Mitomycin C (MMC) is a mainstay in the armamentarium of glaucoma surgeons, offering a means to improve surgical success rates by enhancing the wound healing process. However, its efficacy comes with the risk of potential toxicity. In this discussion, glaucoma surgeons Drs. Simon K. Law and JoAnn Giaconi delve into the polarized perspectives surrounding MMC’s role in glaucoma surgery.

Arguments for the Use of Mitomycin C During Glaucoma Surgery

Simon K. Law, MD 

When significant intraocular pressure (IOP) reduction is required to arrest further progression of severe or aggressive glaucoma, glaucoma procedures such as trabeculectomy or tube shunt procedures are often required. For these types of glaucoma surgery, tissue scarring caused by the natural healing process poses a major threat to long-term success. To modulate the wound-healing process, different agents and techniques have been studied, including human amniotic membrane spacers, tissue plasminogen activator, triamcinolone acetonide, dendrimers, radiation, inhibitors of different growth factors, antifibrotic agents such as 5-fluorouracil and MMC, and many others. 

Mitomycin C surpasses others in its effectiveness in modulating the healing process and enhancing the success of glaucoma surgery.^1,2 Besides the convenience in administration, whether by application or injection via a subconjunctival route, glaucoma surgeons have accumulated 4 decades of experience in handling MMC. However, safety of MMC in glaucoma surgery remains an issue due to its toxicity.

Like any medication or surgery, MMC use in glaucoma surgery is not a foolproof solution, because MMC is rather toxic to the ocular tissue. Postoperative endophthalmitis from thin or leaky conjunctival tissue is among the most devastating complications. It is due to toxicity that some argue against its use, or even advocate abandoning trabeculectomy altogether.

Patients and sometimes surgeons alike decide on glaucoma surgery or MMC use in an all-or-none approach. Surgeons ignore the variability that comes with surgery; even the same glaucoma surgery done with identical technique can result in different outcomes in different patients or at different times. The healing process is one of the many variables that is difficult to predict or control. However, there are many surgical steps and techniques that an experienced surgeon can adjust according to the individual case, and a good surgeon always considers reducing risks and complications of surgery as the utmost priority. 

It is not the toxicity of MMC that determines whether a surgeon should use it or whether to do a particular surgery, but rather how to use MMC and adjust the technique to maximize benefit and reduce risk. Considerations of how MMC is used, such as the concentration, weight, or volume of MMC; duration of application; injection vs application; and location of application/injection; are imperative for incorporation into surgical planning. These should be decided on an individual basis, rather than interpreting them in isolation. Intraoperative MMC use together with postoperative suture adjustment may uniquely help titrate the aqueous outflow according to the individual’s healing response and the pressure reduction needed. 

At the very least, good surgical planning involves a discussion between surgeon and patient regarding risk and benefit, what to expect, and what level of risk the patient is willing to take when considering a glaucoma surgery, including the use of MMC. The discussion should also include a long-term plan regarding postoperative monitoring of any complication. When MMC use is tailored according to individual disease conditions, it may achieve benefits in controlling glaucoma and helping glaucoma patients with advanced disease to maintain stable visual function for long periods. Ideally, something better than MMC with less toxicity and greater effectiveness will someday replace MMC. Until that occurs, however, MMC should be considered or even be expanded in its application in glaucoma surgery.

Arguments Against the Use of Mitomycin C During Glaucoma Surgery

JoAnn Giaconi, MD

Mitomycin C use in conjunction with trabeculectomy first appeared in the literature in the 1980s. There is good evidence showing that MMC increases the success rate of trabeculectomy compared to 5-fluorouracil use or no antimetabolite use.¹ In fact, 97% of surgeons in the American Glaucoma Society report using MMC during trabeculectomy.³ Bleb-forming microinvasive glaucoma surgeries (MIGS), in which scarring can lead to failure, also benefit from MMC use. There are a few studies that show benefit of using MMC when implanting traditional glaucoma drainage devices.⁴

However, in this world we never seem to get something for nothing. With MMC, the tradeoff of improved success rates overall is a higher rate of certain complications in some patients. Mitomycin C inhibits fibroblast proliferation and suppresses vascular ingrowth. The inhibition may vary from patient to patient depending on the dose delivered, duration of exposure, preparation method, and tissue-related factors. 

If there is total inhibition of fibroblasts and no scarring of the trabeculectomy flap and/or overlying Tenon/conjunctival tissue, patients can experience hypotony, hypotony maculopathy, and subsequent reduction in vision. In these cases, revision operation is usually recommended to raise eye pressure. Any surgeon who does these revision surgeries knows that once the tissue is opened, it can be found to be totally avascular and friable, which can make it difficult to place sutures that do not cheese wire through the tissue.   

Suppressed scarring can also lead to thin, avascular, hypocellular blebs. These blebs are more prone to conjunctival breakdown and bleb leaks. Bleb leaks are associated with high rates of blebitis (Figure 1) and endophthalmitis, which is sight threatening. Avascular, hypocellular conjunctiva and Tenon layer is also problematic if there is a foreign device underneath it. Microinvasive stents, as well as traditional glaucoma drainage devices, can more easily erode through MMC-treated tissue, potentially leading to endophthalmitis and loss of vision. And, of course, revision of an implant can be very difficult when working with MMC-treated tissue. In some cases, the device may need to be removed entirely because it cannot adequately be covered again.  

Mitomycin C applied to the sclera or injected has also been shown to reach the ciliary body and ciliary epithelium. It can have a toxic effect on those tissues, and it can reduce aqueous humor production, which for some eyes can lead to difficult-to-reverse hypotony. Also, MMC application directly at the limbus, with pledgets or injection, can damage limbal stem cells, leading to limbal stem cell deficiency and visual problems from a damaged ocular surface. Finally, MMC is toxic intracamerally. There is a risk of intraoperative confusion of mitomycin with moxifloxacin, which is injected into the anterior chamber, particularly with combined cataract/glaucoma cases, and this could lead to devastating toxicity to the eye.  

Even though the use of MMC has become routine, there are patients for whom MMC is better withheld or used at a very low, cautious dose. GP

Simon K. Law, MD, is a clinical health sciences professor in the Stein Eye Institute of the David Geffen School of Medicine at University of California Los Angeles. He reports no relevant financial disclosures.

JoAnn Giaconi, MD, is a health sciences professor of ophthalmology at David Geffen School of Medicine, vice chair of affiliate hospitals at Stein Eye Institute, and chief of ophthalmology at the Greater Los Angeles Veterans Administration in Los Angeles, California. She reports no relevant financial disclosures.

 References

1. Wilkins M, Indar A, Wormald R. Intra-operative mitomycin C for glaucoma surgery. Cochrane Database Syst Rev. 2005;2005(4):CD002897. doi:10.1002/14651858.CD002897.pub2

2. Cabourne E, Clarke JC, Schlottmann PG, Evans JR. Mitomycin C versus 5-fluorouracil for wound healing in glaucoma surgery. Cochrane Database Syst Rev. 2015;2015(11):CD006259. doi:10.1002/14651858.CD006259.pub2

3 Vinod K, Gedde SJ, Feuer WJ, et al. Practice preferences for glaucoma surgery: a survey of the American Glaucoma Society. J Glaucoma. 2017;26(8):687-693. doi:10.1097/IJG.0000000000000720

4. Cui QN, Hsia YC, Lin SC, et al. Effect of mitomycin c and 5-flurouracil adjuvant therapy on the outcomes of Ahmed glaucoma valve implantation. Clin Exp Ophthalmol. 2017;45(2):128-134. doi:10.1111/ceo.12811