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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 the


Purpose: We assessed the efficacy and tolerability of topical bevacizumab group. ClinicalTrials.gov identifier:
topical bevacizumab 0.05% when used as an adjunc-tive NCT01311960. (Clin Ther. 2015;]:]]]–]]])
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 who bevacizumab, pterygium, pterygium surgery, recurrence
underwent pterygium surgery with the use of the bare pterygium.
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 INTRODUCTION
the block of four randomization method. Topical Pterygium is a degenerative and proliferative fibrovascu-
bevacizumab and placebo were applied in the respective lar disorder of the ocular surface, usually a triangular- or
groups 4 times daily for 3 months. Follow-up evaluations wing-shaped tissue, extending from the conjunctiva onto
for recurrence by slit-lamp photography were conducted the cornea. Various adjunctive measures are applied to
once monthly. Ocular and systemic adverse events were prevent recurrence of pterygia after excision, including
assessed every 2 weeks during the 3 months of treatment. medical methods (ie, mitomycin-C [MMC], β-
The slit-lamp photographs were masked and analyzed. irradiation) and surgical methods (ie, conjunctival graft,
The primary and secondary outcomes were the differ- amniotic membrane graft). Both MMC and β-irradiation
ences in the pterygial recurrence rates between the groups are associated with recurrence rates that range from 0%
and adverse events at 3 months, respectively. Corneal to 38%. However, their use was associated with serious
recurrence was defined as recurrent fibrovas-cular tissue sight-threatening adverse events, including necrotizing
1
invading the cornea; conjunctival recur-rence was defined scleritis and perforation. Many studies have reported
as either recurrent vessels or fibrous tissue in the excised that conjunctival and limbal autografts with MMC reduce
area without corneal invasion. the rates of pterygial recurrence (0%–7%). However,
various factors, including primary or recurrent status of
Findings: All 22 patients completed follow-up at 3 the pterygia, patient age, surgeon, or patient preference,
months after the start of the trial medications. After 3 affect the surgical outcomes. Until now, the data could
months of treatment, 1 patient (8.33%) and 3 patients not definitively recommend a specific adjuvant as a
(30.00%) from the bevacizumab and placebo groups, beneficial choice.
2

respectively, had a corneal recurrence. No significant (P In the past 2 decades, studies of vascular endothe-lial
¼ 0.293) differences were found be-tween the groups as growth factor (VEGF) drugs have led to the deve-
determined by Fisher’s exact test. However, conjunctival lopment of new ophthalmic therapies, including those for
and corneal recurrences were found in 4 (33.33%) and 9 pterygia. The overexpression of VEGF in the pterygium
(90.00%) patients, respectively, in the bevacizumab and tissue suggested that this factor was involved
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-tive 0149-2918/$ - see front matter
treatment after pterygium excision, was well & 2015 Elsevier HS Journals, Inc. All rights reserved.

] 2015 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 with the use of the bare sclera technique. Tetracaine 2.0%
monoclonal antibody to VEGF-A, prevents attachment of without adrenaline was injected subconjunctivally. The
VEGF-A to its receptors. Because bevacizumab inhibits pterygial head was removed from the apex with the use
proliferation of endothelial cells and formation of new of a surgical scalpel blade no. 15. The pterygial body was
4 dissected from the overlying conjunctiva.
blood vessels, the drug was suggested as a potential
adjunctive treatment after pterygial excision. This Subconjunctival pterygia also were excised to achieve as
randomized, double-masked controlled trial was designed clear a margin as possible. The bare scleral area was 5 7
to evaluate the efficacy and tolerability of topical mm. Postoper-atively, all patients received tobramycin
bevacizumab 0.05% eye drops as an adjunctive therapy with dexame-thasone eye drops that were administered 4
after excision of primary pterygia via the bare sclera times daily for 1 month, followed by fluorometholone
technique. 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 was assigned to the bevacizumab or placebo group with the
calculated with the use of a statistical superiority design use of the block of four method, and all random-ization
formula with a power of 0.8, a two-tailed significant level numbers were concealed in closed envelopes. The
of 0.05. This indicated a sample size of 9 patients per bevacizumab group (12 eyes, 12 patients) re-ceived
group. Twenty percent of the sample size was added in bevacizumab 0.05% eye drops and the control group (10
anticipation of drop-out patients; the total sample size of eyes, 10 patients) received normal saline eye drops 4
the present study was 22 cases. The Institutional Review times daily for 3 months. All patients and an outcomes
Board, Faculty of Medicine, Chulalongkorn University, assessor were blinded to the treatment assignments.
approved and monitored the study, which is registered at Bevacizumab 0.05% eye drops were prepared from the
clinical-trials.gov as NCT01311960. The study adhered standard intravenous solution diluted in 0.9% saline
to the tenets of the Declaration of Helsinki. All patients under laminar flow at the hospital pharmacy department
5
provided written informed consent to participate in this and stored at –201C until use. All patients were
research. instructed to store the study medication and placebo at
41C during use.
Patients diagnosed with primary pterygia and The demographic data, including sex, age, duration of
scheduled for a pterygial excision with the use of the bare outdoor activity, laterality of the pterygia, and appearance
sclera technique were enrolled consecutively. Patients of the preoperative pterygia were recor-ded. Assessments
with corneal melt, corneal epitheliopathy, and abnormal for recurrent pterygia were per-formed on weeks 4, 8,
healing of a corneal epithelial wound, and those who and 12 after starting the study medication. The grading
were pregnant, lactating, or allergic to bevacizumab or scale used to assess pterygial recurrence is shown in
steroids were excluded. 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

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

] 2015 3
Clinical Therapeutics

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

4 Volume ] Number ]
N. Kasetsuwan et al.

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