ophthalmol. 2011; 56: 95-113Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar For example, VEGF has been implicated in alveolar development and lung maturation.25Kasahara Y. Tuder R.M. Taraseviciene-Stewart L. et al.Inhibition of VEGF receptors causes lung cell apoptosis and emphysema.J Clin Invest. 2000; 106: 1311-1319Crossref PubMed Scopus (964) Google Scholar, 26Compernolle V. Brusselmans K. Acker T. et al.Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice.Nat Med. 2002; 8: 702-710Crossref PubMed Google Scholar In the BEAT-ROP trial, there was 1 death caused by lung disease in the laser arm and 4 in the bevacizumab arm, 2 of whom died after they were discharged to home and were off oxygen monitoring at about 49-50 weeks postmenstrual age.1Mintz-Hittner H.A. Kennedy K.A. Chuang A.Z. BEAT-ROP Cooperative GroupEfficacy of intravitreal bevacizumab for stage 3 retinopathy of prematurity.N Engl J Med. 2011; 364: 603-615Crossref PubMed Scopus (999) Google Scholar This difference was not statistically significant, but the study was not powered to evaluate safety.1Mintz-Hittner H.A. Kennedy K.A. Chuang A.Z. BEAT-ROP Cooperative GroupEfficacy of intravitreal bevacizumab for stage 3 retinopathy of prematurity.N Engl J Med. 2011; 364: 603-615Crossref PubMed Scopus (999) Google Scholar We know that lung disease is a common comorbidity in infants with ROP and may have nothing to do with the use of bevacizumab, yet there is now evidence that systemic VEGF levels can be depressed for many weeks, if not months, after an injection of intravitreal bevacizumab. Consideration should be given to decreasing the systemic exposure by injecting a lower effective dose and/or changing to a drug such as ranibizumab, which has much more rapid systemic clearance. Further studies evaluating lower doses of these drugs are indicated to achieve the full potential of anti-VEGF therapy for ROP with minimal risk of side effects in this susceptible population.