27

Mitomycin C and Surface Ablation

Scott D.Barnes, MD and Dimitri T.Azar, MD

Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute,

Harvard Medical School

Boston, MA

Excimer keratectomy has been effectively used to correct mild to moderate myopia (1–4), astigmatism (5–7), and hyperopia (8–10). However, such laser ablations appear to activate keratocytes leading to their proliferation (11,12). A number of reports have documented irregularities in basement membrane configuration (13,14), the presence of vacuoles in and around keratocytes (11,12), and disorganization in the lamellar structure of the corneal stroma (11,12,14,15). These changes have been theorized to be responsible for corneal light scatter and the cause of corneal haze formation and refractive regression (16,17).

Compared to early reports, the incidence of visually significant haze has been decreasing with the continued advances in laser technology and refinements of surgical technique (18–21). However, it has not been eliminated, particularly in the highly myopic patient (22,23).

Corticosteroids have been a main agent in prophylaxis against excessive haze formation as well as treatment once visually significant haze presents (17,24–26). However, the possibility of steroid-induced adverse effects (27,28) and cases of treatment failures (29) have led to the investigation of mitomycin C (MMC) as a possible alternative treatment.

In 1991, Talamo, et al. began to investigate the use of MMC to modulate corneal wound healing after laser keratectomy (30). The initial success in rabbits and cats did not quickly transition into human trials, perhaps because of the advent of LASIK (with associated reduction in haze formation) as well as a number of reported complications with conjunctivaland scleral-based applications of MMC (31,32). However, patients with an inadequate corneal thickness for LASIK combined with recent reports of intraoperative and postoperative complications of LASIK have led to a renewed interest in surface based ablations. An interest in methods of prevention and treatment of corneal haze (LASEK vs. PRK; MMC vs. steroids) has likewise arisen.

PHARMACOLOGY OF MMC

MMC is a potent alkylating agent with antineoplastic and antibiotic properties. MMC can be isolated from the fermentation filtrate of Streptomyces caespitosus. The ability to crosslink DNA between adenine and guanine is responsible for inhibition of DNA synthesis. The inhibition by MMC of DNA, cellular RNA, and protein synthesis is

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thought to suppress proliferation of fibroblasts and keratocytes. While its actions occur primarily during the late G1 and S phases, MMC is not limited to this phase. However, rapidly dividing cells are preferentially sensitive to MMC (33,34).

Ocular Applications of MMC

Local application of MMC has long been used with glaucoma filtration (35,36), pterygium excision (37,38), and in treating conjunctival/corneal intraepithelial neoplasia (39–41). Recent reports with dacryocystorhinostomy (42), conjunctival/corneal melanoma (43), ocular cicatricial pemphigoid (44), and as prevention in posterior capsule opacification after lens removal (45) have shown a growing interest in the potential of MMC.

Ocular Complications With MMC

Originally used as a systemic antineoplastic agent, bone marrow suppression, mucous membrane ulceration, and renal insufficiency were concerning side effects (46). While numerous reports of topical application have not shown any such systemic effects, caution is still necessary in using MMC based on the occurrence of ocular complications found in these reports (31,32,35–45). The reactions range from mild (delayed conjunctival re-epithelialization, SPK, mild anterior chamber inflammation, hyperemia) to more vision-threatening (secondary glaucoma, corneal edema, corneal perforation, corneoscleral melt).

However, most of these adverse outcomes were associated with prolonged topical administration rather than a single application. One case report does describe a corneoscleral melt and perforation with mild ocular trauma 5 weeks after pterygium surgery (47). The surgery involved a single application of 0.2 mg/mL MMC to bare sclera for 3 minutes. This unique complication may be caused, in part, by MMC application involving the limbal region, which may have led to ischemia-induced damage.

A balancing view is seen in the most recently published study of MMC use with pterygium resection. Avisar et al. (48) compared the recurrence rate using 0.2 mg/mL MMC for 3-minute and 5-minute applications. They followed-up 143 consecutive patients over 26 months and found no instances of ocular toxicity or alteration in corneal epithelium healing. They further reported that the longer duration was associated with significantly less recurrences, again sparking the debate over the optimum concentration and duration of application.

While the data related to pterygium and glaucoma surgery are enlightening, the results with corneal intraepithelial neoplasia (CIN) may have played a more direct part in considering MMC in refractive surgery. Frucht-Pery et al. (39) reported their success using 0.2 mg/mL MMC drops to treat CIN involving the central visual axis. All three of their patients’ abnormal cells were replaced with normal epithelium without evidence of dysplasia during the 12 months of follow-up examinations. Wilson et al. (40) reported on the use of 0.4 mg/mL MMC drops with surgically unresponsive corneal epithelial dysplasia and neoplasia. Six of seven eyes showed complete resolution and one eye showed partial resolution. In both reports, the patients experienced transient toxic side

effects (hyperemia, pain, blepharospasm, tearing, punctuate epithelial keratopathy), which resolved with cessation of the MMC. No permanent effects or delayed epithelial healing was noted.

The step toward using MMC for refractive surgery is based on a theory that subepithelial haze/fibrosis may result from abnormal activation and/or proliferation of stromal keratocytes. In this regard, such development may be similar to that seen in neoplastic proliferation (basis for using MMC in CIN). The experience with CIN, combined with the reported lack of permanent damage to corneal structures other than in direct application to the exposed vascular limbus, led to further investigation of MMC use and the eventual desire for a single application to the avascular cornea.

CONCENTRATION AND DURATION OF APPLICATION

Most of the studies regarding concentration and duration are related to pterygium and glaucoma surgery. While there are differences in what are considered optimal outcomes, there is unanimity in a desire to use the lowest concentration for the least amount of time to minimize the complications while still achieving “success;” however, the “ideal” parameters are yet to be defined. Decisions on concentration and duration have their origins in various laboratory studies and clinical experience with pterygium excision.

Jampel (49) found that a 0.4 mg/mL concentration had a similar effect on fibroblast inhibition whether applied for 1 minute or 5 minutes in vitro. Ando and Yamamoto (50) reported that MMC was able to suppress keratocyte proliferation in vivo using concentrations of 0.01 mg/mL, 0.1 mg/mL, and 1 mg/mL. While the effect increased proportionally to the concentration, it is interesting to note that suppressive effects were seen even with the lowest concentration studied.

Concentration and duration of application are important in effectiveness and toxicity of MMC. Intraoperative concentrations of 0.4 mg/mL for 3 minutes was found similarly effective to 0.2 mg/mL applied for 5 minutes. Lam et al (51) found that 0.2 mg/mL concentration was less effective in preventing recurrences of pterygium when applied for 3 minutes than when applied for 5 minutes. Cano-Perra et al. (52) found a recurrence rate of 3.3% using 0.1 mg/mL MMC for 5 minutes as compared to Helal’s (53) rate of 5.8% when using the same concentration for only 3 minutes.

Ando et al. (50) found that concentrations of MMC less than 0.4 mg/mL had no deleterious effect on corneal epithelial growth. Manning (37) and Frucht-Pery (38) found that MMC at 0.4 mg/mL and 0.2 mg/mL concentrations in pterygium surgery was not associated with delayed corneal epithelial healing.

Methods of Application of MMC

Similar to the varied course regarding concentration and duration of application, the mode of application has also been evolving. Although a clear consensus has not been reached, most ophthalmologists seem to be finding that lower concentrations, shorter application times and minimizing the necessary contact area are proving successful in addressing corneal haze/scarring while avoiding previously noted toxic effects.

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Talamo’s rabbits received twice daily dosing of 0.5 mg/mL MMC (along with steroids and erythromycin) for 14 days after laser keratectomy. Talamo et al.’s (30) initial use of MMC was similar to the topical drop application later seen in Singh et al.’s (54) report with pterygium surgery.

Borrowing from glaucoma filtration surgery, Schipper et al. (24) began the current trend of a single intraoperative application, using a 6-mm sponge soaked in 0.4 mg/mL MMC. This sponge was left on the rabbit’s recently ablated corneal surface for 5 minutes, after which the surface was irrigated with 250 mL of balanced salt solution (BSS).

Majmudar et al. (29) reported using 0.2 mg/mL MMC to treat subepithelial fibrosis found in five patients after RK or PRK. A Beaver blade was used to remove the corneal epithelium and fibrosis. A 6-mm “corneal light shield” was soaked in 0.2 mg/mL MMC and then placed on the surface for 2 minutes. The ocular surface was then irrigated with 30 mL of BSS.

Xu et al. (17) and Carones et al. (22) have published reports in which they have used the technique described by Majmudar, although Xu extended the application time to 5 minutes.

While it appears the concentration/technique described by Majmudar is the most widely accepted, there are other styles of application being reported. Maldonado (55) has described using Majmudar’s technique supplemented by a 2-week postoperative course of 0.2 mg/mL MMC eye drops in his most severe cases. Azar and Jain (56) reported using MMC-soaked (0.25 mg/mL and 0.5 mg/mL) filter paper discs compared to annular rings placed on de-epithelized rabbit corneas for 1 minute, after which a 100-micron PTK was performed.

Results of MMC Application

The results of MMC use in surface ablation have to be approached with caution. Applying findings in rabbits or other animal models to humans may be misleading, as seen with the early PRK experience; laser ablation in animals revealed a much greater tendency toward postoperative haze than actually seen when human trials were conducted (57–64). The data relating to preventing haze development may not directly correlate to using MMC to treat the actual presence of subepithelial fibrosis. However, even using the proper caution, the various reports are quite promising.

Prophylactic Use in Animals

Talamo et al.’s (30) initial study actually involved 14 rabbit eyes randomized into one of three groups receiving different postoperative medications twice daily for 14 days after a 100-micron ablation (erythromycin alone, erythromycin plus steroids, or erythromycin/ steroids and 0.5 mg/mL MMC). There was no statistical difference noted in haze, with haze developing in all eyes by 14 to 21 days, which measured 1 to 2+ haze by the time of enucleation at 10 weeks. However, histological analysis showed none to mild subepithelial scarring in the eyes receiving MMC, moderate to severe scarring in the erythromycin only group, and mild to moderate scarring in the erythromycin/steroid treated group. Fluorescence microscopy revealed new collagen deposition directly

proportional to the subepithelial scarring. There were no reports of ocular toxicity attributed to the use of MMC.

Schipper et al. (24) studied a 5-minute application of 0.4 mg/mL MMC to eight rabbit eyes after an 81-micron PRK compared to eight rabbit eyes receiving BSS after similar PRK. Like Talamo’s study, there appeared no statistically significant difference in clinical haze during the examinations as the rabbits were killed between week 1 and 26. Light and electron microscopy revealed significant scar tissue on only one of eight corneas in the MMC group as compared to five of eight in the BSS group. Schipper further reported that a significant decrease in number of keratocytes was found in the MMC group as compared to the BSS or control group (nonoperated rabbit corneas). While they reported no ocular toxicity with the MMC eyes, one rabbit developed a severe, acute infection in its MMC-treated eye (the one of eight that had scar tissue on histopathology). The source of this infection was not adequately addressed, causing one to wonder about the role of MMC on the involved rabbit’s ocular health.

Xu et al. (17) performed bilateral 120-micron PRK in 20 rabbits. The right corneas received a 5-minute application of 0.2 mg/mL MMC while the left corneas received nothing. During all examinations from weeks 2 to 26, corneal haze was significantly less in the MMC group (P<0.01). On a scale of 0 to 4, the majority of the PRK alone group measured grade 1 or 2 with a few at grade 3, while no MMC cornea measured more than grade 1. The number of keratocytes in the MMC corneas was significantly less and the number of keratocytes in the PRK alone group was significantly greater (four-fold) than those found in nonablated control corneas. This difference returned to baseline by the twelfth week in both groups. The lamellar arrangement of the anterior stroma was markedly more irregular in the PRK alone group as compared to the minimal irregularities in the MMC group; once again, the lamellar arrangement in both groups returned to “normal” by the twelfth week. As a measure of effect on epithelium, time to re-epithelialization and thickness of corneal epithelium were measured; epithelial thickness was increased in both groups compared to control eyes, but no difference was noted between the two groups. The time to re-epithelialize was equal between the groups as well. No reports of ocular toxicity was noted during the course of the study.

Azar and Jain (56,65), using a previously developed scatterometer, measured corneal after which, a 100-micron PTK was performed. Corneal light scatter was least in the eyes light scatter in rabbits after PTK. MMC-soaked (0.25 mg/mL and 0.5 mg/mL) filter paper discs were compared to annular rings placed on de-epithelized rabbit corneas for 1 minute, treated with annular rings, greater in the PTK control eyes, and, surprisingly, greatest in the eyes treated with the paper disc. Azar and Jain felt these results suggest the annular zone of MMC application might suppress/minimize the centripetal migration of keratocytes with subsequent collagen deposition.

Therapeutic Use in Humans

Armed with the early success in animal studies and perhaps frustrated with repeated failures with multiple debridements, Majmudar et al. (29) reported using MMC to treat subepithelial fibrosis found in five patients after RK or PRK. After manual debridement, 0.2 mg/ mL MMC was applied to the cornea for 2 minutes. The results were very impressive as all corneas remained clear and visual acuity improved in every case. These

LASEK, PRK, and excimer laser stromal surface ablation 348

findings remained consistent throughout the entire follow-up period (6–25 months, mean 14 months). The most marked improvement was found in the four PRK cases (i.e., 20/400 to 20/20); they had more central fibrosis than seen in the eyes with RK. Of note is the fact that no incidence of ocular toxicity was found. One year after his original publication, Majmudar further reports that he has had excellent outcomes using MMC debridement in an additional 20 eyes with visually significant haze.

Maldonado (55) has described using Majmudar’s technique in 13 eyes, adding a 2- week postoperative course of 0.2 mg/mL MMC eyedrops in his most severe cases. Maldonado indicated “the efficacy of treatment was spectacular…and no noticeable complication developed.” The lack of ocular toxicity is encouraging but it was not stated how many eyes received the supplemental drops nor how long the eyes were followedup. Maldonado further noted “even in the most favorable cases…the central cornea was not crystal clear long after the application…of the discs.” The lack of central clarity was thought to be in the deeper corneal layers and not to be visually significant by Majmudar (66).

However, this central finding was alluded to in Azar and Jain’s rabbit study showing more scatter using MMC discs vs. annular rings (56,65). While they point out that the study did not address the annular ring effect on human eyes with preexisting corneal haze/scar, their case report on using a 0.2 mg/mL MMC-soaked annular ring to treat a 44- year-old patient with visually significant post-PRK haze was promising (67). The patient’s reticular haze was eliminated within 2 months of the treatment. The central cornea remained clear and the patient was symptom-free during the 5 months of reported follow-up.

Prophylactic Use in Humans

Carones et al. (22) recently addressed the issue of prophylactic use of MMC in patients undergoing PRK because of refractive errors too high to allow at least 250 microns of residual stromal thickness after LASIK. A prospective, randomized study of 60 consecutive eyes in 60 patients with thin corneas and spherical equivalents between −6.00 and −10.00 diopters was conducted. Epithelial removal was accomplished with dry microsponges after 20 seconds of exposure to a 20% alcohol solution. After laser ablation (6.0-mm optical zone with 3.0-mm transition zone), 30 eyes had a 0.2 mg/mL MMCsoaked 8.0 mm Merocel (Xomed) sponge placed over the ablation area for 2 minutes, followed by vigorous irrigation with BSS. The 30 control eyes had laser ablation without any MMC or BSS irrigation. All eyes were treated with a bandage contact lens, diclofenac for 24 hours, tobramycin until re-epithelialization, artificial tears, and fluorometholone drops tapered over 2 months.

Specific areas of interest during the 6 months of postoperative measurements were rate and quality of re-epithelialization, refractive error, uncorrected corrected visual acuity (UCVA) and best corrected visual acuity (BCVA), and the development and quality of corneal haze.

Re-epitheliazation was complete in all eyes between days 2 and 5. No differences in the quality or rate of re-epithelialization was found between groups. There was no difference noted with regard to discomfort, side effects, or ocular toxicity. No eye in

either group had an epithelial defect or any signs of ocular toxicity after reepithelialization.

Mean preoperative refractive error was nearly identical for both groups. Although the absolute difference was greatest at 1 month (−0.67 D for MMC, −0.87 D for control) and identical at 3 months (−0.44 D vs. −0.33 D) and 6 months (−0.12 D vs. −0.21 D), the smaller absolute difference at 6 months was found to be statistically significant.

While no statistically significant difference in UCVA was noted at 1 month, a significant difference was present at the 3-and 6-month examinations. Comparing the MMC-treated eyes to the controls at 6 months, 100% and 83%, respectively, attained 20/40 or more acuity. The difference was even greater for those eyes achieving acuity of 20/20 or better: 60% for the MMC group compared to 30% for the control eyes.

Perhaps the most impressive observation was found in the development of corneal haze, reported on a 0 to 4 scale. At the 1-month examinaiton, 27% of the MMC-treated eyes had grade 1 haze, with the remainder either having zero or grade 0.5 haze; 53% of control eyes had haze of grade 1 or higher. The results at 6 months were even more impressive; 60% of the MMC group had zero to grade 0.5 haze and 40% had grade 1 haze, whereas 40% of the controls had grade 1 haze and 40% had grade 2 to 4 haze.

The BCVA change from baseline to 6 months after treatment is also notable. More than 50% (16/30) of eyes in the MMC group experienced an increase of one to two lines of acuity compared to approximately 17% (5/30) in the control group. While the significant corneal haze may be responsible for close to 25% (7/30) of the eyes in the control group losing between one and three lines of acuity, the fact that no eyes in the MMC group experienced any such loss speaks favorably for the safety of the MMC use in this study.

MMC USE IN LASEK

Currently, there are no published studies regarding use of MMC with LASEK, either prophylacticly or in treating postoperative corneal haze. This may be caused in part by less clinically significant corneal haze reported with LASEK and in part with a smaller number of clinicians performing this fairly new technique.

While one theoretical advantage of LASEK is a decreased incidence of corneal haze caused by the epithelial sheet, larger numbers are needed to ascertain whether this is a consistent finding or somehow related to the numerous surgical variables found among clinicians.

If there is a need to address corneal haze in LASEK, it would appear reasonable to apply the principles associated with the PRK experience. While the physiology of LASEK and PRK are different, they do share similarities, such as ablation effects on Bowman’s layer and the anterior stroma, which may allow similar actions with MMC.

Therapeutic or Prophylactic Use?

With the advent of better lasers and surgical techniques, postoperative corneal haze is not as common as during the early days of PRK (18–21). Does one subject all surface ablation patients to MMC in the attempt to prevent corneal haze in a small percentage?

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For what level of refractive error does the percentage become high enough to justify the application? The correlation of clinically observed haze (back-scatter) to functional impairment (front-scatter) is not so clearly established. While “clinically significant” generally is taken as an objective decrease in previously attained visual acuity, would corneal haze associated with a change from 20/10 to 20/15 or from 20/15 to 20/20 be “clinically significant” enough to warrant treatment with MMC?

All of these questions basically address one point: is it reasonable to use MMC as a prophylactic measure or only as a therapeutic treatment? Given the success in treating postoperative corneal haze with no reports of actual toxic effects, therapeutic use of MMC seems quite reasonable. However, justification for prophylactic use is not as obvious.

There will likely always be two camps when it comes to the risk-to-benefit ratio of using MMC to prevent corneal haze. The main argument would seem to settle on toxic effects or complications associated with MMC. Most of the ocular complications have been associated with continued topical application or direct application to vascularized tissues seen in pterygium or glaucoma surgery. All of the recent studies involving a single intraoperative application of MMC to prevent or treat corneal haze/fibrosis have failed to show any such complications to date (17,22,29,55,56,65–67). While it is difficult to assure long-term safety with follow-up times ranging from 6 to 26 months at the time of publication, it is helpful to note that the reported complications with MMC in ocular surgery generally developed within 6 months. While the animal studies had definite end points in their follow-up, quite a number of years have passed since the first human applications in 1998, and there continues to be no reports of toxicity or complications associated with those applications of MMC.

If the risk of corneal haze is high (Carones showed a 40% rate of grade 2 to 4 in patients with −6.00 D or more), the tolerance for variable visual acuity caused by severity and duration of such haze is low, and the prospect of long-term corticosteroid use is undesirable, a case could be made for prophylactic use of MMC. However, one must step cautiously until further studies involving larger numbers of patients followed-up for greater lengths of time can more definitively answer the question of the wisdom, safety, and best application of this impressive agent.

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