Widely known for its ability to keep blebs from scarring and trabeculectomy sites patent, the anti-cancer drug mitomycin C is rapidly gaining favor as a powerful treatment for stromal haze after refractive surgery and a variety ocular surface lesions and neoplasias.

Clearing Corneas
Refractive surgeons and corneal specialists find MMC effective in resolving stromal haze after refractive surgery, most commonly PRK. Christopher J. Rapuano, MD, uses mitomycin C for severe haze after PRK. “Haze post-PRK is not uncommon; it’s usually mild and doesn’t affect vision. But that isn’t always the case,” says Dr. Rapuano, an attending surgeon on the cornea service and co-director of the refractive surgery department at Wills Eye Hospital, and a professor at Jefferson Medical College, Philadelphia.

He describes a referred patient who had photorefractive keratectomy about 10 months earlier from another physician who attempted to resolve all 19 D of her myopia with a single treatment. When Dr. Rapuano saw the patient, she had

Figure 1. Ocular cicatricial pemphigoid.

Figure 2. Ocular cicatricial pemphigoid stable and quiet five years after subconjunctival injection of 0.50 cc of 0.15 mg/mL of Mitomycin C.

All images: Eric Donnenfeld, MD

regressed to 20/200 BCVA in one eye and 20/80 BCVA in the other eye. He treated the 20/200 eye with mitomycin C by scraping off the epithelium, which he says was “super thick, probably three times normal-thickness epithelium,” and performing a mild excimer laser phototherapeutic keratectomy to smooth the corneal bed. He then applied MMC 0.02 % formulation (the same as the 0.2 mg/mL solution).

The eye healed well, with mild, diffuse stromal haze, and now is 20/60 uncorrected, with a total corneal thickness of 250 µm. At three months, he says the patient is “thrilled with how well her first eye is doing. Whether the reticulated haze she presented with will recur is unknown. We haven’t fitted her with a contact lens because we want the epithelium to heal. I will wait about six months before treating the second eye. This patient suffered severe reticular corneal haze, which the MMC treated well. What we don’t know are the long-term results,” he adds.

Application Protocol
Dr. Rapuano carefully controls the MMC delivery. “I cut out a 6-mm disc of filter paper with a trephine, moisten the disc with a few drops of MMC, and put it on the central cornea for two minutes,” he says. [The MMC] is not indiscriminately applied to the eye; it is placed just on the central 6 mm of the cornea after it is absorbed in the paper. This way I know exactly where the MMC is and for exactly how long.”

He uses a Weck cell sponge to lift the filter paper off the cornea, then irrigates the eye with 30 cc of saline. “I treat them as I would a regular post- PTK patient. Some of those patients get a bandage contact lens, but most get patched for 24 hours.”

Eric Donnenfeld, MD, believes strongly in using MMC for patients with recurrent haze and regression following PRK. He waits six months to a year before treating patients who have not responded to steroids.
Dr. Donnenfeld, co-chairman of corneal external disease at Manhattan Eye and Ear, New York, conducted a study of LASIK over corneal transplants. The procedure worked well in eyes that did not have an original pathology of keratoconus. “I originally treated these eyes with PRK, but stopped due to excessive haze,” he says. He then performed LASIK in these eyes and noticed an increase in cylinder in the eyes. “I’m concerned about LASIK after corneal transplant for keratoconus. I am reluctant to create a flap in an ectactic eye with a thin cornea,” he says.

He now performs PRK with MMC for corrections up to -9 D in eyes that have corneal transplants for keratoconus. He does not believe in prophylactic

Figure 3. Recurrent pterygium.

Figure 4. Regression of recurrent pterygium after 0.10 cc mg/mL of Mitomycin C.

use of MMC in routine cases. “There are too many side effects and the long-term complications can take 10 years to develop,” he says. He uses MMC in LASEK or PRK only if the patient has a significant risk for haze. He’s used it prophylactically with good results in about 30 PRK patients with myopia of 7 D and higher.

Chicago surgeon Randy Epstein, MD, uses MMC for patients with corneal haze following refractive surgery and as prophylaxis in primary treatment. He soaks a corneal light shield with MMC 0.02 mg/mL and places it on the central cornea for two minutes after debridement or PTK, then irrigates the eye thoroughly with BSS. For prophylaxis, he applies it after the laser treatment on bare stroma for two minutes, then irrigates the eye with BSS.
Great care must be taken, he cautions, to rinse off all the agent. “If you don’t remove it all, residual rather than recurrent haze can occur. In these cases, additional PTK or other treatments are possible, but not a repeat of the MMC,” he says.

He notes that myopic progression is caused by the haze, and not because of an initial undercorrection. “If you remove the haze in a refractively neutral manner, you’ll restore them to their previous level of refractive error,” he says. It’s a big mistake, he warns, to treat 5 to 6 D of myopic regression along with haze because “you’ll end up overcorrecting patients.”

Prophylaxis with PRK is controversial, Dr. Epstein notes. He offers it to patients over -7 D and finds that about half the patients are comfortable with it and half say they don’t want it. He and partner Parag Majmudar, MD, have used MMC prophylaxis in 20 patients with primary procedures, and in 15 patients who have received PRK through complicated flaps. “We do our standard PRK or LASEK and cut back 10 percent on the treatment parameters, then place the MMC for two minutes at the end of the procedure, again rinsing it thoroughly,” Dr. Epstein explains.

The final recommendation on prophylaxis remains unresolved, he says. “Studies so far show no evidence of endothelial toxicity and excellent and predictable refractive outcomes. The long-term effects are still unknown, however,” Dr. Epstein says.

Ocular Surface Lesions
MMC’s anti-fibrotic and anti-metabolite qualities are being exploited to treat a wide range of ocular surface lesions. Dr. Donnenfeld uses MMC in patients with ocular cicatricial pemphigoid to prevent progression of the subconjunctival fibrosis. He’s used it for several years in patients who are unresponsive to or are unable to take anti-metabolites, such as dapsone or cyclophosphamide. He has performed a contralateral eye study of 20 patients. It indicated that “the condition progressed more slowly in MMC-treated eyes compared to control eyes,” he says.

He also uses MMC subconjunctivally for recurrent pterygia. He injects 0.15 cc of MMC 0.15 mg/mL. The subconjunctival delivery prevents topical ocular surface toxicity, he says, causing less damage to the stem cells, less retardation of epithelial healing, with less long-term sequelae such as melting. He notes that only two of 65 pterygium patients had mild recurrences.

Stephen Pflugfelder, MD, professor and director of the ocular surface center at Baylor College of Medicine’s Cullen Eye Institute, Houston, also has had success using MMC for pterygium. “There are different indications for treating pterygia, and the most common is cosmetic,” he says. “Left untreated, aggressive pterygia grow over the cornea and the pupil, causing decreased vision from direct blocking of the visual axis. Frequently, they induce severe irregular astigmatism.”

Pterygium can be a blinding condition, especially in sub-tropical and tropical climates. Most commonly, people who work outside and those who are in bright sunlight are affected. “I have lived in Florida and Texas, places which get a lot of UV light exposure, so I’ve treated my share of pterygia,” Dr. Pflugfelder explains.

While he reserves MMC for recurrent pterygia, he notes that some physicians use it for primary pterygium treatment. The recurrence rate varies, but reports indicate that when the lesion is excised without performing a graft, the recurrence rate can range from 5 to 50 percent.

Pterygium Treatment
Dr. Pflugfelder excises the lesion, then performs a conjunctival-limbal autograft. With this procedure, his recurrence rate is 1 to 5 percent. If the pterygium recurs, he repeats the excision and places a sponge soaked with 0.02 percent on the sclera in the area of the pterygium for 30 to 60 seconds, rinses it off, applies amniotic membrane and performs the graft.

 “If [the pterygium] is very bad, I rinse the eye and replace the sponge for another 30 seconds,” he says. “The consensus is that if you put MMC on the sclera and cover it with a graft, you’re OK. No one has reported serious comps.” However, placing it on bare sclera and not covering the site with a graft can cause scleral melting, he warns. And it can set the stage for infection and non-healing ulcers.

The amniotic membrane is anti-inflammatory, anti-angiogenic and anti-fibrotic. “Epithelial cells like to grow on it,” he explains. “In the past two years, I’ve had

Figure 5. Haze following photorefractive keratectomy.

six patients referred to me with severe, recurrent pterygia. After this treatment, they have been disease-free for two years. They are what I consider cured.”
“[Mitomycin C] for pterygium got bad press early on,” Dr. Pflugfelder says, partly because of one doctor’s

Figure 6. Resolution of the haze following topical application of Mitomycin C.

recommendation, which consisted of using higher concentration drops, just excising the pterygia and not grafting the site of application.

With the 0.02 % MMC preparation and his amniotic membrane and auto-grafting procedure, Dr. Pflugfelder has seen no adverse sequelae. “Patients have no ocular surface consequences,” he notes. “The treatment is localized to the site of the lesion and the agent is applied with a lightly moistened sponge. We’re not bathing the eye surface with it so there’s no need to plug the puncta.”

The agent can be dangerous, however, and he cautions that surgeons must ensure that the medication is mixed correctly and take precautions to prevent punctal and canalicular damage.

Dr. Rapuano has another application for MMC—treatment for recurrences of Salzmann’s nodules after PTK. In routine cases, he removes the nodules with a blade under an operating microscope or at the slit lamp. In some cases, the lesions won’t easily peel off the cornea. In these eyes he uses PTK. Occasionally, the lesions recur and in for those cases, he performs the PTK again and applies topical MMC for two minutes at the end of the procedure. With this procedure, he reports good results, with no recurrences at 12 months.

Neoplasms
In addition to ocular surface lesions, ophthalmologists are considering MMC as an anti-neoplastic agent, notes Dr. Pflugfelder. The agent, he explains, has been reported to be effective for intra-epithelial neoplasia on the ocular surface or carcinoma intraepithelial neoplasia (CIN), with multi-center clinical trials reporting its efficacy in recurrent lesions. “There is a bit of controversy about whether doctors should use [this] as first-line therapy or whether the lesions should be excised or frozen,” he says.

Usually CIN lesions arise at the limbus and grow toward the cornea, but they can grow under the conjunctiva. “If they’re not prevented, the lesions can expand over the entire bulbar conjunctiva, even into the fornix. Prior to using MMC, there was little we could do for these aggressive cases. End-stage disease often required evisceration,” he explains.

Usually Dr. Pflugfelder removes the lesions by excision or cryotherapy. When lesions recur, he treats again, applying topical MMC. The agent is toxic to the lacrimal drainage system, so he plugs the upper and lower puncta to avoid scarring the canaliculi. He orders 5 mL of 0.02% MMC from a formulation pharmacy. Patients use the drops q.i.d. for one week. “This protocol,” he explains, “is done under close observation. I see patients back in one week. I want to make sure the patient returns.”

He’s used this regimen in four eyes of four patients, and reports that all are disease-free at two years. “We know that mitomycin C prevents mitosis and is cytotoxic,” he says. “Cancerous and pre-cancerous cells are undergoing division much more rapidly than normal cells, and this may account for why [it] seems to be tolerated reasonably well. We worried that the agent might wipe out the stem cells on the ocular surface, but so far it doesn’t seem to.”

There are reports that MMC is useful for ocular melanoma. Paul Finger, MD, an ocular oncologist at the New York Eye and Ear Infirmary, used a similar drug regimen to that used for other cancerous lesions and found that the agent works well, Dr. Pflugfelder says.

Toxicity and uncertainty of long-term side effects leave many ophthalmologists reluctant to use MMC as a first-line therapy for neoplastic lesions. “Most neoplasias are small and easily excised, but if [simple excision] doesn’t work or the tumor is so extensive that it can’t be removed without a lot of problems, then MMC is a good option,” he says.

When used judiciously and as recommended by peer-reviewed studies, MMC offers many exciting new uses ranging from the inhibition of fibrosis to the elimination of certain ocular surface neoplasias. However, its long-term safety is unknown and for that reason, its use must be carefully monitored, experts say.