A Randomized Controlled Prospective Study to Assess the role of Subconjunctival Bevacizumab in Preventing Recurrence in Primary Pterygium Excision

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1 IOSR Journal of Dental and Medical Sciences (IOSR-JDMS e-issn: , -ISSN: Volume 15, Iss 11 Ver. IX (November. 216, PP A Randomized Controlled Prosective Study to Assess the role of Subconjuncti Bevacizumab in Preventing Recurrence in Primary Pterygium Excision Ekta Singla,Sachin Walia,Harsimran Singh,Navreet Kaur Abstract Purose: To euate the safety and efficacy of subconjucti bevacizumab on reventing the recurrence in rimary terygium excision Methods: This randomized, lacebo controlled clinical trial was conducted on eyes of atients attending the ohthalmology OPD,Rajindra Hosital Patiala, randomized to 1 (bevacizumab 2 atients and (balanced salt solution 2 atients. 1 underwent terygium excision and received a total of ml subconjucti bevacizumab( 2.5mg/ml on the day of surgery. received balanced salt solution in the same manner. Recurrence defined as any fibrovascular tiss crossing the limbus, and the number of atients with >1.5mm fibrovascular overgrowth on the cornea were comared between the study grous. Results: There were no statistically significant differences between the grous for all measured variables excet for the statistically significant rise in IOP in grou 1 at the one week visit. Four atients in each grou at the three- and six-month visits, resectively, had more than 1.5 mm fibrovascular tiss overgrowth on the cornea. Four eyes in grou 1 and 2 exerienced recurrence(=1 at month 3 and thereafter. Conclusion: Subconjucti Bevacizumab had no significant effect on the recurrence rate of rimary terygium excision and was not associated with any adverse effects. Keywords: Bevacizumab; Pterygium; Pterygium Recurrence; Neovascularisation I. Introduction A terygium is a triangular wing-like growth consisting of conjuncti eithelium and hyertrohied subconjuncti connective tiss that occurs nasally in the interalebral fissure, encroaching onto the cornea with unknown athology. [1,2] Pterygium may be defined as rimary or recurrent, the latter may occur several weeks to months after excision of a rimary terygium. A terygium consists of a head at its aex, an avascular ca and body. Tan et al. [3] develoed a simle clinical slit-lam grading scale based on relative translucency of the body of the terygium, which was redictive of recurrence. In this grading, T1 (atrohic denotes a terygium in which eiscleral vessels underlying the body of the terygium are unobscured and clearly distinguished. Grade T3 (fleshy denotes a thick terygium in which eiscleral vessels underlying the body of the terygium are totally obscured by fibrovascular tiss. Pterygia in which the eiscleral vessel details are indistinctly seen or artially obscured are categorized as grade T2 (intermediate. Pterygium occurs commonly in warm and dry climate with commonest age of onset aears to be in the 2s and 3s. [,5,6,7] The major environmental risk factor for the develoment of terygium is exosure to UV light which is absorbed by the cornea and conjunctiva romoting cellular damage and subseqnt cellular roliferation. [7-1] Another risk factors include genetic factors,dust, low humidity, and microtrauma from articulate matter, dry eyes and the human ailloma virus. [11-13] Pterygium is characterized by abnormal subeithelial tiss containing altered collagen fibres hence described as elastotic degeneration. [1-16] A number of treatment methods have been described which includes adjunctive medical methods (mitomycin c, 5 flurouracil, daunorubicin, thiotea dros, and cyclosorine dros instillation, beta irradiation and surgical methods (conjuncti autograft, amniotic membrane grafts, conjuncti flas, bare sclera techniq, and excision with lamellar keratolasty. [17] It has been well established that terygia are comosed of roliferating fibrovascular tiss and the terygium formation, and rogression require neovascularization, many molecules regulate angiogenesis have been identified, suggesting that the vascular endothelial growth factor (VEGF may be involved directly or indirectly in the athogenesis of terygia.[1] Various studies have shown that recurrence is high from 3% to % after simle excision in terygium and in excision with bare sclera it may be 32%. [1] VEGF has been detected in increased amounts in terygium eithelium, comared with normal conjunctiva by studies emloying immunohistochemistry. [2] DOI: 17/ Page

2 A Randomized Controlled Prosective Study To Assess The Role Of Subconjuncti Bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA, USA is a recombinant, humanized anti VEGF antibody that binds all VEGF isoforms and exerts a neutralizing effect by inhibiting the VEGF recetor interaction. It has been suggested as a ossible adjunctive theray for terygium excision that decreases the vascularity of newly formed blood vessels, hence decreasing the recurrence rate and aears to have a role in revention of recurrence. [21] In this study we euated the effect of a 2.5 mg dose of subconjuncti bevacizumab on the recurrence rate of rimary terygium excision. II. Methods This randomized, lacebo-controlled clinical trial was conducted on the atients attending the ohthalmology OPD of Rajindra hosital Patiala from July 215 to July 216 with recurrent terygium. Written informed consent was obtained from all atients and they were exlained about the ossible conseqnces. We interviewed the atient before hand to obtain information like ersonal data, contact number, any medical or ocular history, any history of drug allergy. Inclusion Criteria 1. Decreased visual acuity d to involvement of the visual axis 2. Discomfort and irritation unresonsive to lubricants 3. Restricted ocular motility. Cosmetic concerns 5. More than 3 mm extension of the terygium over the cornea. Exclusion Criteria 1. Patients with dry eye syndrome 2. Patients with collagen vascular disease 3. Patients with seudoterygium. Ocular surface disorders or infections 5. Previous ocular surgery 6. Allergy to Bevacizumab All the atients underwent slit lam examination to rule out any ocular surface disorder. Best corrected visual acuity (BCVA, manifest refraction and keratometry (Tocon Medical Systems, Inc., IOP (measured by schiotz indentation tonometry, detailed slit lam examination including horizontal length of the terygium in mm, and fundus examinations was done. Routine investigations like blood ressure, random blood sugar was done to all the atients. Toical antibiotic was started rior to the day of surgery. The following conditions were regarded as risk factors for recurrence: inflamed terygium, occuations with considerable solar exosure, recurrent terygium in the fellow eye, arcus senilis and age < 3 years. [22] We randomized the atients into 2 grous.patients in grou 1 (bevacizumab grou underwent terygium excision with a rotational conjuncti fla, and received 2.5 mg subconjuncti bevacizumab ( 2.5 mg/ ml on the day of surgery. Patients in grou also had terygium excision and a rotational conjuncti fla but received.2 ml balanced salt solution (BSS at the end of surgery but no more injections thereafter. Post-excision, the atients were examined at day 1, week 1, and months 1, 3, and 6 by the same examiner who was blind to the grous (second author. In ostoerative visits, the following factors were euated: horizontal dimension of the corneal eithelial defect in mm,conjucti congestion, conjuncti fla status (retraction, melting, or infection, refraction, keratometry, IOP, and recurrence (defined as more than 1.5 mm of fibrovascular tiss overgrowth on the cornea and any fibrovascular tiss crossing the limbus.[ 22,23] Surgical Techniq The surgery was erformed under local anaesthesia.to accomlish anesthesia, after instilling aracaine eye dros, subconjuncti lignocaine/ einehrine was injected under the area of the terygium, and the injected lignocaine was directed to the area of conjuncti fla harvest in the sueronasal quadrant using a cotton-ti alicator. The terygium was excised from its conjuncti side, and the corneal comonent was eeled off. After excision of the terygium, a edunculated conjuncti fla devoid of Tenon s casule was created from the adjacent suerior conjunctiva and was laced over the bare sclera and sutured with - Vicryl sutures. At the end of the surgery, ml bevacizumab (2.5 mg or BSS was injected in the inferior fornix deending on randomization. Postoeratively, a toical antibiotic (1%moxifloxacin, four times daily, a corticosteroid (% betamethasone, four times daily, and artificial tears (hydroxyroyl methylcellulose, four times daily were initiated and taered over the course of weeks. All sutures were removed at the one month visit. DOI: 17/ Page

3 A Randomized Controlled Prosective Study To Assess The Role Of Subconjuncti III. Results The study was conducted on eyes of atients with 2 eyes in each grou. All atients comleted the ostoerative visits, excet three who were lost to follow-u at month three and another subject at month six. There was no statistically significant difference between the study grous in terms of demograhic data, oerated eye, horizontal size of the terygium, duration of daily sun exosure, reoerative BCVA, keratomeric readings, corneal astigmatism, and IOP (Table 1. Regarding recurrence risk factors, there was also no significant difference between the study grous (Table 2. As shown in Table 3 the recurrence rate of terygium, changes in keratometry, corneal astigmatism, and conjuncti congestion in both grous revealed no statistically significant difference. Although no statistically significant difference was seen between grous for recurrence at all ostoerative visits, the number of atients who had fibrovascular tiss crossing the limbus in grou was twice that of grou 1 (7 versus at three months and versus at six months. Locally, no necrosis, ischemia, infection in the surgical bed area, or conjuncti retraction and melting develoed. Although baseline IOP was similar in both grous, atients in grou 1 exerienced a statistically significant rise at week one ostoeratively (P=. IOP returned to baseline levels in later visits with no intervention (Figure 1. The me standard deviation of keratometric readings on the first ostoerative month in grou 1 was 2.5±12. mm which was not significantly different from that of grou (2.6±11.7 mm, P=. Corresonding figures at the three and six monthly visits were also non-significant(p=1 & P=3 resectively. Post-oerative corneal astigmatism also failed to reach a statistically significant difference.(p=.36 Table 1: Table 1. Demograhics and ocular characteristics of the study atients 1 X 2 Number 2 2 Gender (Female/Male /11 1/ Eye (Right/Left /12 5/15.1 Age (Years.71± ± Sun exosure er day (hours.2± ± Horizontal terygium size (mm 2.5± ± Preoerative BCVA (logmar ±.5 ± Preoerative corneal astigmatism 2.15± ± (dioters Preoerative IOP (mmhg 13.12± ± BCVA, best corrected visual acuity; IOP, intraocular ressure Vals are resented in me standard deviations Table 2. Preence of risk factors for recurrence of terygium in grous 1 and 2 1 Inflamed terygium Occuations with considerable solar exosure Recurrent terygium in fellow eye 2.1 Arcus senilis Age <3 years No risk factor 1 2 Table 3. Recurrence of terygium and changes in keratomery, and corneal astigmatism over the ostoerative course in grous 1 and 2 Preo era tive Mont h 1 Mont h 3 Mon th 6 Recu rrenc e (any fibro vasc ular over grow th on the corn Gro u /2 (5% X 2 2/2 (1% DOI: 17/ Page /1 (15.7 % 7/1 (36. % X /1 (22. 22% /1 (2.1 % X

4 ntracular Pressure (mmhg A Randomized Controlled Prosective Study To Assess The Role Of Subconjuncti ea Recu rrenc e (> 1.5 mm fibro vasc ular over grow th on the corn ea Kera tome try SDa Conj uncti cong estio n SD Corn eal astig mati sm SD ± ( ± ±1.7 ( ± /1 (21. 5% ±12. (2.7 ± ± ±1 1.7 (2.62.2± ± ±11. 7 (2.65 2± ± 1.2 /1 (21. 5% 2.5 ±11. (2.56 ±.3 1.2± /1 (22. 22% 2.2 5±11.5 (2.5 ± ±1. /1 (21. 5% 1.5 ±11.2 ( ± ± IOP IV. Discussion The high rate of recurrence of terygium ost excision makes it a difficult task to manage. Since VEGF lays an imortant role in the athogenesis of the terygium, hence it was thought that Anti-VEGF could be beneficial.the resent study was conducted to euate the safety and efficacy of subconjucti bevacizumab on the recurrence rate of terygia when used as an adjunct to rimary excision and a rotational conjuncti fla. This is comatible with some other studies reorting no beneficial effect from bevacizumab administration on revention of terygium recurrence. In the resent study, all atients were followed for at least 6 months. Recurrence was defined as any fibrovascular growth of conjuncti tiss extending more than 1.5 mm across the limbus. The recurrence rate in both grous was similar and no serious ocular side effect was observed. A study conducted at Ohthalmology Deartment, Faculty of Medicine, Mansoura University, Mansoura, Egyt by Maha MS et al concluded that intraoerative subconjuncti bevacizumab following rimary terygium excision is not useful and ossibly harmful hence larger studies are needed.[2] DOI: 17/ Page

5 A Randomized Controlled Prosective Study To Assess The Role Of Subconjuncti Another study byrazeghinejad M.R conducted at Deartment of Ohthalmology,Khalili Hosital, Shiraz University of Medical Sciences concluded that a single intraoerative subconjuncti bevacizumab injection had no effect on recurrence rate or early ostoerative conjuncti erythema, lacrimation, hotohobia or healing of corneal eithelial defects following terygium excision. [25] A study by Sonia D et al showed that Bevacizumab does not imrove recurrence rates for terygia when used as an adjunctive theray ostoeratively. It may even cause increased rates of recurrence, although further studies are needed before arriving at this conclusion. [26] Another study conducted by Mohammad-Reza et al revealed that subconjuncti bevacizumab injections had no statistically but a robably clinically significant effect on the recurrence rate of terygia.[27] V. Conclusion In conclusion,this study found that although subconjucti Bevacizumab was not associated with any local adverse effects but it failed to show any significant reduction in rimary terygium recurrence.the limited number of atients,lack of routine follow-u and the difficulty in measuring the size of terygium before and after excision were the short comings of the study. However,It does not imly that Bevacizumab has no role in the management of terygium. Newer anti-angiogenic theraies will hoefully give better results in the future. References [1]. Duke-Elder S: Diseases of the outer eye. Syst Ohthalmol 165; : [2]. Coster D: Pterygium: an ohthalmic enigma. Br J Ohthalmol 15; 7:3-35. [3]. Tan DTH, Chee SP, Dear KBG, Lim ASM: Effect of terygium morhology on terygium recurrence in a controlled trial comaring conjuncti autografting with bare sclera excision. Arch Ohthalmol 17; 115: []. Saw SM, Tan D: Pterygium: reence, demograhy and risk factors. Ohthalmic Eidemiol 1; 6(2: [5]. Talbot G: Pterygium. Trans Ohthalmol Soc NZ 1; 2:2-5. [6]. Moran DJ, Hollows FC: Pterygium and ultraviolet radiation: a ositive correlation. Br J Ohthalmol 1; 6: [7]. 7.Hirst LW: Distribution, risk factors, and eidemiology of terygium. In: Taylor HR, ed. Pterygium, The Netherlands: Kugler Publications; 2:15-2. []. Coroneo M: Pterygium as an early indicator of ultraviolet insolation: a hyothesis. Br J Ohthalmol 13; 77: []. Cameron M: Ultra-violet radiation. Pterygium Throughout the World [1]. Liincott S, Blum H: Neolasms and other lesions of the eye induced by ultraviolet radiation in Strain A mice. J Natl Cancer Inst 13; 3: [11]. Rajiv, Mithal S, Sood A: Pterygium and dry eye a clinical correlation. Indian J Ohthalmol 11; 3: [12]. Dimitry T: The dust factor in the roduction of terygium. Am J Ohthalmol 137; 2:-5. [13]. Varinli S, Varinli I, Erkisi M, Doran F: Human aillomavirus in terygium. Central Afr J Med 1; :2-26. [1]. Austin P, Jakobiec FA, Iwamoto T: Elastodyslasia and elastodystrohy as the athologic bases of ocular terygia and ingcula. Ohthalmology 13; (1:6-1. [15]. Ansari M, Rahi A, Shukla B: Pseudoelastic nature of terygium. Br J Ohthalmol 17; 5: [16]. Vass Z, Taaszto I: The histochemical examination of the fibers of terygium by elastase. Acta Ohthalmol 16; 2:-5. [17]. Ang LP, Chua JL, Tan DT. Current concets and techniqs in terygium treatment. Curr Oin Ohthalmol 27;1:3 13. [1]. Hill JC, Maske R. Pathogenesis of terygium. Eye (Lond 1;3(Pt 2: [1]. Pajic B, Greiner RH. Long term results of non surgical, exclusive strontium /yttrium beta irradiation of terygia. Radiother Oncol 25;7:25. [2]. Lee DH, Cho HJ, Kim JT, Choi JS, Joo CK. Exression of vascular endothelial growth factor and inducible nitric oxide synthase in terygia. Cornea 21;2:73 2. [21]. Wu PC, Kuo HK, Tai MH, Shin SJ. Toical bevacizumab eyedros for limbal conjuncti neovascularization in imending recurrent terygium. Cornea 2;2:13. [22]. Razeghinejad MR, Hosseini H, Ahmadi F, Rahat F, Eghbal H. Preliminary results of subconjuncti bevacizumab in rimary terygium excision. Ohthalmic Res 21;3:13-13 [23]. Young AL, Tam PM, Leung GY, Cheng LL, Lam PT, Lam DS. Prosective study on the safety and efficacy of combined conjuncti rotational autograft with intraoerative 2% mitomycin C in rimary terygium excision. Cornea 2;2: [2]. Maha MS, Amal ME, Mohamed ME.Intraoerative Subconjuncti Bevacizumab as an Adjunctive Treatment in Primary Pterygium: A Preliminary Reort.Ohthalmic Surgery Lasers and Imaging August 212; 3(6:1- [25]. Razeghinejad MR,Hosseini H,Ahmadi F,Rahat F,Eghbal H. Preliminary Results of Subconjuncti Bevacizumab in Primary Pterygium Excision.Ohthalmic Res 21;3:13 13 (DOI:115/252 [26]. Sonia D,Howard G,Keith T. Role of Subconjuncti Bevacizumab in Post-Pterygium Excision Management. Investigative Ohthalmology & Visual Science June 213, Vol.5, 312. [27]. Mohammad-RR, Mohammad B. Subconjuncti Bevacizumab for Primary Pterygium Excision; a Randomized Clinical Trial. J Ohthalmic Vis Res. 21 Jan; (1: DOI: 17/ Page