Though the antimetabolite mitomycin-C has served refractive surgeons well in their efforts to prevent haze after surface ablation, some wonder if there will be any long-term complications associated with the drug. In this article, several surgeons discuss the issues their colleagues should be aware of when using the powerful agent, and the best way to use it without running into problems.

Current Protocols

When used prophylactically, most surgeons who use MMC use the protocol established by Chicago surgeons Parag Majmudar and Randy Epstein. “For prophylaxis, whenever we’re going to treat more than about -7 D, which is roughly 85 µm of ablation depth, we apply a concentration of 0.02% mitomycin for 12 seconds,” explains Dr. Epstein. For therapeutic applications to corneas that already have haze and need to be treated, Dr. Epstein uses the same concentration, but for two minutes.

There is also some evidence that patients who have undergone previous corneal procedures may be at a higher risk for haze, so surgeons will often use MMC on them, regardless of the refractive error being corrected. Cleveland Clinic surgeon Steve Wilson usually uses MMC for surface ablation cases of 5 D or greater, but will alter his approach in some instances. “The caveat is that I strongly believe that if a patient has had prior refractive surgery, such as PRK, RK or a LASIK, he is set up for getting late haze,” he says. “So, even if this patient requires a low correction of 1 D of sphere or 1 to 2 D of astigmatism, I think it’s acceptable to use mitomycin.”

Toxicity Risks

When surgeons express concerns about MMC, they refer to the possibility of toxicity to the following tissues:

 • Limbal stem cells. Surgeons make every effort to keep the drug away from the limbus. “You want to make sure you restrict the treatment to the central cornea so you don’t somehow damage the limbal stem cells of the epithelium,” says Dr.  Wilson. “This is best done by applying the mitomycin-C to a sponge—I use a circular sponge about 6 to 7 mm in diameter—and keep that in the center of the cornea. That way, you don’t have any risk of it getting on the limbal stem cells and potentially producing limbal stem cell deficiency.”

A cornea that’s had previous refractive surgery is at greater risk for late-onset haze after subsequent surface ablation.
Louisville, Ky., surgeon Asim Piracha uses a sponge for his MMC application but in a different way. “I don’t put the sponge on the cornea,” he explains. “Instead, I wipe the cornea and make sure the mitomycin is evenly applied. I ensure that the stroma is wet with mitomycin, but not dripping, and I keep wiping so it keeps an even lubrication of mitomycin on the stroma. Usually when I do it, I have the MMC sponge in one hand and a dry Weck-Cel in the other so I can dry off any leakage before it can stay on the peripheral cornea and limbus.”

 • Keratocytes. Dr. Wilson says ophthalmology has had a good experience with using mitomycin for 15 to 20 years, but says that he hopes the 30-to-40-year time frame doesn’t resemble the old story about the man who jumps from the Empire State Building: “As he passes people on the 63rd floor, he says, ‘So far, so good,’ ” Dr. Wilson jokes.

“We’ve always had a concern that there could be long-term decreased keratocyte cell density with mitomycin-C use,” says Dr. Wilson. “We’ve shown that that actually happens in rabbit models using immunohistochemical methods up to six months after the initial PRK procedure. There are a lot of longer-term confocal studies, including in humans, and most seem to indicate that at a year or so after mitomycin-C use, the keratocyte density is relatively normal.1 That is, of course, an average, and some individual patients could have a decrease in their keratocyte density over the long term. But, at this point, we haven’t seen any repercussions from it.”

 • The endothelium. As with any corneal intervention, questions arise regarding the health of the all-important endothelium. Surgeons say, however, that the research hasn’t found the endothelium to be in particular danger. “There were really only two studies published in the peer-reviewed literature that showed endothelial toxicity with mitomycin,” says Dr. Epstein. They both were in fairly small numbers of patients. One showed a 16-percent decrease in cell density, but this was associated with mitomycin contact times longer than what’s currently used, and they didn’t really look at morphometric data, which is a more sensitive indicator of corneal health than just cell density.2 The other only had nine patients and an exposure of 30 seconds.”3 Dr. Epstein says other studies have found no issues with endothelial toxicity.1,4

Alternatives to MMC

Even though MMC has been used with minimal issues for about 17 years, there are those who are still searching for alternative ways to prevent haze that don’t risk the toxicity of MMC.

 • Vitamin C. Surgeons say ascorbic acid might help blunt a corneal haze response caused by UV light. “There are reports of patients getting haze when exposed to a lot of UV light in situations such as trips toward the equator or up in the mountains,” says Dr. Wilson. “Some studies suggest that oral vitamin C can mitigate these effects. If you’re operating somewhere that gets a lot of sun, vitamin C might be something you could use, since it at least won’t hurt the patient.”

 • Smooth surface. Researchers say one culprit behind haze formation is a rough cornea postop. “An excellent way to help prevent that is to smooth the surface,” says Dr. Wilson. “That was shown by Paulo Vinciguerra years ago.5 In those studies when the researchers performed high-correction PRKs they’d always use a smoothing PTK procedure at the end to make sure the surface was as smooth as possible. People criticized the studies and wondered why that would even work—but it did. We now know that any type of roughness of the surface can impede basement membrane regeneration. This is why the higher the attempted correction, the more surface irregularity can occur and the greater the chances of severe late haze.

“Now, however, a lot of people don’t like to include a PTK step,” Dr. Wilson continues. “I think they are worried it will throw off their algorithm, which may vary from patient to patient and therefore might not be as precise as it could be when just using mitomycin.”

 • Other molecules. Surgeons are still searching for a more selective haze-blocking agent. “Mitomycin indiscriminately kills all the cells in the anterior 20 to 40 percent of the stroma,” explains Dr. Wilson. “So that’s keratocyte cells and precursors to myofibroblasts, continuing for a time after the surgery. It would be great to have a magic bullet that only killed the precursor cells to myofibroblasts, because those are the ones that cause the problem.”

Two studies have come close to this magic bullet, but weren’t able to topple MMC from its perch. The first used a compound called Resolvin E1. “This was partially effective because it only blocked the generation of myofibroblasts from bone-marrow-derived cells, not the pathway of generating them from keratocytes or corneo­fibroblasts,” says Dr. Wilson, who co-authored the paper.6

The second study looked at a molecule called PRM-151, an inhibitor of monocyte development. “It turns out the cells from bone marrow that give rise to myofibroblasts are monocyte lineage cells,” says Dr. Wilson, who investigated the molecule. “But, PRM-151 only worked when injected subconjunctivally, not topically, at least in the concentrations we tried.”7  REVIEW

1. Santhiago MR, Netto MV, Wilson SE. Mitomycin C: Biological effects and use in refractive surgery. Cornea 2012;31:3:311-21.
2. Nassiri N, Farahangiz S, Rahnavardi M, Rahmani L, Nassiri N. Corneal endothelial cell injury induced by mitomycin-C in photorefractive keratectomy: Nonrandomized controlled trial.
 J Cataract Refract Surg 2008;34:6:902-8.
3. Morales AJ, Zadok D, Mora-Retana R, Martínez-Gama E, Robledo NE, Chayet AS. Intraoperative mitomycin and corneal endothelium after photorefractive keratectomy. Am J Ophthalmol 2006;142:3:400-4.
4. Goldsberry DH, Epstein RJ, Majmudar PA, Epstein RH, Dennis RF, Holley G, Edelhauser HF. Effect of mitomycin C on the corneal endothelium when used for corneal subepithelial haze prophylaxis following photorefractive keratectomy. J Refract Surg 2007;23:7:724-7.
5. Vinciguerra P, Azzolini M, Airaghi P, Radice P, De Molfetta V. Effect of decreasing surface and interface irregularities after photorefractive keratectomy and laser in situ keratomileusis on optical and functional outcomes. J Refract Surg 1998;14:S199.
6. Torricelli AA, Santhanam A, Agrawal V, Wilson SE. Resolvin E1 analog RX-10045 0.1% reduces corneal stromal haze in rabbits when applied topically after PRK. Mol Vis 2014 23;20:1710-6.
7. Santhiago MR, Singh V, Barbosa FL, Agrawal V, Wilson SE. Monocyte development inhibitor PRM-151 decreases corneal myofibroblast generation in rabbits. Exp Eye Res 2011 Nov;93:5:786-9.