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Clinical Therapeutics/Volume ], Number ], 2015

Prevention of Recurrent Pterygium with Topical Bevacizumab


0.05% Eye Drops: A Randomized Controlled Trial
Ngamjit Kasetsuwan, MD; Usanee Reinprayoon, MD; and Vannarut Satitpitakul, MD
Department of Ophthalmology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn
Memorial Hospital, Bangkok, Thailand

ABSTRACT tolerated. The trend for recurrence was lower in


Purpose: We assessed the efficacy and tolerability of the topical bevacizumab group. ClinicalTrials.gov
topical bevacizumab 0.05% when used as an adjunc- identifier: NCT01311960. (Clin Ther. 2015;]:]]]–]]])
tive therapy after excision of primary pterygia. & 2015 Elsevier HS Journals, Inc. All rights reserved.
Methods: This randomized double-masked study Key words: antivascular endothelial growth factor,
included 22 patients (22 eyes) with primary pterygia bevacizumab, pterygium, pterygium surgery, recurrence
who underwent pterygium surgery with the use of the pterygium.
bare sclera technique. After pterygium excision,
22 patients were randomized to receive the topical
bevacizumab 0.05% (12 eyes) or the placebo (10 eyes) INTRODUCTION
with the use of the block of four randomization Pterygium is a degenerative and proliferative fibrovascu-
method. Topical bevacizumab and placebo were lar disorder of the ocular surface, usually a triangular- or
applied in the respective groups 4 times daily for 3 wing-shaped tissue, extending from the conjunctiva onto
months. Follow-up evaluations for recurrence by slit- the cornea. Various adjunctive measures are applied to
lamp photography were conducted once monthly. prevent recurrence of pterygia after excision, including
Ocular and systemic adverse events were assessed medical methods (ie, mitomycin-C [MMC], β-irradiation)
every 2 weeks during the 3 months of treatment. and surgical methods (ie, conjunctival graft, amniotic
The slit-lamp photographs were masked and analyzed. membrane graft). Both MMC and β-irradiation are
The primary and secondary outcomes were the differ- associated with recurrence rates that range from 0% to
ences in the pterygial recurrence rates between the 38%. However, their use was associated with serious
groups and adverse events at 3 months, respectively. sight-threatening adverse events, including necrotizing
Corneal recurrence was defined as recurrent fibrovas- scleritis and perforation.1 Many studies have reported
cular tissue invading the cornea; conjunctival recur- that conjunctival and limbal autografts with MMC
rence was defined as either recurrent vessels or fibrous reduce the rates of pterygial recurrence (0%–7%).
tissue in the excised area without corneal invasion. However, various factors, including primary or
Findings: All 22 patients completed follow-up at recurrent status of the pterygia, patient age, surgeon, or
3 months after the start of the trial medications. After patient preference, affect the surgical outcomes. Until
3 months of treatment, 1 patient (8.33%) and 3 now, the data could not definitively recommend a
patients (30.00%) from the bevacizumab and placebo specific adjuvant as a beneficial choice.2
groups, respectively, had a corneal recurrence. No In the past 2 decades, studies of vascular endothe-
significant (P ¼ 0.293) differences were found be- lial growth factor (VEGF) drugs have led to the deve-
tween the groups as determined by Fisher’s exact test. lopment of new ophthalmic therapies, including those
However, conjunctival and corneal recurrences were for pterygia. The overexpression of VEGF in the
found in 4 (33.33%) and 9 (90.00%) patients, pterygium tissue suggested that this factor was involved
respectively, in the bevacizumab and placebo groups,
a difference that reached significance (P ¼ 0.01). No Accepted for publication August 31, 2015.
significant adverse events developed. http://dx.doi.org/10.1016/j.clinthera.2015.08.023
Implications: Topical bevacizumab, as an adjunc- 0149-2918/$ - see front matter
tive treatment after pterygium excision, was well & 2015 Elsevier HS Journals, Inc. All rights reserved.

] 2015 1
Clinical Therapeutics

in the pathogenesis of the disorder.3 Bevacizumab One surgeon (N.K.) performed all pterygial sur-
(Avastin, Genentech Inc, South San Francisco, CA), a geries with the use of the bare sclera technique.
monoclonal antibody to VEGF-A, prevents attachment Tetracaine 2.0% without adrenaline was injected
of VEGF-A to its receptors. Because bevacizumab subconjunctivally. The pterygial head was removed
inhibits proliferation of endothelial cells and formation from the apex with the use of a surgical scalpel blade
of new blood vessels,4 the drug was suggested as a no. 15. The pterygial body was dissected from the
potential adjunctive treatment after pterygial excision. overlying conjunctiva. Subconjunctival pterygia also
This randomized, double-masked controlled trial was were excised to achieve as clear a margin as possible.
designed to evaluate the efficacy and tolerability of The bare scleral area was 5  7 mm. Postoper-
topical bevacizumab 0.05% eye drops as an adjunctive atively, all patients received tobramycin with dexame-
therapy after excision of primary pterygia via the bare thasone eye drops that were administered 4 times
sclera technique. daily for 1 month, followed by fluorometholone 0.1%
4 times daily for another 2 months.
PATIENTS AND METHODS After completion of the epithelial healing, all study
This prospective, randomized controlled study was patients were randomly assigned to either the bevaci-
conducted at the Department of Ophthalmology, King zumab or control groups. The patients were randomly
Chulalongkorn Memorial Hospital. The sample size assigned to the bevacizumab or placebo group with
was calculated with the use of a statistical superiority the use of the block of four method, and all random-
design formula with a power of 0.8, a two-tailed ization numbers were concealed in closed envelopes.
significant level of 0.05. This indicated a sample size The bevacizumab group (12 eyes, 12 patients) re-
of 9 patients per group. Twenty percent of the ceived bevacizumab 0.05% eye drops and the control
sample size was added in anticipation of drop-out group (10 eyes, 10 patients) received normal saline eye
patients; the total sample size of the present study was drops 4 times daily for 3 months. All patients and an
22 cases. The Institutional Review Board, Faculty of outcomes assessor were blinded to the treatment
Medicine, Chulalongkorn University, approved and assignments. Bevacizumab 0.05% eye drops were
monitored the study, which is registered at clinical- prepared from the standard intravenous solution
trials.gov as NCT01311960. The study adhered to the diluted in 0.9% saline under laminar flow at the
tenets of the Declaration of Helsinki. All patients hospital pharmacy department and stored at –201C
provided written informed consent to participate in until use.5 All patients were instructed to store the
this research. study medication and placebo at 41C during use.
Patients diagnosed with primary pterygia and The demographic data, including sex, age, duration
scheduled for a pterygial excision with the use of the of outdoor activity, laterality of the pterygia, and
bare sclera technique were enrolled consecutively. appearance of the preoperative pterygia were recor-
Patients with corneal melt, corneal epitheliopathy, ded. Assessments for recurrent pterygia were per-
and abnormal healing of a corneal epithelial wound, formed on weeks 4, 8, and 12 after starting the study
and those who were pregnant, lactating, or allergic to medication. The grading scale used to assess pterygial
bevacizumab or steroids were excluded. recurrence is shown in Table I.6 The patients were

Table I. Grading scale for assessing recurrence of pterygium.

Grade Description

1 No differences in the appearance of the operated site compared with normal, healthy controls
2 Some fine episcleral vessels in the excised area extending up to, but not beyond, the limbus and
without any fibrous tissue
3 Additional fibrous tissues in the excised area that have not invaded the cornea
4 A true recurrence, with fibrovascular tissue invading the cornea

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N. Kasetsuwan et al.

Table II. Demographic data of the study population.

Demographic data Bevacizumab group (n ¼ 12) Placebo group (n ¼ 10)

Female sex, n (%) 7 (58.3) 5 (50.0)


Age, mean (SD) [range], y 50.7 (10.4) [37–65] 59.3 (11.3) [42–75]
Outdoor activity, mean (SD) [range], h/wk 5.3 (4.9) [1–21] 9.1 (8.5) [0.5–25]
Left laterality, n (%) 7 (58.33) 6 (50.00)
Preoperative pterygium, n (%)
Atrophic 0 (0.00) 1 (10.0)
Intermediate 9 (75.00) 7 (70.0)
Fleshy 3 (25.00) 2 (20.0)

evaluated for ocular adverse events that included with artificial tears, and the defects resolved without
corneal melt, corneal and conjunctival epithelial recurrence within 7 days. No systemic adverse events
defects, and systemic adverse events, including dry developed.
mouth, voice changes, loss of appetite, stomach pain,
back pain, stroke, and patient compliance at weeks 2, DISCUSSION
4, 6, 8, 10, and 12 postoperatively. Recurrence of pterygia is a major complication after
Fisher’s exact test was used to assess the differences pterygium surgery. Although the pathogenesis for
in the recurrence rates for pterygia between both recurrent pterygia was studied widely, the mechanism
groups at 3 months with the use of SPPSS version remains unknown. The typical degenerative connec-
21 software (IBM Corporation, Armonk, NY). P o tive tissue changes seen in primary pterygia are absent
0.05 was considered significant. in the histologic findings in recurrent pterygia. Re-
current pterygia often have more exuberant fibrovas-
RESULTS cular growth.3 Many growth factors, including VEGF,
Twenty-two eyes of 22 patients were included in fibroblast growth factor, platelet-derived growth fac-
this study. The demographic data are shown in tor, transforming growth factor-β, and tumor necrosis
Table II. factor-α were found in pterygial tissues and are
The outcomes assessor was masked before data believed to play a key role in the formation of the
analysis. Three months after medications were started, fibrovascular tissue in recurrent pterygia.7
most patients in the bevacizumab group had a grade 1 VEGF-A is part of the platelet-derived growth
recurrence, whereas most patients in the placebo factor supergene family and plays a major role in
group had a grade 2 recurrence. One and 3 patients the angiogenesis process via VEGF receptor-1 and -2.8
in the bevacizumab and the placebo groups, respec- Increased concentrations of VEGF-A were detected in
tively, developed true recurrence (grade 4). The
recurrence rates between the groups did not differ
significantly (P ¼ 0.29). Four (33.33%) and 9 Table III. Recurrence scores for pterygium after 3
(90.00%) patients in the bevacizumab and placebo months of treatment.
groups, respectively, had conjunctival and cornea
Recurrence Bevacizumab Placebo group
recurrences (grades 2–4). The recurrence rates for
grading, n (%) group (n = 12) (n = 10)
grades 2 to 4 differed significantly between the groups
(P ¼ 0.01) (Table III). 1 8 (66.67) 1 (10.00)
A conjunctival epithelial defect developed in 1 2 2 (16.67) 5 (50.00)
patient in the bevacizumab group at week 2. A corneal 3 1 (8.33) 1 (10.00)
epithelial defect was observed in 1 patient in the 4 1 (8.33) 3 (30.00)
placebo group at week 4. Both patients were treated

] 2015 3
Clinical Therapeutics

pterygial epithelium, and its expression also is corre- have a major role in development of low-grade
lated with postoperative recurrences.7,9 Moreover, recurrent pterygia, but VEGF-C may play a more
overexpression of VEGF receptor-2 is thought to be important role in preventing progression of conjunc-
primarily responsible for proangiogenic signaling and tival recurrence to corneal recurrence.
also is correlated positively with postoperative recur- To prevent recurrence of pterygia, complete removal
rent pterygium.10,11 Blocking VEGF may inhibit fi- of the pterygial tissue is necessary, otherwise it serves as a
brovascular growth formation in recurrent pterygia. source of VEGF-A in the recurrence process. A combi-
Bevacizumab is a monoclonal antibody that blocks nation of topical anti–VEGF-A with a topical steroid can
VEGF-A. Previously, 2 different modalities of bevacizu- help prevent recurrences especially in the first 3 months
mab were investigated for the treatment of primary postoperatively, which is the most critical period for
pterygia: subconjunctival bevacizumab alone or as an recurrences. Other anti–VEGF-C or antilymphagiogenic
adjunctive therapy after pterygial excision. Two random- factors such as GS-101, thrombospondin-1 inhibitor,21
ized controlled trials,12,13 1 case series,14 and 1 case and vasohibin122 also can help prevent recurrences,
report,15 found that subconjunctival bevacizumab re- but additional studies are needed.
duced the symptoms and sizes of pterygia, but the The limitations of this study were the small number
effect was temporary and not clinically relevant.12–15 of patients and the short follow-up period. Moreover,
Furthermore, Razeghinejad et al16 and Shenasi et al17 until now no standard regimens for both the concen-
reported that subconjunctival bevacizumab used as an trations and frequencies of the drugs have been used.
adjunctive therapy after primary pterygial surgery did not The various concentrations and regimens of bevaci-
significantly prevent recurrence of pterygia, even though zumab eye drops used to prevent pterygial recurrence
the treatment was well tolerated. The reason for this may should be studied to address these limitations.
be because of the short-term temporary effect of the drug.
Topical bevacizumab eye drops may be more CONCLUSIONS
appropriate and effective than the subconjunctival Topical bevacizumab 0.05%, as an adjunctive treatment
form for inhibiting continuous generation of VEGF. after pterygial excision for 3 months, tended to lower the
In the present study, topical bevacizumab was used combined rate of conjunctival and corneal recurrences
during the first 3 months postoperatively, which is the compared with placebo. However, the rates of corneal
most critical period for recurrences.18 The study found recurrence at 3 months did not differ significantly
a declining trend for corneal recurrences in the between topical bevacizumab 0.05% and placebo. No
bevacizumab group. Most patients in the bevaci- significant local and systemic side effects developed in
zumab group had a grade 1 recurrence, which association with instillation of topical bevacizumab.
indicated that there were no differences in the
appearance of the conjunctiva postoperatively and ACKNOWLEDGMENTS
3 months after treatment. In addition, the prevalence Dr. Kasetsuwan contributed in study design, data
rates of conjunctival and corneal recurrences were collection and writing. Dr. Reinprayoon contributed
markedly lower in the patients in the bevacizumab in data collection and interpretation. Dr. Satitpitakul
group than patients in the placebo group. contributed in literature search, table creation, study
In the present study, topical bevacizumab prevented design, data collection, data interpretation and writing.
large changes in the appearance of the conjunctiva This study was funded by Asia Research Center,
postoperatively. This finding confirmed the findings Chulalongkorn University.
from previous studies that reported that the VEGF-A
concentration was significantly higher in conjunctival CONFLICTS OF INTEREST
recurrence of pterygia compared with normal conjunc- Asia Research Center, Chulalongkorn University,
tiva. However, no difference was found in the VEGF-A Bangkok, Thailand funded this study The study
expression in moderate to high-grade corneal recur- sponsor had no role in the study design, data collec-
rence pterygia. In contrast to VEGF-A, VEGF-C tion, data interpretation, manuscript writing, and
expression was increased slightly in low-grade pterygia decision to submit the manuscript for publication.
but dramatically expressed in high-grade pterygia.19,20 The authors have indicated that they have no conflicts
We hypothesized that VEGF-A and angiogenesis may of interest regarding the content of this article.

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N. Kasetsuwan et al.

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