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   Table of Contents      
Year : 2007  |  Volume : 55  |  Issue : 6  |  Page : 417-420

Bevacizumab: Off-label use in ophthalmology

University Eye Hospital at the Centre of Ophthalmology, Eberhard-Karls University of Tuebingen, Germany

Date of Submission13-Apr-2007
Date of Acceptance02-Jul-2007

Correspondence Address:
Salvatore Grisanti
University Eye Hospital, Centre of Ophthalmology, Eberhard-Karls University of Tuebingen Schleichstrasse 12-15 72076 Tuebingen
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0301-4738.36474

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Bevacizumab is a full-length, humanized monoclonal antibody directed against all the biologically active isoforms of vascular endothelial growth factor (VEGF-A). The antibody was initially designed and studied as an anti-angiogenic strategy to treat a variety of solid tumors. After approval by the US Food and Drug Administration, bevacizumab gained access into ophthalmology to treat various types of neovascular diseases. Since the first report in 2005 more than 100 publications share the experience with bevacizumab in ophthalmology. Two authors independently assessed the research results from Pubmed to April 2007. The reference list is a selection of key publications related to the issue. Currently, there is no well-designed randomized controlled trial yet to establish the efficacy and safety of intraocular bevacizumab for any ocular disease in spite of its assumed characteristics representing the most cost-effective VEGF inhibitor.

Keywords: Bevacizumab, intravitreal injection, neovascular ocular disease

How to cite this article:
Grisanti S, Ziemssen F. Bevacizumab: Off-label use in ophthalmology. Indian J Ophthalmol 2007;55:417-20

How to cite this URL:
Grisanti S, Ziemssen F. Bevacizumab: Off-label use in ophthalmology. Indian J Ophthalmol [serial online] 2007 [cited 2020 Sep 27];55:417-20. Available from: http://www.ijo.in/text.asp?2007/55/6/417/36474

More than 35 years ago a man had a dream. Judah Folkman hypothesized that cancer may be treated by abolishing the nutrients and oxygen-providing blood vessels. The term anti-angiogenic therapy was born and bevacizumab (AVASTIN , Genentech, Inc.) became the first therapy approved by the US Food and Drug Administration (FDA) designed to inhibit angiogenesis in tumors.

Angiogenesis is a complex multifaceted process influenced by several factors. Inducers and inhibitors balance the angiogenic switch which finally turns the process on or off. Though the number of known factors is steadily increasing, vascular endothelial growth factor (VEGF)-A seems to play a very pivotal role and is the primary target of recent anti-angiogenic strategies. An extensive number of experimental studies have established that VEGF plays a central role in the development of several ocular pathologies characterized by neovascularization and increased vascular permeability.

The logical consequence was a therapeutic regimen specifically targeting VEGF. Though other VEGF inhibitors are being developed or already licensed to treat ocular diseases, the anticancer drug, bevacizumab, found its way into ophthalmology and clinical practice all around the world.

  Description of Bevacizumab Top

Bevacizumab is a full-length, humanized monoclonal antibody directed against all the biologically active isoforms of VEGF-A. [1] It is a recombinant IgG1 antibody with a molecular weight of about 149kD that is produced in a Chinese Hamster Ovary mammalian cell expression system in a nutrient medium containing the antibiotic gentamicin. [2] AVASTIN (bevacizumab) is a clear to slightly opalescent, colorless to pale brown, sterile solution with pH 6.2. It was originally designed for intravenous (IV) infusion and is supplied in 100 mg and 400 mg preservative-free, single-use vials to deliver 4 mL or 16 mL of AVASTIN (25 mg/mL). The product is formulated in alpha-trehalose dihydrate, sodium phosphate (monobasic, monohydrate), sodium phosphate (dibasic, anhydrous), polysorbate and water for injection. [2]

  Mechanism of Action Top

Bevacizumab binds to the receptor-binding domain of all VEGF-A isoforms. Consequently, it prevents the interaction between VEGF-A and its receptors (Flt-1 and KDR) on the surface of endothelial cells which starts the intracellular signaling pathway leading to endothelial cell proliferation and new blood vessel formation. [1]

  Clinical Application Top

Bevacizumab was primarily developed for the treatment of a variety of solid tumors. [3],[4],[5] In 2004, the FDA approved bevacizumab for the treatment of metastatic colorectal cancer in combination with standard chemotherapy. [4] The recommended dose of bevacizumab for colorectal cancer is 5 mg/kg given once daily every two weeks as an IV infusion.

Though not formally studied or approved for any intraocular disease, Rosenfeld's pioneering work [6],[7] and the unavailability of a related ocular drug, ranibizumab, led to rapid and wide use of bevacizumab all over the world. After initial studies were done with IV injections, this route of administration was not generally accepted due to higher costs and due to a more conceivable risk of systemic side-effects. [8],[9]

Efficacy of intravitreal bevacizumab in experimental and clinical studies

Preclinical data suggested that full-length antibodies would not penetrate the retina and be useful for subretinal pathologies such as choroidal neovascularization (CNV) in age-related macular degeneration (AMD). [10] The publication of clinical cases demonstrating the impressive resolution of macular fluid in neovascular AMD and central retinal vein occlusion (CRVO), however, raised doubts about the previous assumption. [6],[7] Meanwhile, several studies demonstrated that bevacizumab is able to penetrate the retina after intravitreal injection. [11],[12] More published case series of bevacizumab treatment for different neovascular ocular pathologies indicated a positive anatomical and functional effect. [13],[14],[15],[16],[17] First clinical results indicate a promising efficacy profile for neovascular AMD. [18],[19] Though only small numbers have been investigated yet, there seems to be no difference between distinct types of CNV. [13] Promising results have been shown also for myopic CNV [20],[21],[22] , CNV secondary to angioid streak [23],[24] and juxtafoveal telangiectasia. [25],[26] Currently, only short-term results on efficacy and safety are available. [27],[28] Further aspects, such as pretreatment and/or combination with other therapies and different treatment intervals are making our understanding more complicated. [29],[30],[31],[32],[33]

Safety of intravitreal bevacizumab in experimental and clinical studies

Bevacizumab was not intended and therefore not formally studied or approved for intraocular use. The need for a potent drug led to its off-label use, but also to an impressive research effort to exclude local and systemic side-effects. In clinical practice, local side-effects did not seem to differ compared to other intraocular drugs. [34],[35],[36] Rarely, intraocular inflammation was observed. [37] A small series of patients did not reveal an increase in flare. [38],[39] In electrophysiological studies no negative side-effects were seen on the retina. In contrast, the results showed a recovery effect on photoreceptors even at the site of the CNV. [40] Most of the in vitro , ex vivo and in vivo experiments excluded short-term negative effects on ocular cells and histology. [41],[42],[43],[44],[45] A recent paper, however, discloses mitochondrial disruption in the inner segment of photoreceptors and apoptosis after high doses of intravitreal bevacizumab in the rabbit eye. [46] The electrophysiological investigation and light microscopy, in contrast appeared unaltered. This suggests that potential side-effects on the cellular level cannot be detected with the present diagnostic tools in clinical practice.

A potential side-effect that strikes the clinician is the apparently increased incidence of retinal pigment epithelium (RPE) tears (5 to 10%), most often after large and hemorrhagic pigment epithelium detachment. [47],[48] It has been postulated that the fast resolution of fluid and/or contraction of the fibrous tissue may cause the rip.

Although the full-length antibody bevacizumab is larger in size and has therefore extended half-life (5.5 days) in the eye, it still leaves the ocular compartment and gets access to the systemic circulation. [49] This explains the biological effects observed in the contralateral eye after intravitreal application. [13] The risk of hypertension and thromboembolic events has been described for systemic application in cancer patients. [4] The risk of systemic side-effects in multiple applications remains unclear. Some patients displayed significantly elevated blood pressure levels after intravitreal injections [50],[51] but there is no controlled collection of adverse events yet. Patients must be, therefore, meticulously informed about all potential risks of intraocular injection in general and about bevacizumab therapy in particular. [52],[53]

  Conclusions Top

Though data from controlled trials are lacking, bevacizumab appears to be safe and effective in the short term. The evidence for efficacy and safety is increasing, but the quality of the studies is still low compared to controlled multicenter trials for drug approval. The physician has to be aware of their responsibility towards the patient. This not only includes the risks associated with the off-label use, but also the cost problem and the availability of approved drugs for different ocular pathologies.

  References Top

Ferrara N, Hillan KJ, Nowotny W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 2005;333:328-35.  Back to cited text no. 1
Available from: http://www.gene.com/gene/products/information//oncology/avastin.  Back to cited text no. 2
Presta LG, Chen H, O'Connor SJ, Chisholm V, Meng YG, Krummen L, et al . Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 1997;57:4593-9.  Back to cited text no. 3
Hurwitz HI, Fehrenbacher L, Hainsworth JD, Heim W, Berlin J, Holmgren E, et al . Bevacizumab plus irnotecan, fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-42.  Back to cited text no. 4
Yang JC, Harworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, et al . A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for mewztastatic renal cancer. N Engl J Med 2003;349:427-34.  Back to cited text no. 5
Rosenfeld PJ, Mosfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2005;36:331-5.  Back to cited text no. 6
Rosenfeld PJ, Fung AE, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for macular edema from central retinal vein occlusion. Ophthalmic Surg Lasers Imaging 2005;36:336-9.  Back to cited text no. 7
Michels S, Rosenfeld PJ, Puliafito CA, Marcus EN, Venkarraman AS. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: Twelve-week results of an uncontrolled open-label clinical study. Ophthalmology 2005;112:1035-47.  Back to cited text no. 8
Nguyen QD, Shah S, Tatlipinar S, Do DV, Anden EV, Campochiaro PA. Bevacizumab suppresses choroidal neovascularization caused by pathological myopia. Br J Ophthalmol 2005;89:1368-70.  Back to cited text no. 9
Mordenti J, Cuthbertson RA, Ferrara N, Thomsen K, Berleau L, Licko V, et al . Comparisons of the intraocular tissue distribution, pharmacokinetics and safety of 125J-labeled full-length and Fab antibodies in rhesus monkeys following intravitreal administration. Toxicol Pathol 1999;27:536-44.  Back to cited text no. 10
Shahar J, Avery RL, Heilweil G, Barak A, Zemel E, Lewis GP, et al . Electrophysiologic and retinal penetration studies following intravitreal injection of Bevacizumab (Avastin). Retina 2006;26:362-9.  Back to cited text no. 11
Heiduschka P, Fietz H, Hofmeister S, Schultheiss S, Mack A, Ziemssen F, et al . Penetration of bevacizumab through the retina after intravitreal injection in monkey. Invest Ophthalmol Vis Sci 2007;48:2814-23.  Back to cited text no. 12
Avery RL, Pearlman J, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, et al . Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology 2006;113:1695.e1-15.  Back to cited text no. 13
Spaide RF, Fisher YL. Intravitreal bevacizumab (Avastin) treatment of proliferative diabetic retinopathy complicated by vitreous hemorrhage. Retina 2006;26:275-8.  Back to cited text no. 14
Spaide RF, Laud K, Fine HF, Klancnik JM Jr, Meyerle CB, Yannuzzi LA, et al . Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina 2006;26:383-90.  Back to cited text no. 15
Iturralde D, Spaide RF, Meyerle CB, Klancnik JM, Yannuzzi LA, Fisher YL, et al . Intravitreal bevacizumab (Avastin) treatment of macular edema in central retinal vein occlusion: A short-term study. Retina 2006;26:279-84.  Back to cited text no. 16
Avery RL. Regression of retinal and iris neovascularization after intravitreal bevacizumab (Avastin) treatment. Retina 2006;26:352-4.  Back to cited text no. 17
Aisenbrey S, Ziemssen F, Volker M, Gelisken F, Szurman P, Grisanti S, et al . Intravitreal bevacizumab (Avastin) for occult choroidal neovascularization in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2006;Epub ahead of print.  Back to cited text no. 18
Yoganathan P, Deramo VA, Lai JC, Tibrewala RK, Fastenberg DM. Visual improvement following intravitreal bevacizumab (Avastin) in exudative age-related macular degeneration. Retina 2006;26:994-8.  Back to cited text no. 19
Sakaguchi H, Ikuno Y, Gomi F, Kamei M, Sawa M, Tsujikawa M, et al . Intravitreal injection of bevacizumab for choroidal neovascularization caused by pathological myopia. Br J Ophthalmol 2006;91:161-5.  Back to cited text no. 20
Laud K, Spaide RF, Freund KB, Slakter J, Klancnik JM. Treatment of choroidal neovascularization in pathologic myopia with intravitreal bevacizumab. Retina 2006;26:960-3.  Back to cited text no. 21
Tewari A, Dhalla MS, Apte RS. Intravitreal bevacizumab for treatment of choroidal neovascularization in pathologic myopia. Retina 2006;26:1093-4.  Back to cited text no. 22
Teixeira A, Moraes N, Farah ME, Bonomo PP. Choroidal neovascularization treated with intravitreal injection of bevacizumab (Avastin) in angioid streaks. Acta Ophthalmol Scand 2006;84:835-6.  Back to cited text no. 23
Lommatzsch A, Spital G, Trieschmann M, Pauleikhoff D. Intraocular application of bevacizumab for the treatment of choroidal neovascularization secondary to angioid streaks. Ophthalmologe 2007;104:325-8.  Back to cited text no. 24
Jorge R, Costa RA, Calucci D, Scott IU. Intravitreal bevacizumab (Avastin) associated with the regression of subretinal neovascularization in idiopathic juxtafoveolar retinal telangiectasis. Graefes Arch Clin Exp Ophthalmol 2007;245:1045-8.  Back to cited text no. 25
Mandal S, Venkatesh P, Abbas Z, Vohra R, Garg S. Intravitreal bevacizumab (Avastin) for subretinal neovascularization secondary to type 2A idiopathic juxtafoveal telangiectasia. Graefes Arch Clin Exp Ophthalmol 2007;Epub ahead of print.  Back to cited text no. 26
Rich RM, Rosenfeld PJ, Puliafito CA, Dubovy SR, Davis JL, Flynn HW Jr, et al . Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Retina 2006;26:495-511.  Back to cited text no. 27
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