Mitomycin C (MMC) is an antifibrotic agent that has long been used as an adjunct to inhibit the proliferation of fibroblasts at the time of glaucoma filtration surgery.^1,2 Since its inclusion in the glaucoma armamentarium, there has been significant mystery surrounding the optimal use of this medication. Given that overuse of MMC can lead to bleb leaks, blebitis, and overfiltration, and that underuse can lead to bleb failure, finding the right dose and method of use is the ambition of every glaucoma specialist. The challenge in finding the ideal dose of MMC based on evidence-based medicine is that every surgeon has a different trabeculectomy technique as well as a different MMC algorithm. MMC variables that are frequently altered include concentration, duration of application, and method of delivery, including number and placement of MMC-soaked sponges vs injection of MMC directly into tenons. If all these variables were not confusing enough, many surgeons will also change these treatment algorithms based on patient race, age, or other risk factors. It quickly becomes understandable how the science of MMC utilization can often devolve into unsubstantiated dogma.

First MMC dogma: Treating surgeons should vary MMC concentration and duration based on patient-specific risk.

When it comes to MMC concentration and duration, surgeons have a wide variety of protocols at their disposal. Mytomycin C concentration varies in published studies from 0.02 mg/mL to 0.4 mg/mL and duration varies from 30 seconds to 5 minutes. Protocols to vary the concentration and duration based on a risk-factor-assigned point system have even been developed and studied.³

Some studies suggest that varying doses and times may lead to different results. Robin et al studied 4 groups: placebo, 0.2 mg/mL for 2 minutes, 0.2 mg/mL for 4 minutes, and 0.4mg/mL for 2 minutes. They concluded that increased dosing has a possible slight benefit.⁴ They also showed an increase complications with higher doses. Other studies seem to show that 0.2 mg/mL concentration is the most effective.^5,6

Although these few studies demonstrate a trend toward a dose-related response to MMC concentration, other studies show the opposite result. The evidence seems to most clearly refute that the MMC duration significantly alters results. In studies looking at varying times of MMC, exposure time has not been shown to impact postoperative IOP.^7,8 Several studies have compared 0.1 to 0.2 and 0.4 mg/mL and found little difference in efficacy.^3,9,10 Those studies did, however, find a trend toward increased complications in the higher 0.4 mg/mL dose.⁹ Sihota et al, in a 2015 prospective study with 2-year follow-up, compared 0.1 to 0.2 mg/mL applied for 1 minute and found no difference in the 2 cohorts.¹¹ The aforementioned study that assigned dose and duration based on a point system failed to demonstrate a different outcome based on concentration or duration.³

In a 2015 extensive review article on this subject, Habash et al concluded that “most studies appear to suggest that lower concentrations of MMC and shorter exposure times are as effective in achieving lower IOPs when compared to higher concentrations/prolonged exposure times. In contrast, higher MMC concentrations and prolonged exposure times may be associated with a higher risk of complications.”¹² While the studies on dose and duration are somewhat conflicting, it is likely that this is one dogmatic reasoning that is not supported by the data.

Second MMC dogma: Using subconjunctival sponges is the safest, most predictable method to deliver MMC.

Over the past decade, the dogma of using soaked sponges to deliver MMC to the subconjunctival space has been challenged. This practice has been replaced in many surgeons’ hands with preoperative injection of MMC in the subconjunctival space. The duration of MMC applied with sponges followed by copious irrigation has traditionally been a strictly regimented procedure. Longstanding belief that prolonged exposure would lead to overexposure, thus increasing the risks of hypotony and blebitis maintained this rigid practice.

While these concerns and reservations are understandable, there have been several studies proving not only the safety of MMC injection but also proposed benefits with this treatment approach.^13-15 Khouri et al, in a comparative study, showed that there were no safety or IOP differences in the 2 methods. In addition, they demonstrated that the injection group had a lower rate of needling procedures.¹⁴ In a prospective study, Pakravan et al also showed equivalent safety and IOP results, but the study also demonstrated a more favorable bleb morphology.¹⁵ Blebs in the injection group had a lower, more diffuse bleb.

In addition to these outcomes benefits, the injection method provides the additional benefits of decreased surgical time, ensuring the patient receives the entire intended dose, and no risk of retained sponges. Given these benefits and improved outcomes, the previously held dogma directing the use of sponges should be safely replaced by data supporting the advantages of MMC injection.

Future Directions

Since its adoption in filtration surgery, MMC has greatly enhanced the success of this procedure. It appears that employing the fixed concentration approach and the injection method are supported by the data. Newer filtering devices, including the Xen Gel Stent from Allergan and the MicroShunt (DE-128) from Santen, have standardized the filtration procedure. The optimal MMC dose and technique for these procedures are yet to be elucidated.

Data on these devices is quickly expounding our knowledge. The ideal usage of MMC with these new devices will likely be the next great MMC debate. GP

References

1. Kitazawa Y, Kawase K, Matsushita H, Minobe M. Trabeculectomy with mitomycin: a comparative study with fluorouracil. Arch Ophthalmol. 1991;109(12):1693-1698.
2. Yamamoto T, Varani J, Soong HK, Lichter PR. Effects of 5-fluorouracil and mitomycin C on cultured rabbit subconjunctival fibroblasts. Ophthalmology. 1990;97:1204-1210.
3. Lee SJ, Paranhos A, Shields MB. Does titration of mitomycin C as an adjunct to trabeculectomy significantly influence the intraocular pressure outcome? Clin Ophthalmol. 2009;3:81-87.
4. Robin AL, Ramakrishnan R, Krishnadas R, et al. A long-term dose-response study of mitomycin in glaucoma filtration surgery. Arch Ophthalmol. 1997;115(8):969-974.
5. Laube T, Ritters B, Selbach M, Hudde T. [Clinical experiences and results of mitomycin C in trabeculectomy]. Article in German. Klin Monbl Augenheilkd. 2003;220(9):618-624.
6. Kitazawa Y, Suemori-Matsushita H, Yamamoto T, Kawase K. Low-dose and high-dose mitomycin trabeculectomy as an initial surgery in primary open-angle glaucoma. Ophthalmology. 1993;100(11):1624-1628.
7. Manners T, Salmon JF, Barron A, Willies C, Murray AD. Trabeculectomy with mitomycin C in the treatment of post-traumatic angle recession glaucoma. Br J Ophthalmol. 2001;85(2):159-163.
8. Mégevand GS, Salmon JF, Scholtz RP, Murray AD. The effect of reducing the exposure time of mitomycin C in glaucoma filtering surgery. Ophthalmology 1995;102(1):84-90.
9. Sanders SP, Cantor LB, Dobler AA, Hoop JS. Mitomycin C in higher risk trabeculectomy: a prospective comparison of 0.2- to 0.4-mg/cc doses. J Glaucoma. 1999;8(3):193-198.
10. Maquet JA, Dios E, Aragón J, Bailez C, Ussa F, Laguna N. Protocol for mitomycin C use in glaucoma surgery. Acta Ophthalmol Scand. 2005;83(2):196-200.
11. Sihota R, Angmo D, Chandra A, Gupta V, Sharma A, Pandey RM. Evaluating the long-term efficacy of short-duration 0.1 mg/mL and 0.2 mg/mL MMC in primary trabeculectomy for primary adult glaucoma. Graefes Arch Clin Exp Ophthalmol. 2015;253(7):1153-1159.
12. Al Habash A, Aljasim LA, Owaidhah O, Edward DP. A review of the efficacy of mitomycin C in glaucoma filtration surgery. Clin Ophthalmol. 2015;9:1945-1951.
13. Lee E, Doyle E, Jenkins C. Trabeculectomy surgery augmented with intra-Tenon injection of mitomycin C. Acta Ophthalmol. 2008;86(8):866-870.
14. Khouri AS, Huang G, Y Huang L. Intraoperative injection vs sponge-applied mitomycin C during trabeculectomy: one-year study. J Curr Glaucoma Pract. 2017;11(3):101-106.
15. Pakravan M, Esfandiari H, Yazdani S, et al. Mitomycin C-augmented trabeculectomy: subtenon injection versus soaked sponges: a randomised clinical trial. Br J Ophthalmol. 2017;101(9):1275-1280.

Jacob W. Brubaker, MD, is a glaucoma specialist with Sacramento Eye Consultants in Sacramento, California. He reports consultancy to Aerie Pharmaceuticals, Alcon, Allergan, Glaukos, and New World Medical. Reach him at jacobbrubaker@gmail.com.