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Mitomycin
C in pterygium treatment
Thiago Gonçalves dos Santos Martins1, Ana
Luiza Fontes de Azevedo Costa2, Milton Ruiz Alves2, Roger
Chammas2, Paulo Schor1
1Federal University of São Paulo (UNIFESP), São Paulo 04023062, Brazil
2University of
São Paulo (USP), São Paulo 01246903, Brazil
Correspondence to: Thiago Gonçalves dos Santos Martins. Dona Maria st number 71 bl 1 apartament 1404, Rio de Janeiro 20541030,Vila Isabel, Brazil. thiagogsmartins@yahoo.com.br.
Received: 2015-04-19 Accepted: 2015-07-02
Pterygium is a benign lesion usually growing from the
nasal side of the conjunctiva onto the cornea. Most cases of pterygium does not
cause problem or requires specific treatment. The exact cause of pterygium is
not clear yet, but some factors are pointed as causes, being the most important
the long-term ultraviolet ray exposure. Pterygium surgery is usually considered
when there are symptoms that do not respond to conservative treatment.
Recurrence is the main complication of the surgery, and much has been done to
avoid it. Mitomycin C (MMC) has been used as a fibroblast proliferation
inhibitor during the surgery to reduce the chance of recurrence of the
pterygium. This review describes the use of MMC as an adjunctive, the optimal
dosage, the duration of administration of MMC and possible complications, when
used during, after and before the surgery. Most studies suggest that increased
exposure (dose or duration) of MMC is associated with a lower recurrence, but
with higher risks of complications.
KEYWORDS: mitomycin C; pterygium surgery; recurrence rate
DOI:10.18240/ijo.2016.03.25
Citation: Martins
TGS, Costa ALFA, Alves
MR, Chammas
R, Schor P. Mitomycin C
in pterygium treatment. Int
J Ophthalmol 2016;9(3):465-468
INTRODUCTION
The pterygium is classically defined as a degenerative disease of the ocular surface with triangular fibrovascular tissue formation, which grows from the conjunctiva towards the surface of the cornea[1]. Although its pathogenesis has not been fully elucidated, it is very likely that the pterygium represents a degenerative response of the fibrous connective tissue to different stimuli. Among the risk factors, exposure to ultraviolet radiation appears to play an important role in inducing damage to the limbal stem cells. As a result, there is a migration of the conjunctiva towards the cornea, chronic inflammation and fibrovascular tissue formation[2]. Other risk factors described related to the development of pterygium are the micro-traumas in the corneal limbus region and hereditary factors.
The main risk factor is exposure to ultraviolet rays, and a possible
explanation of this fact would be the location of pterygium, mainly in the
interpalpebral fissure, which is more exposed to sun rays and dust, leading to
inflammation of the ocular surface. Recently, it was suggested that there is a mutation in the p53 gene on
chromosome 17 as the cause of this disease, and changes in the expression of
various growth factors, such as vascular
endothelial growth factor A (VEGFA). Histologically, the pterygium is
characterized by elastotic degeneration of the conjunctival substantia propria,
with eosinophilic and basophilic deposits and fibroblast proliferation[1]. The pterygium is twice as common in men as women[2].
Pterygium was first described in 1000 by AC Susruta, the first ophthalmic surgeon according to the literature[3]. Over the years, many medical treatments have been used, such as bile, urine, acids, radiotherapy, thiotepa, 5-fluorouracil and more recently, mitomycin C (MMC). In the past, the use of horse hair was described to remove pterygium[4]. Surgery is indicated when the patient is feeling discomfort, despite lubricant eye drops, when there is restriction of ocular motility, growth on the visual axis and aesthetic complaints. Currently, conjunctiva transplantation and amniotic membrane transplantation are used. Some surgical techniques consist in excising the pterygium leaving the sclera exposed, but the recurrence rate is up to 88%[5-6]. The purpose of the use of MMC as an adjunctive treatment is to prevent the recurrence of pterygium after the surgery[7].
METHODS
Data collection was made through extensive
computer-assisted searches in PubMed for English-language articles and then
their references were cross checked. Articles showing recent findings of the
use of MMC as an adjunctive treatment of pterygium, optimal dosage, duration of
administration and possible complications were included in this review.
Mitomycin C MMC is an alkylating agent which inhibits DNA
synthesis. By inhibiting DNA synthesis, it leads to the death of cells caused
by the inability to repair the genotoxic injury caused by alkylation. It acts
against all cells regardless of the cell cycle and even acts in cells that are
not synthesizing DNA. Inhibition of DNA synthesis leads to reduction in the
number of mitoses, especially when MMC comes into contact with cells that are
in the late G1 and early S phases of the cell cycle. It can be used before,
during or after pterygium surgery applied locally or in the form of eye drops.
The injection application directly on the pterygium has the advantage of
protecting the corneal endothelium and epithelium. Subconjunctival injection
allows a more precise dose to be applied to the patient's eye, which usually
does not occur with MMC application when using sponges directly on the sclera
during surgery. Its action in the prevention of pterygium recurrence occurs by
inhibition of fibroblast proliferation in the episclera region. The increased
concentration and duration of the application may be associated with
complications such as necrotizing scleritis, scleral calcification, ulceration,
corneal edema, iritis, glaucoma, cataract, hypotony by injury of the ciliary
body and damage to the corneal epithelium and endothelium [8-10].
The administration of MMC in the pterygium surgery is
considered off-label by the Food and Drug Administration (FDA), but it is used
in cancer treatment.
Mitomycin C During the
Surgery Twenty-two
trials[11-32] that used
MMC application in different concentrations (0.002% to 0.4% for 3 to 5min)
applied to the bare sclera after pterygium excision were evaluated. Some studies with primary pterygium
determined that all MMC concentrations, from 0.002% to 0.04%, given for 3 to
5min, reduced significantly (P less
than 0.0045) the recurrence of pterygium when compared to excision with bare
sclera [11,13,15,18].
The recurrence rate reported in the literature for
intraoperative use of MMC in primary pterygium surgery varies from 6.7% to
22.5%[32-33]. The most common dose, according to the
literature, is 0.02% for 3min in the bare sclera[34]. The
surgical technique most used in the studies is the excision of the pterygium with conjunctival
autograft transplantation, which has a lower recurrence rate.
In a study, the recurrence rate was 22.5% when MMC was
used intraoperatively[11],
while other study had a 16.13% recurrence rate.
Complications related to the intraoperative use of MMC
vary according to the concentration and the duration of application. With the
most commonly used dose, of 0.02 % for 2min, there were no severe complications
reported[34].
Delayed epithelialization can occur with the use of
intraoperative MMC 0.04% for 3 to 5min, but it was not reported with MMC 0.02%
for 3min. Iritis and corneal dellen have been reported in 3% of cases when MMC
0.01% was used for 5min intraoperatively[13].
Further studies are needed to determine the optimal concentration of MMC, the
exposure time and if it should be applied on the bare sclera, on the Tenon or
below the conjunctiva.
Mitomycin C After the
Surgery The analysis included 12 trials [16-18,22,25-28,31,35-37] with application of different concentrations of MMC
after surgery at different times.
In two studies with MMC application post operatively
(0.02% twice a day for 5d) there was reduced primary pterygium recurrence[22,25].
High concentrations of MMC (0.04% 3 to 4 times daily
for
7d) result in a significant
reduction in the recurrence of pterygium compared to excision with bare sclera[37].
Studies with primary pterygium[23,26] or combined with recurrent pterygium[25,27] reported
no significant changes, comparing the use intraoperative or postoperative use
of MMC.
Sclera ulceration occurred in a proportion that varied
from 5% to 19% in eyes
with postoperative MMC 0.02% applied twice daily for 5d[16], with MMC 0.02% applied 4 times daily for
7d[23] and 0.04% applied
3 times daily for 7d[27].
Iritis and corneal dellen occurred with post-operative
use of MMC 0.02% four times daily for 7d in 3% of the cases[27].
Two studies[13,17]
have shown increased risk of scleral thinning with increasing concentration of
MMC application.
Mitomycin C Before the
Surgery The pre-operative subconjunctival injection of MMC, in
a study of 25 eyes, proved to be efficient, with two cases of delayed
epithelialization. Ninety-two
percent of eyes with MMC application had no recurrence, 8% had a two week delay
in corneal epithelialization. No serious complications were reported[38].
Donnenfeld reported the efficiency and safety of using
pre-operative MMC injection of 0.1 mL (0.15 mg/mL) in the pterygium body one
month prior to the surgery for pterygium recurrence. The results showed less
vascularization and inflammation within the pterygium one month after injection
of MMC with a 6% recurrence after 2y of follow up[39].
The
risk of preoperative injection is due to the impossibility of washing the MMC
that is in the subconjunctival space and can generate toxicity. Studies showed
that subconjunctival injection of MMC 0.2 mL (0.4 mg/mL) injected 2 mm posterior to the limbus caused cell changes, such
as flattening and pyknotic nuclei in the ciliary body epithelium, leading to
reduction of aqueous humor production a month after the injection[40].
Carrasco et al[41] reported a case of
scleral necrosis in a patient who received a subconjunctival injection of MMC 0.15
mg/dL one month before pterygium surgery, but it was a patient with a severe
dry eye history.
The subconjunctival injection does not allow the tear
to dilute the MMC, which increases the exposure time.
In conclusion, the data from the studies show that the use of MMC, along with the
conjunctival autograft technique, reduces even more the recurrence of
pterygium, and the use of MMC alone does not reduce recurrence as much as when
the adequate surgical technique is used along with MMC[42].
Intraoperative and postoperative use of MMC with
conjunctival transplantation demonstrated low recurrence rate and good cosmetic
results in the treatment of pterygium.
The preoperative injection of MMC with a low dose
before surgery showed good results in preventing the recurrence of pterygium.
Most studies suggest that increased exposure (dose or
duration) of MMC is associated with a lower recurrence, but with higher risks
of complications. Thus, there is a need for new long-term studies to determine
the optimal dosage and duration of administration of MMC, since many
complications described in literature occur years after the procedure.
ACKNOWLEDGEMENTS
Conflicts
of Interest: Martins TGS, None; Costa
ALFA, None; Alves MR, None; Chammas
R, None; Schor P, None.
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