Drug Drought

Europe and Asia are currently afflicted by a sudden availability crisis of mitomycin C (MMC). This is significant as the majority of trabeculectomy procedures performed in modern times utilize antimetabolites, and 63 percent of those use MMC (1). After an issue with the sterile processing of the drug was detected, Kyowa Kirin – a Japanese pharmaceutical and biotechnology company – ceased production of MMC pending investigation, and a Class 2 product recall of all shelf stock is currently underway. In the UK, Kyowa Kirin’s drug is the only MMC product licensed for ophthalmic use. MMC licensed for intravesical application is still available in theory but supply is taken up by urological cancer requirements, leaving no surplus. Other routes of non-licensed supply were available, but the instant surge in demand meant those were quickly exhausted. This has left the UK, Europe and parts of Asia with no access to MMC, and hence trabeculectomy, tube shunt surgery and sub-conjunctival MIGS procedures (such as XEN or PRESERFLO) face significant challenges. The effects are expected to last at least until spring 2020.

5FU and filtration surgery

The wound healing response is the single most important determinant of the final intraocular pressure (IOP) after glaucoma surgery. Despite contemporary opinion holding that MMC is pivotal to surgical outcomes, only a decade ago MMC was viewed very differently. A UK survey in 2004 showed that 18 percent of trabeculectomy surgeons never used antimetabolites, 82 percent used them infrequently, and only 9 percent used antimetabolites routinely, with the preferred antimetabolite being 5FU. MMC was used in primary trabeculectomy by just two percent of all surgeons, with those who did use it reserving it for re-do surgery. In the US, between 33 and 55 percent of surgeons used MMC for first-time trabeculectomy in 2004 (2).

A recent Cochrane review compared 5FU with MMC in trabeculectomy surgery. It suggested that the risk of trab failure at one year was slightly lower for MMC than for 5FU, although this was statistically insignificant. Similarly, the review suggested that MMC was more effective at lowering IOP than 5FU in both high and low-risk participants but again did not reach statistical significance. No difference was found for the use of post-operative medication between the groups (3). A Cochrane review on the use of MMC for tube shunt procedures gave a similar outcome (4). Evaluating safety across multiple studies reveals slightly more favorable outcomes using MMC, particularly with regard to the incidence of corneal epitheliopathy and hyphema. But there was a trend towards more bleb leaks, wound leaks, late hypotony and cataract formation in the MMC-treated group.

One Cochrane review compares postoperative use of 5FU versus no antimetabolite treatment. A significant reduction in surgical failure is seen in the first year after trabeculectomy in patients treated with 5FU; however, repeated post-operative injections were required (5). A further meta-analysis last year showed that MMC is more effective in reducing IOP and increasing qualified success rate compared to 5FU. However, a higher incidence of complications with MMC compared to 5FU – such as bleb leak, late hypotonia, narrow anterior chamber, endophthalmitis and cataract development – was also noted (6). Taken together, the evidence suggests that the safety profile of 5FU is no worse than MMC, and confirms that 5FU is still a viable option in antimetabolite augmented trabeculectomy surgery.

(Unproven) alternative options

While MMC is currently the most effective antimetabolite used in glaucoma surgery, there is ongoing research into alternative agents that could augment surgical outcomes without the conjunctival thinning, bleb leak and endophthalmitis that MMC may predispose to. In a rabbit model of glaucoma filtration surgery, topical administration of silver nanoparticles resulted in improved bleb function when compared to MMC (7). The important role of VEGF in the cascade of wound healing, inflammation and angiogenesis has prompted numerous studies investigating anti-VEGF drug bevacizumab as an adjunct to trabeculectomy. Although the safety profile of bevacizumab seems comparable to MMC, the effectiveness of the drug in reducing IOP seems less certain (8). Another study suggested that the effect may be additive if multiple drugs are combined. Bleb morphology and IOP reduction were noted to be superior if MMC and ranibizumab were used concurrently (9). Beta-radiation has also shown significant promise in African populations and may translate well to more typical European/American demographic and conjunctival characteristics, but requires head-to-head comparison with standard MMC surgery (10).

Conclusion

The major confounding factor in comparing 5FU and MMC outcomes is the natural progression of surgical technique over time. Antimetabolite handling and conjunctival closure have improved greatly over the decades and, with the transition from 5FU to MMC occurring concurrently, we risk comparing the older 5FU technique to newer MMC techniques. We must account for this evolution when making comparisons, and care should be taken when directly comparing 5FU and MMC, unless the technique is standardized.

We are yet to see how this drug shortage will affect the future of glaucoma surgery. Although we may not be enjoying this enforced “step backward” in pharmacological surgical augmentation, it’s important to make the most of any positives in the situation. Maybe the MMC drought will allow for future direct comparison with standardized techniques, providing important data that we are currently lacking.  It may even open the door for a paradigm shift towards other emerging options, such as beta radiation or combination antifibrotic/anti-VEGF approaches.