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

3 One surgeon (N.K.) performed all pterygial sur-geries

in the pathogenesis of the disorder. Bevacizumab
(Avastin, Genentech Inc, South San Francisco, CA), a
monoclonal antibody to VEGF-A, prevents attachment of
VEGF-A to its receptors. Because bevacizumab inhibits
proliferation of endothelial cells and formation of new
4 dissected
blood vessels, the drug was suggested as a potential
adjunctive treatment after pterygial excision. This
randomized, double-masked controlled trial was designed
to evaluate the efficacy and tolerability of topical
bevacizumab 0.05% eye drops as an adjunctive therapy
after excision of primary pterygia via the bare sclera
technique.
with the use of the bare sclera technique. Tetracaine 2.0%
without adrenaline was injected subconjunctivally. The
pterygial head was removed from the apex with the use
of a surgical scalpel blade no. 15. The pterygial body was
from the overlying conjunctiva.
Subconjunctival pterygia also were excised to achieve as
clear a margin as possible. The bare scleral area was 5 7
mm. Postoper-atively, all patients received tobramycin
with dexame-thasone eye drops that were administered 4
times daily for 1 month, followed by fluorometholone
0.1% 4 times daily for another 2 months.

PATIENTS AND METHODS
This prospective, randomized controlled study was
conducted at the Department of Ophthalmology, King
Chulalongkorn Memorial Hospital. The sample size was
calculated with the use of a statistical superiority design
formula with a power of 0.8, a two-tailed significant level
of 0.05. This indicated a sample size of 9 patients per
group. Twenty percent of the sample size was added in
anticipation of drop-out patients; the total sample size of
the present study was 22 cases. The Institutional Review
Board, Faculty of Medicine, Chulalongkorn University,
approved and monitored the study, which is registered at
clinical-trials.gov as NCT01311960. The study adhered
to the tenets of the Declaration of Helsinki. All patients
provided written informed consent to participate in this
research.
Patients diagnosed with primary pterygia and
scheduled for a pterygial excision with the use of the bare
sclera technique were enrolled consecutively. Patients
with corneal melt, corneal epitheliopathy, and abnormal
healing of a corneal epithelial wound, and those who
were pregnant, lactating, or allergic to bevacizumab or
steroids were excluded.
After completion of the epithelial healing, all study
patients were randomly assigned to either the bevaci-
zumab or control groups. The patients were randomly
assigned to the bevacizumab or placebo group with the
use of the block of four method, and all random-ization
numbers were concealed in closed envelopes. The
bevacizumab group (12 eyes, 12 patients) re-ceived
bevacizumab 0.05% eye drops and the control group (10
eyes, 10 patients) received normal saline eye drops 4
times daily for 3 months. All patients and an outcomes
assessor were blinded to the treatment assignments.
Bevacizumab 0.05% eye drops were prepared from the
standard intravenous solution diluted in 0.9% saline
under laminar flow at the hospital pharmacy department
5
and stored at –201C until use. All patients were
instructed to store the study medication and placebo at
41C during use.
The demographic data, including sex, age, duration of
outdoor activity, laterality of the pterygia, and appearance
of the preoperative pterygia were recor-ded. Assessments
for recurrent pterygia were per-formed on weeks 4, 8,
and 12 after starting the study medication. The grading
scale used to assess pterygial recurrence is shown in
6
Table I. 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

2 Volume ] Number ]
 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 corneal
melt, corneal and conjunctival epithelial defects, and
systemic adverse events, including dry mouth, voice
changes, loss of appetite, stomach pain, back pain, stroke,
and patient compliance at weeks 2, 4, 6, 8, 10, and 12
postoperatively.
Fisher’s exact test was used to assess the differences in
the recurrence rates for pterygia between both groups at 3
months with the use of SPPSS version 21 software (IBM
Corporation, Armonk, NY). P o 0.05 was considered
significant.
RESULTS
Twenty-two eyes of 22 patients were included in this
study. The demographic data are shown in Table II.
The outcomes assessor was masked before data
analysis. Three months after medications were started,
most patients in the bevacizumab group had a grade 1
recurrence, whereas most patients in the placebo group
had a grade 2 recurrence. One and 3 patients in the
bevacizumab and the placebo groups, respec-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 (90.00%) patients in the
bevacizumab and placebo groups, respectively, had
conjunctival and cornea recurrences (grades 2–4). The
recurrence rates for grades 2 to 4 differed significantly
between the groups (P ¼ 0.01) (Table III).
A conjunctival epithelial defect developed in 1 patient
in the bevacizumab group at week 2. A corneal epithelial
defect was observed in 1 patient in the placebo group at
week 4. Both patients were treated
with artificial tears, and the defects resolved without
recurrence within 7 days. No systemic adverse events
developed.
DISCUSSION
Recurrence of pterygia is a major complication after
pterygium surgery. Although the pathogenesis for
recurrent pterygia was studied widely, the mechanism
remains unknown. The typical degenerative connec-tive
tissue changes seen in primary pterygia are absent in the
histologic findings in recurrent pterygia. Re-current
pterygia often have more exuberant fibrovas-cular
3
growth. Many growth factors, including VEGF,
fibroblast growth factor, platelet-derived growth fac-tor,
transforming growth factor-β, and tumor necrosis factor-
α were found in pterygial tissues and are believed to play
a key role in the formation of the fibrovascular tissue in
7
recurrent pterygia.
VEGF-A is part of the platelet-derived growth factor
supergene family and plays a major role in the
8
angiogenesis process via VEGF receptor-1 and -2.
Increased concentrations of VEGF-A were detected in
Table III. Recurrence scores for pterygium
after 3 months of treatment.
Recurrence Bevacizumab Placebo group
grading, n (%) group (n = 12) (n = 10)
1 8(66.67) 1 (10.00)
2 2(16.67) 5 (50.00)
3 1(8.33) 1 (10.00)
4 1(8.33) 3 (30.00)

] 2015 3
 Clinical Therapeutics
pterygial epithelium, and its expression also is corre-lated
7,9
with postoperative recurrences. Moreover,
overexpression of VEGF receptor-2 is thought to be
primarily responsible for proangiogenic signaling and
also is correlated positively with postoperative recur-rent
10,11
pterygium. Blocking VEGF may inhibit fi-
brovascular growth formation in recurrent pterygia.
Bevacizumab is a monoclonal antibody that blocks
VEGF-A. Previously, 2 different modalities of bevacizu-
mab were investigated for the treatment of primary
pterygia: subconjunctival bevacizumab alone or as an
adjunctive therapy after pterygial excision. Two random-
12,13 14
ized controlled trials, 1 case series, and 1 case
15
report, found that subconjunctival bevacizumab re-
duced the symptoms and sizes of pterygia, but the effect
12–15
was temporary and not clinically relevant.
16 17
Furthermore, Razeghinejad et al and Shenasi et al
reported that subconjunctival bevacizumab used as an
adjunctive therapy after primary pterygial surgery did not
significantly prevent recurrence of pterygia, even though
the treatment was well tolerated. The reason for this may
be because of the short-term temporary effect of the drug.
Topical bevacizumab eye drops may be more
appropriate and effective than the subconjunctival form
for inhibiting continuous generation of VEGF. In the
present study, topical bevacizumab was used during the
first 3 months postoperatively, which is the most critical
18
period for recurrences. The study found a declining
trend for corneal recurrences in the bevacizumab group.
Most patients in the bevaci-zumab group had a grade 1
recurrence, which indicated that there were no differences
in the appearance of the conjunctiva postoperatively and
3 months after treatment. In addition, the prevalence rates
of conjunctival and corneal recurrences were markedly
lower in the patients in the bevacizumab group than
patients in the placebo group.
In the present study, topical bevacizumab prevented
large changes in the appearance of the conjunctiva
postoperatively. This finding confirmed the findings from
previous studies that reported that the VEGF-A
concentration was significantly higher in conjunctival
recurrence of pterygia compared with normal conjunc-
tiva. However, no difference was found in the VEGF-A
expression in moderate to high-grade corneal recur-rence
pterygia. In contrast to VEGF-A, VEGF-C expression
was increased slightly in low-grade pterygia but
19,20
dramatically expressed in high-grade pterygia. We
hypothesized that VEGF-A and angiogenesis may
4 Volume ] Number ]
have a major role in development of low-grade recurrent
pterygia, but VEGF-C may play a more important role in
preventing progression of conjunc-tival recurrence to
corneal recurrence.
To prevent recurrence of pterygia, complete removal
of the pterygial tissue is necessary, otherwise it serves as
a source of VEGF-A in the recurrence process. A combi-
nation of topical anti–VEGF-A with a topical steroid can
help prevent recurrences especially in the first 3 months
postoperatively, which is the most critical period for
recurrences. Other anti–VEGF-C or antilymphagiogenic
21
factors such as GS-101, thrombospondin-1 inhibitor,
22
and vasohibin1 also can help prevent recurrences, but
additional studies are needed.
The limitations of this study were the small number of
patients and the short follow-up period. Moreover, until
now no standard regimens for both the concen-trations
and frequencies of the drugs have been used. The various
concentrations and regimens of bevaci-zumab eye drops
used to prevent pterygial recurrence should be studied to
address these limitations.
CONCLUSIONS
Topical bevacizumab 0.05%, as an adjunctive treatment
after pterygial excision for 3 months, tended to lower the
combined rate of conjunctival and corneal recurrences
compared with placebo. However, the rates of corneal
recurrence at 3 months did not differ significantly
between topical bevacizumab 0.05% and placebo. No
significant local and systemic side effects developed in
association with instillation of topical bevacizumab.
ACKNOWLEDGMENTS
Dr. Kasetsuwan contributed in study design, data
collection and writing. Dr. Reinprayoon contributed in
data collection and interpretation. Dr. Satitpitakul
contributed in literature search, table creation, study
design, data collection, data interpretation and writing.
This study was funded by Asia Research Center,
Chulalongkorn University.
CONFLICTS OF INTEREST
Asia Research Center, Chulalongkorn University,
Bangkok, Thailand funded this study The study sponsor
had no role in the study design, data collec-tion, data
interpretation, manuscript writing, and decision to submit
the manuscript for publication. The authors have
indicated that they have no conflicts of interest regarding
the content of this article.

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