Original Article
Subconjunctival Bevacizumab as an
Adjunct to 5-Fluorouracil Enhanced Trabeculectomy: Short Term Results
Sana Nadeem
Pak J Ophthalmol 2018, Vol. 34, No. 4
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See end of article for authors affiliations …..……………………….. Correspondence to: Sana Nadeem Assistant Professor, Department of Ophthalmology, Foundation University
Medical College/ Fauji Foundation Hospital, Rawalpindi. E-mail: sana.nadeem018@gmail.com |
Purpose: To compare the results of
trabeculectomy with subconjunctival Bevacizumab and 5-Fluorouracil (5-FU);
with trabeculectomy with 5-Fluorouracil alone in the short term (i.e. 3
months). Study Design: Prospective, interventional
study Place and Duration of Study:
Department of Ophthalmology, Fauji Foundation Hospital, Rawalpindi, from 18th
December 2013 till 16th August 2018. Material and Methods: A
total of 30 eyes (15 in each group) in patients above 40 years of age with primary
glaucoma, underwent trabeculectomy with 5-Fluorouracil (5-FU) (50 mg/ml)
applied for 5 minutes. At the end of surgery, sub-conjunctival Bevacizumab
(Avastin® 2.5 mg in 0.1 ml) was injected in one group. The postoperative IOP,
bleb configuration, and complications at 1 day, 1 week, 1 month, and then
monthly for 3 months was observed for both groups. Results: The mean pre-operative IOP in
the 5-FU group was 30.6 ± 17.1 mm Hg compared to 28.9 ± 18.9 mm Hg in the
5-FU + Bevacizumab group. The mean IOP of the 5-FU group at 3 months was 13.8
± 4.25 mm Hg, compared to Conclusion: There is no added benefit of
subconjunctival Bevacizumab used as an adjunct to 5-FU enhanced
trabeculectomy in the short term. Key Words: Trabeculectomy, 5-Fluorouracil,
Bevacizumab, glaucoma, intraocular pressure. |
Success of trabeculectomy for glaucoma may
be limited by gradual subconjunctival and episcleral scarring, which causes its
failure. The use of antimetabolites like 5-fluorouracil (5-FU) and mitomycin C
(MMC) has long been attributed to decrease post-operative scarring1.
These, too have not been entirely satisfactory. However; the need arises for a
newer agent which may enhance the effect of these drugs. Vascular endothelial growth factor (VEGF) is
a cytokine, known to be elevated in patients with glaucoma and to promote
scarring and angiogenesis during wound healing1,2. Bevacizumab
(Avastin®) is a full length monoclonal antibody against all isoforms of VEGF-A
and has been studied scantily to assess its anti-angiogenic and inhibitory
effects on fibroblast proliferation, postoperative scarring and eventual
success in glaucoma filtration surgery.3 Few of those who have
studied its effect have presented encouraging results and safety4,5.
The rationale of this study was to assess the effect of anti-VEGF on the
success of trabeculectomy in our local population.
The aim of this study is
to compare the effect of subconjunctival bevacizumab as an adjunct to 5-FU
enhanced trabeculectomy to the effect of 5-FU alone, mainly in terms of
intraocular pressure (IOP) lowering, bleb formation, and complications, in the
short term (i.e. three months), and to see if it gives an added benefit.
MATERIAL AND METHODS
A total of 30 eyes in consecutive patients
with glaucoma presenting to the operating surgeon, were included in this ongoing
study (15 in each group), carried out in the Department of Ophthalmology, Fauji
Foundation Hospital, Rawalpindi, which is a tertiary care, teaching hospital
affiliated with Foundation University Medical College; from 18th
December, 2013 to 16th August, 2018. Approval from the ethical
committee was taken. Inclusion criteria were, patients above 40 years of age
with primary open angle glaucoma (POAG) or Primary angle closure glaucoma
(PACG), and pseudoexfoliative glaucoma (PXF), with uncontrolled IOP after
maximally tolerated medical therapy, or non-compliance, or advanced
glaucomatous damage at presentation, or as a combined procedure for cataract
and glaucoma if on multiple medications. Patient preference for trabeculectomy as
a treatment option was also considered if on 2 or more topical anti-glaucoma medications.
Exclusion criteria were young patients with glaucoma, congenital, juvenile,
secondary, uveitic, traumatic, neovascular, aphakic or patients with ocular
surface disease. Pre-operatively, a thorough slit lamp examination was
performed of the anterior and posterior segments, along with visual acuity
estimation and refraction, Goldmann applanation tonometry, pachymetry and
gonioscopy. The patients were assessed and monitored for glaucomatous
progression by serial Humphrey perimetry and optical coherence tomography (OCT)
of the optic nerve head and retinal nerve fiber layer.
All surgeries were performed under local
anesthesia by the author using a standardized technique with facial nerve and
retrobulbar blocks. A fornix based approach for trabeculectomy was used with a
limbal conjunctival peritomy performed, and then fashioning of a triangular
superficial scleral flap measuring 4 x 4 mm with blade # 15, then 5-FU (50
mg/ml) was applied above and below the superficial flap with cotton pledgets
for 5 minutes. After thorough washing of the 5-FU, a paracentesis was done, and
a deep scleral window was made 1.5 x 2 mm in size with a blade # 11, and a
peripheral iridectomy was performed with Vannas scissors. Then the superficial
flap was approximated to the sclera with 10/0 nylon sutures one at the apex,
and one on the right side with the left side being left unstitched. Then the
conjunctiva was sutured with 8-0 silk or 6-0 vicryl on the right side ensuring
a water-tight closure. Fluid was injected through the paracentesis to ensure
bleb formation and patency of the procedure. In cases of subconjunctival
bevacizumab injection (2.5 mg in 0.1 ml), the injection was performed from the
left side with a bent needle of a 1 cc (30 G) syringe, horizontally into the
bleb 8 mm from the limbus. A subconjunctival antibiotic and steroid injection
was given at the end of the surgery. In case of phaco-trabeculectomy, after
peritomy and fashioning of superficial flap, phacoemulsification with
intraocular lens implantation was performed, after which the trabeculectomy was
completed.
The patients were examined by the operating
surgeon on the post-operative visits at Day 1, 1 week, 1 month, and then
monthly for 3 months. Visual acuity, Goldmann tonometry, and slit lamp
examination with fundus assessment was done as routine post operative
examination. Bleb assessment using a
simple grading system6-8 was done after healing of the conjunctiva,
according to which blebs were classified into four types; Type 1: thin-walled,
polycystic (well-functioning), Type 2: Diffuse, flatter and thicker (good
functioning), Type 3: Flattened bleb with scarring and little or no function,
and Type 4: Encapsulated (Tenon’s cyst) with engorged blood vessels and poor
function.
The data was analyzed
using SPSS version 20. Frequencies and
percentages were calculated for all the variables. Unpaired and paired samples t-tests were used for the data analysis as the
case may be. The Wilcoxon signed-rank test was used to assess the types of bleb
formation between the two groups, as well as complications between the two
groups. A p-value of less than 0.05
was considered statistically significant.
RESULTS
A total of 30 eyes of 22 patients were
included in this study, with 15 eyes in each group assigned randomly, one group
undergoing ‘Enhanced trabeculectomy with 5-FU’ alone, and the other group
undergoing ‘Enhanced trabeculectomy with 5-FU + subconjunctival Bevacizumab’. These
patients were consecutive patients presenting to the operating surgeon, who
fulfilled the inclusion criteria for trabeculectomy. The majority of patients
were females accounting for 21 (95.4%) cases. Primary open angle glaucoma was
predominant with 18 (60%) eyes, primary angle closure in 9 (30%) eyes, and
pseudoexfoliative glaucoma in the rest of 3 (10%) eyes (Table 1). Enhanced
trabeculectomy with 5-FU alone or combined 5-FU with subconjunctival
Bevacizumab was performed in 22 (73.3%) eyes and PhacoTrab was performed in 8
(26.7%) eyes.
The mean pre-operative
IOP in the 5-FU group was 30.6 ± 17.1 mm Hg (range 15-68), while the mean
pre-operative IOP in the 5-FU + Bevacizumab group was 28.9 ± 18.9 mm Hg (range 14-78).
However, the difference between the two was not statistically
Table 1: Baseline patient
characteristics.
|
Age, years (Mean ± SD) Range, years |
62.8 ± 7.2 50-84 |
|
Gender N (%) Male Female |
22 1 (4.5) 21(95.4) |
|
Eye N (%) Right Left |
17 (56.7) 13 (43.3) |
|
Glaucoma Diagnosis N (%) POAG PACG PXF |
18 (60) 9 (30) 3 (10) |
|
Pre-op Anti-glaucoma
Medicines 5-FUř group Mean ± SD Range 5-FU + Bevacizumab group Mean ± SD Range |
2.87 ± 0.35 (2-3) 2.93 ± 0.25 (2-3) |
|
Surgical
Procedure N (%) Enhanced
Trabeculectomy PhacoTrab |
22 (73.3) 8 (26.7) |
significant (P = 0.758). IOP differences
were analyzed at day 1, week 1, month 1, and month 3, and were compared with
pre-operative IOP as well as between the two groups (Table 2). The mean IOP of
the 5-FU group at day 1 was 10.0 ± 5.8 mm Hg, at Week 1 was 8.9 ± 5.36 mm Hg,
at month 1 was 10.6 ± 5.4 mm Hg, and at month 3 was 13.8 ± 4.25 mm Hg. The
differences between pre-operative and post-operative IOP in the 5-FU group was significant
at all occasions; day 1 (p = 0.001), week 1 (p = 0.001), month 1 (p = 0.001),
and month 3 (p = 0.002), thus depicting surgical success in the short term
period.
In case of the 5-FU + Bevacizumab group,
the mean IOP at day 1 was 11.2 ± 6.8 mm Hg, at week 1 was 9.2 ± 4.25 mm Hg, at
month 1 was 16.2 ± 7.39 mm Hg, and at month 3 was 12.5 ± 3.37 mm Hg. . The differences
between pre-operative and post-operative IOP in the 5-FU + Bevacizumab group
was also significant at all occasions; day 1 (p = 0.005), week 1 (p = 0.003), month
1 (p = 0.042), and month 3 (p = 0.008). This too amounts to successful surgery
in the short term.
Comparison of differences in the mean IOP
between the two groups revealed lower mean IOP in the 5-FU group at day 1 (p =
0.556), week 1 (p = 0.872), and month 1 (p=0.042),
but higher at month 3 (p = 0.339). However, only the IOP differences at month 1
were statistically significant between the two groups (Table 3).
Analysis of bleb formation and comparison
between the two groups, revealed equal number of cystic bleb formation in the
two groups with 5 (33.3%) in each group, with early bleb failure in 2 (13.4%)
cases of the 5-FU group, 1 case of a flattened bleb and 1 case of an
encapsulated bleb, which required needling (Table 4). However, bleb comparison
between the two groups did not reveal statistically significant differences (P
= 0.405).
Table 2: IOP§ at different
time periods.
|
IOP§ mm Hg (Mean ±SD) |
Pre-op |
Day 1 |
Week 1 |
Month 1 |
Month 3 |
|
|
|
Trabeculectomy with
5-FUř |
30.6 ± 17.1 [Maximum 68] [Minimum 15] |
10.0 ± 5.8 |
8.9 ± 5.36 |
10.6 ± 5.4 |
13.8± 4.25 |
|
|
Trabeculectomy with
5-FUř + S/C¤ Bevacizumab |
28.9±18.9 [Maximum 78] [Minimum 14] |
11.2 ±6.8 |
9.2± 4.25 |
16.2± 7.39 |
12.5±3.37 |
ř
5-fluorouracil §
Intraocular pressure ¤
subconjunctival
Table 3: Paired samples t-Test in the
5-FU group & 5-FU + Bevacizumab group.
|
Paired Samples Test |
|||||||||
|
|
Paired
Differences |
t |
df |
Sig.
(2-tailed) |
|||||
|
Mean |
Std.
Deviation |
Std.
Error Mean |
95%
Confidence Interval of the Difference |
||||||
|
Lower |
Upper |
||||||||
|
Pair 1 |
Pre-Op
IOP in 5FU group - Pre-Op IOP in Bevacizumab + 5-FU group |
1.66 |
20.51 |
5.29 |
-9.69 |
13.02 |
.315 |
14 |
.758 |
|
Pair 2 |
IOP
Day 1 5FU group - IOP Day 1 Bevacizumab + 5-FU group |
-1.13 |
7.26 |
1.87 |
-5.15 |
2.89 |
-.604 |
14 |
.556 |
|
Pair 3 |
IOP
Week 1 5-FU group - IOP Week 1 Bevacizumab + 5-FU group |
-.26 |
6.30 |
1.62 |
-3.75 |
3.22 |
-.164 |
14 |
.872 |
|
Pair 4 |
IOP
at 1 month 5-FU group- IOP at 1 month Bevacizumab + 5-FU group |
-5.53 |
9.59 |
2.47 |
-10.84 |
-.21 |
-2.233 |
14 |
.042 |
|
Pair 5 |
IOP
at 3 months 5-FU group- IOP at 3 months Bevacizumab + 5-FU group |
1.33 |
5.21 |
1.34 |
-1.55 |
4.22 |
.989 |
14 |
.339 |
Table 4: Bleb Analysis.
|
Type of Bleb |
Trabeculectomy with 5-FU N (%) |
Trabeculectomy with 5-FU +
S/C Bevacizumab N (%) |
|
Type 1 Cystic |
5 (33.3) |
5 (33.3) |
|
Type 2 Diffuse |
8 (53.3) |
10 (66.7) |
|
Type 3 Flattened |
1 (6.7) |
0 |
|
Type 4 Encapsulated |
1 (6.7) |
0 |
|
Z |
-.832b |
|
Asymp. Sig. (2-tailed) |
.405 |
a. Wilcoxon Signed Ranks Test
b. Based on positive ranks.
The number of pre-operative anti-glaucoma
medications in both groups ranged from 2-3 (Table 1), and there was a
significant reduction of medicines post-operatively in both groups, at 3
months. The comparison for the 5-FU group between the pre-operative medicines
(2.87 ± 0.35) and the post-operative medicines (0.20 ± 0.414), was
statistically significant (p = 0.000), with only 3 eyes requiring 1
anti-glaucoma agent at 3 months. For the 5-FU + Bevacizumab group, similarly
the comparison between the pre-operative anti-glaucoma medicines (2.93 ± 0.25)
and post-operative medicines (0.27 ± 0.458), were statistically significant (p
= 0.000), with 4 eyes requiring 1 drop at 3 months. The difference in
anti-glaucoma agents at 3 months between the two groups was not statistically
significant (p = 0.334).
A few early
complications were encountered in both groups, summarized in Table 5, with a
slightly higher number in the 5-FU + Bevacizumab group, but the differences between
the two groups were not found to be statistically significant (p = 0.373). Shallow
Table 5: Complications
of Trabeculectomy.
|
Complications Trabeculectomy with 5-FU |
N (%) |
|
Hyphema Failure
of filtration Bleb
leak |
1 (6.7) |
|
2 (13.3) |
|
|
2 (13.3) |
|
|
Trabeculectomy with 5-FU + S/C Bevacizumab |
N (%) |
|
Epithelial
defect |
1 (6.7) |
|
Imperforate
PIα |
1 (6.7) |
|
Hyphema |
1 (6.7) |
|
Shallow
ACβ & Choroidal detachment |
1 (6.7) |
|
Peaked
pupil |
1 (6.7) |
|
Posterior
synechiae |
2 (13.3) |
|
Z |
-.891b |
|
Asymp. Sig. (2-tailed) |
.373 |
|
a. Wilcoxon Signed Ranks Test |
|
|
b. Based on negative ranks. |
|
α
Peripheral iridectomy β anterior chamber
anterior chamber (AC)
was considered only if iris cornea touch was present in the mid-peripheral iris
and this was present in 1 (6.7%) case which led to choroidal detachment, in the
5-FU + Bevacizumab group, which resolved with steroids and cycloplegics. Also 1
case of imperforate peripheral iridectomy (PI) required Nd: YAG iridotomy
post-operatively, also in the same group. Bleb leaks were found in 2 (13.3%)
cases of the 5-FU group, managed by bandage contact lenses (BCL). The complications
encountered did not have a considerable long lasting effect in terms of
success.
DISCUSSION
The results of our study indicate no added
benefit of subconjunctival bevacizumab used as an adjunct to 5-FU enhanced trabeculectomy,
in terms of IOP lowering, as the mean IOP in the 5-FU group was lower at all
occasions except at month 3. Similarly, no significant differences in bleb
formation or complication rate were seen on comparison of the two surgical
groups. Mean post-operative IOP was significantly lower in both groups at all
times, when compared to the pre-operative IOP.
A vascularized bleb is long known to cause
trabeculectomy failure. Failure of trabeculectomy is invariably caused by
subconjunctival and episcleral fibrosis, which is the result of myofibroblast
transformation9 triggered by vascular endothelial growth factor
(VEGF), by the induction of transforming growth factor (TGF)-β1. Thus
factors inhibiting VEGF would result reduce this fibrosis. Wound modulation by
subconjunctival bevacizumab in rabbits undergoing trabeculectomy was
demonstrated in 2014 by Ozgonul10 and colleagues, who concluded it
to be superior to subconjunctival 5-FU. Evidence in literature initially
suggested adjunctive treatment of bevacizumab in trabeculectomy to be promising
as indicated by Frieberg et al1 in 2013, who used this agent and it
reduced the number of post-operative injections of 5-FU. However, similar to
our study, no statistically significant reduction in IOP, bleb morphology or
complications was observed. Sedhipour et al2 in 2011 assessed the
short-term benefit of bevacizumab and found no significant difference when
compared to placebo, similar to our results. Jukowska-Dudzińska11
et al found more patients with the bevacizumab group needing medical therapy at
1 year, compared to 5-FU, the rest of results were similar to ours. Nilforushan12
et al in 2011, found benefit of bevacizumab alone on IOP lowering, but less
than that of mitomycin alone. Bitelli5 et al found it to safe and
effective adjuvant therapy with MMC. Suh et al13, Kiddie3
et al, Saeed8 et al and Elgin14 and coworkers, did not
find additional additive effects. The effectiveness and safety of this drug was
assessed by Akkan15 et al in 2015, which appeared to be safe but not
superior to MMC. Mild central bleb avascularity was observed with
subconjunctival bevacizumab by Chua16 and coworkers, but not
significantly so. A meta-analysis of randomized controlled trials carried out
in 2016 by Liu X et al17 found bevacizumab to be superior compared
to placebo, but no difference was seen when used in conjunction with MMC versus
MMC alone, and it was found to increase the rate of bleb associated
complications like bleb leaks and encysted blebs, compared to MMC. In our study
however, on the contrary, bleb leaks and encysted bleb was seen in the 5-FU
group. Wang18et al used subconjunctival bevacizumab as an adjunct to
MMC and found no benefit as well.
Contrary to this, in 2017, adjuvant
bevacizumab was found to be comparable to MMC in the long term, in primary open
angle glaucoma, along with demonstrating significant bleb avascularity, as noted
by Kaushik19 et al in India. Similarly, Popescu20 has
claimed its positive role in inflammatory glaucoma.
Cheng21 and coworkers did an
extensive electronic database search on randomized controlled trials comparing
subconjunctival bevacizumab to other agents, and concluded in 2016, that there
is insufficient and low quality evidence to support or refute its use for wound
healing in glaucoma surgery.
Strengths of our study are that this is the
first of its kind in Pakistan. Equal allotment of cases and good follow up has
been ensured. A standard technique with a single surgeon and patient assessment
has also been standardized.
Limitation of our study
is small sample size. Our department does not have a separate glaucoma facility
and collecting patients has taken a lot of time. These patients will be
continued to be followed up for long term results. Future work required is larger
scale studies with more study subjects and long term assessment.
CONCLUSION
Subconjunctival
bevacizumab in conjunction with 5-fluorouracil enhanced trabeculectomy offers
no additional benefit in terms of IOP lowering, bleb morphology or
post-operative complications; when compared to 5-FU enhanced trabeculectomy
alone, in the short term.
Author’s Affiliation
Dr. Sana Nadeem
MBBS, FCPS, Assistant
Professor
Department of
Ophthalmology
Foundation University Medical College/Fauji
Foundation Hospital, Rawalpindi.
Role of Authors
Dr. Sana Nadeem
Study Design, Manuscript
writing, Statistical analysis and performed all surgeries
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