Review Article
Use of Mitomycin C in Ocular
Surgery; A Narrative Review
P. S. Mahar
Pak J Ophthalmol 2019, Vol. 35, No. 3
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See end of article for authors affiliations …..……………………….. Correspondence to: P.S. Mahar FRCS, FRCOphth Consultant Eye Surgeon Aga Khan University Hospital Professor & Dean Isra Postgraduate
Institute of Ophthalmology Karachi Email: salim.mahar@aku.edu |
Mitomycin C is an alkylating agent with an
anti-proliferative activity. Because of its potent anti-fibroblastic effect,
it is used in multiple ocular surgical procedures where inhibition of
proliferation of fibroblasts and vascular ingrowths is required. It is
dispensed in blue violet crystalline powder and it dissolves in water. MMC is
stable for 2 weeks when refrigerated at 2 – 8 degrees centigrade after the
powder is reconstituted for topical use. Because of its anti-fibroblastic
activity, MMC is used in various ocular surgical procedures. The optimal dose
of MMC is not known but is usually used in concentration of 0.1 mg/ml (0.01%)
to 0.5 mg/ml (0.05%) in different clinical setups. Key Words: Mitomycin C, Fibroblasts,
Ocular Surgery. |
Mitomycin is an alkylating agent with an anti-proliferative
effect. It inhibits DNA synthesis of cells exhibiting highest rate of mitosis.
Mitomycin is isolated
from soil bacterium streptomyces caesopitosus. It has got 3 types mitomycin A,
mitomycin B and mitomycin C which are produced by Streptomyces caesopitosus
under different conditions. Therefore, this medication is called as mitomycin C
(MMC) to differentiate it from others.1Mitomycin C inhibits
proliferation of fibroblasts, suppresses vascular ingrowths and is much more
potent than 5 – fluorouracil (5 FU)2. It is dispensed in blue violet
crystalline powder and it dissolves in water. MMC is stable for 2 weeks when
refrigerated at 2 – 8 degrees centigrade after the powder is reconstituted for
topical use. Because of its anti-fibroblastic activity, MMC is used in various
ocular surgical procedures. The optimal dose of MMC is not known but is usually
used in concentration of 0.1 mg/ml (0.01%) to 0.5 mg/ml (0.05%) in different
clinical setups.
PTERYGIUM SURGERY
Pterygium is a fibro-vascular growth which
extends across the limbus onto the cornea. It is a common corneal disorder
witnessed in countries with hot climate.3 Once grown over cornea,
apart from the cosmetic blemish, it induces irregular astigmatism. If it’s
growth involves the visual axis, it can also severely curtail the vision.
Surgical removal of the pterygium is the
preferred treatment but the rate ofrecurrent pterygium is very high at 30% –
50% after simple excision is performed4,5. Kunitomo and Mori6
were the first workers suggesting the adjunct use of MMC in patients undergoing
surgical excision. In 1988, Hayasaka et al7 published their work on
the instillation of lower dose of MMC after surgery in the treatment of primary
pterygium. They found recurrence rate of 7% in group of patients treated with
0.2 mg/ml MMC drops used for 1 week duration. The recurrence rate was 11% with the
use of 0.4 mg MMC drops and 32% recurrence was noted in their cohort of
patients undergoing simple surgical excision. Singh and co-workers8
reported similar favourable results of non-recurrence in their patients using 1
mg/ml MMC drops postoperatively. Mahar and Nwokora9 in their
published work concluded no recurrence of pterygium when MMC 0.4 mg/ml drops
were used postoperatively for 2 weeks duration.
Lack of optimal dosage and variable
duration of instillation of MMC has led to some serious complications.
Rubenfeld10 described group of patients developing secondary
glaucoma, corneal edema, corectopia, corneal perforation, Iritis and scleral
calcification when MMC was used in higher concentration and for long duration
of upto 4 weeks.
This treatment modality was followed by
many clinicians to use MMC intra-operatively in a single dose after surgical
excision. This has not only successfully reduced recurrence of Pterygium but
showed minimal complications.
Cardillo and colleagues11 in a
prospective study treated 227 patients with primary Pterygia. After surgical
excision these patients were divided in 5 groups: group 1 received single
intra-operative application of 0.2 mg/ml MMC for 3 minutes; group 2 received a
single intra-operative application of 0.4 mg/ml MMC for 3 minutes; group 3
received MMC eye drops 0.2 mg/ml 3 times a day for 7 days; group 4 received 0.4
mg/ml MMC drops 3 times a day for 2 weeks and group 5 acted as control. At mean
follow up of 28 months all groups receiving MMC in single application or drops
showed around 5% recurrence rate in comparison to control group with recurrence
rate of 29.27%. This study indicated that there was no difference in recurrence
between intra-operative application of MMC or drops and also no statistically
difference was found in groups receiving 0.2 mg/ml or 0.4 mg/ml MMC for 3
minutes. Since thenmultiple studies have followed with intra-operative use of
MMC in concentration of 0.2 mg/ml or 0.4 mg/ml with application time of 3 – 5
minutes12,13,14.
Several workers have
also used 0.1 ml of MMC in concentration of 0.2 mg/ml injected under pterygium
head and then removing pterygium with simple excision after 4 weeks. The
success rate of this approach has been comparable to the topical application of
MMC in reducing the recurrence rate of pterygium15,16.
TRABECULECTOMY
The aim of drainage surgery for glaucoma
like trabeculectomy is to create an outflow channel for aqueous humor leading
into subconjunctival space. The common cause of failure of this drainage area
is to get occluded due to fibrosis at conjunctival – scleral interface and
intrasclerally. The various risk factors for the fibrosis resulting in drainage
failure are long term antiglaucoma medication, patients under 50 years of age
and various uveitic, rubeotic and pseudophakic glaucomas. The scarring process
occurs due to proliferation of fibroblasts at the site of surgical fistula17,
resulting in uncontrolled intraocular pressure (IOP). Because of its anti
fibroblastic activity, MMC has been used topically over sclerectomy area to
maintain the drainage facility with controlled IOP.
The first use of MMC in trabeculectomy is
attributed to chen18 who claimed higher success in his cohort of 59
eyes undergoing trabeculectomy in refractory glaucomas. This has been followed
by numerous reports in the literature on the use of MMC in trabeculectomy in
all types of glaucoma achieving higher success rate in maintaining the IOP19–23.
Traditionally MMC soaked sponges are placed
at the time of surgery under conjunctiva before or after scleral flap
dissection. The average concentration of MMC is 0.1 mg/ml – 0.5 mg/ml with
duration of application between 1 – 5 minutes. Afterwards MMC is washed out
with copious irrigation of balanced salt solution (BSS). Some clinicians have
used the sponges placed under the scleral flap and claimed higher success of
IOP control.24One alternative approach for using MMC is to inject it
subconjunctivally over the site of bleb at the start of the surgery25.
Maquet and colleagues26 described protocol for MMC use in glaucoma
surgery. They divided 143 eyes of 124 patients in multiple groups receiving MMC
in different concentrations. First group received MMC 0.1 mg/ml, second group
had 0.2 mg/ml while third group of patients received 0.4 mg/ml. No significant difference were found in final
mean IOP values or in postoperative complications at the end of 12 month
follow-up. Pakravan and co-workers27 in multicentre clinical trial
randomized 80 patients in 2 groups: group 1 received Subtenon injection of 0.1
ml of 0.1 mg/ml MMC while group 2 received 0.2 mg/ml MMC soaked sponges. At the
end of 1 year follow-up both groups showed success of 82.5% in controlling the
IOP. They reported that, blebs tended to be more diffused, less vascularized
and shallower in patients receiving MMC by subtenon injection.
The use of MMC is not
without certain complications when used in higher concentration and for longer
duration. Therefore, it is important to weigh the risks and benefits of MMC use
in glaucoma surgery. The use of MMC can cause corneal epithelium toxicity
resulting in superficial punctuate erosions and corneal abrasions. Conjunctival
wound leaks are also frequently described in patients treated with MMC. The
thin-walled blebs produced with MMC use are also at greater risk for developing
blebitis and endophthalmitis. Hypotony and resulting maculopathy is also
witnessed in patients receiving MMC during trabeculectomy28.
REFRACTIVE SURGERY
Photorefractive Keratectomy (PRK) is the
original surface ablation technique involving removing the epithelium of the
cornea mechanically with subsequent ablation of the bowman’s layer and anterior
stroma using the excimer laser. Although this technique is followed by pain and
discomfort during the first 24 hours and slow visual recovery but it is the
corneal haze formation which complicates the visual outcome. Corneal haze can
develop frequently after treatment of high myopia (≥ 6.00 Diopters) due to ablation
depth. The pathogenesis of haze formation is due to keratocytes apoptosis
caused by laser and is followed by proliferation and migration of surrounding keratocytes
to repopulate the stroma. Some of these keratocytes differentiate into
myofibroblasts which not only are basis for corneal haze but also cause
scattering of light29.
Talamo was the first one using MMC in an
animal model suggesting that it’s use can prevent corneal haze formation30.
Mitomycin C is applied over the
deepitheliazed stroma after laser ablation. It causes lower keratocytes and
myofibroblasts density with reduced deposit of collagen and extracellular
matrix resulting in decreased corneal haze31.
The optimal dose and duration of MMC is not
known in PRK. But it is used in a concentration of
2 mg/ml (0.2%)–0.2 mg/ml (0.02%) with duration of application from 12 seconds
to 2 minutes.
Majmudar first used MMC
as a prophylactic agent in patients undergoing PRK.32 Leccisotti
reported significant less haze in eyes treated with MMC 0.2 mg/ml for 45
seconds. Patients refractive error ranged from – 6.50 to – 10 diopters33.
Similarly Wallu and Campos reported better outcome for PRK with MMC than LASIK
with no haze observed in eyes treated with MMC34. Sigonos and
colleagues advise 30 seconds application of MMC 0.2 mg/ml (0.02 %) for primary
PRK and in complicated cases involving penetrating keratoplasty (PKP), radial
keratotmy (RK), and re-docases 1 minute or more application of MMC is suggested35.
Medina and co-workers found no change in endoethelium cell count, epithelial
thickness, keratocyte density and number of corneal nerve fibers with MMC use
after 5 years postoperatively36.
STRABISMUS SURGERY
Postoperative scarring
and formation of adhesions following strabismus surgery can compromise the
final outcome. The intraoperative adjunctive use of MMC has been found with encouraging
results in rabbit model with reduction in formation of adhesions and scarring37.
Chen and colleagues38 found that use of MMC in dose of 0.2 mg/ml
applied for 5 minutes duration was associated with better range of passive
duction at all postoperative follow-ups in patients undergoing strabismus
surgery. The use of MMC is also associated with delayed adjustments after
strabismus surgery39.
LACRIMAL SURGERY
Dacryocystorhinostomy
(DCR) is the preferred procedure in treating blockage of nasolacrimal duct with
excessive lacrimation. The common cause of failure in DCR is closure of the
common canaliculus and obstruction of the site of osteotomy40,41. This
occurs due to proliferation of fibrous tissue, and formation of granulation
tissue. The MMC soaked sponges (0.2 mg/ml) when placed at the site of osteotomy
and anastomosed flaps can slow proliferation of fibrous tissue and development
of scar. Liao and co-workers treated 44 eyes undergoingDCR surgery with
application of MMC 0.2 mg/ml applied to osteotomy site for 30 minutes. The
non-patency rate in MMC group was 4.5% compared with 11.4% with conventional
group.42Rathore and colleagues placed a nasal pack soaked in 1 ml of
0.5 mg/ml (0.05%) MMC for 48 hours after endonasal DCR. Postoperatively, the
nasal cavity with MMC pack had healthy nasal mucosa during the entire follow-up
as compared to the control group with saline nasal pack which showed synechiae
formation in 65.2% cases43. Xue and co-workers conducted a
meta-analysis of randomized controlled clinical trials related to adjunctive
use of MMC in primary and revision external and endonasal DCR. They concluded
that surgical success rate in primary and revision external DCR can be enhanced
when MMC is applied at the site of osteotomy effectively but there was no
significant advantage in primary endonasal DCR44.
Nair et al in their review suggest that studies should be done on innovative
drug delivery methods like intraoperative injection of MMC in depot form or
using silicone stents coated with MMC45.
CONCLUSION
The use of mitomycin C
is established in various ocular surgical procedures. The optimal dose and
duration of application of MMC is still not known. One has therefore to weigh
the risks and benefits of its use in different clinical conditions.
Financial Interest
None.
Conflict of Interest
None.
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Author’s Affiliation
Prof P.S. Mahar
Consultant Eye Surgeon,
Aga Khan University Hospital
Professor & Dean,
Isra Postgraduate Institute of Ophthalmology, Karachi
Author’s Contribution
Prof. P.S Mahar
Study Design, Manuscript Writing. Data Collection.