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  • Current Trends in the Use of Mitomycin C With Surface Ablation

    Refractive Mgmt/Intervention
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    Mitomycin C (MMC) is a systemic chemotherapeutic agent with cross-linking properties that allow binding to DNA to prevent replication. Due to MMC’s ability to inhibit proliferation of rapidly growing cells such as fibroblasts, the effectiveness of adjunctive MMC in improving the outcome of ophthalmic procedures such as trabeculectomy and pterygium excision has been well established. Also, in recent years, its use in corneal refractive surgery involving surface ablation has become commonplace. Many recent reports in the literature confirm that the prophylactic use of MMC appears to be safe and effective in preventing haze following photorefractive keratectomy (PRK).1-3 It appears that the availability of MMC, with its ability to modulate wound healing, has bolstered the popularity of PRK as well as other variants of surface ablation procedures such as laser-assisted epithelial keratomileusis (LASEK) and epi-LASIK that minimize tissue loss and the risk of ectasia. However, with the increase in prophylactic use of MMC, some have raised concerns regarding its long-term safety. This article addresses those concerns along with current trends in the use of this agent.

    Mechanism of Action

    One of the concerns regarding PRK has been subepithelial haze formation. Laser energy delivered to the cornea essentially results in cellular injury of keratocytes. During the healing process, as the surrounding cells proliferate to replenish the anterior stroma, activated keratocytes differentiate into fibroblasts or myofibroblasts, in addition to depositing ground substance and abnormal collagen, which leads to regression and haze formation. The inhibitory effect of MMC results in apoptosis of activated keratocytes and ultimately a decrease in subepithelial haze. However, the cell loss resulting from even a single application of MMC can last up to 3 months and is of some concern with respect to ocular complications (Invest Ophthalmol Vis Sci. 2004;45(9):2978–2984).

    Indications for Use

    Currently, most refractive surgeons use prophylactic MMC in the treatment of high myopia with PRK. Mitomycin-C also appears to decrease subepithelial haze after other surface ablation procedures such as LASEK (J Refract Surg. 2004;20(5 suppl):S693–S698). Certainly, MMC is indicated in re-treatments of corneas showing haze from a primary procedure.

    As of late, MMC prophylaxis has expanded to include other forms of surface ablation treatments that are more likely to result in corneal haze. Case reports of MMC use in PRK performed on top of previous laser-assisted in situ keratomileusis (LASIK), buttonholed flaps, radial keratotomy (RK), and penetrating keratoplasty appear to demonstrate the effectiveness of haze prevention in these settings.6-8

    Safety Concerns

    The sight-threatening complication of corneoscleral melting with perforation following MMC use in pterygium surgery is well known. Other complications such as iritis, severe secondary glaucoma, corneal edema, corectopia, sudden-onset mature cataracts, and scleral calcification have also been reported. However, the potential long-term complications of MMC in PRK are less clear. Unlike pterygium surgery where MMC is applied to vascular areas, application to the avascular cornea in PRK may significantly reduce complications.

    Still, MMC has been detected in the anterior chamber following PRK in animal models, raising concerns regarding its effects on the endothelium (J Cataract Refract Surg. 2006;32(1):67–71). In addition, a report by Morales et al showing statistically significant endothelial cell loss at 1 month and 3 months in the group of patients treated with MMC supports the notion that judicious use is always prudent when the potential for endothelial toxicity exists (Am J Ophthalmol. 2006;142(3):400–404). However, contrary reports by Lee (D. Lee, AAO, November 10, 2006) and Midena (E. Midena, AAO, November 10, 2006) showing no decrease in endothelial cell count after follow up of 65 months and 60 months, respectively, seem to ease concerns regarding the long-term safety of MMC.

    Practical Considerations

    Many refractive surgeons recommend prophylactic MMC in PRK treatment of moderate to high myopia. While the indications vary among surgeons, the current threshold for MMC use appears to be approximately –4.00 to –6.00 diopters of correction. Because the depth of ablation may be the actual variable rather than the diopter of correction, it may be prudent to consider defining the threshold for MMC use in terms of ablation depth. This becomes more important with wavefront treatments, since even low myopic corrections may require significant corneal tissue ablation with the peak depth being proportional to the amount of higher-order aberrations. The threshold for recommending prophylactic use of MMC based on ablation depth appears to be around the 50–75 micron range.

    In general, MMC’s ability to modulate wound healing means less regression following surface ablation. The tendency for MMC to induce overcorrection remains an important consideration when calculating the treatment plan for each patient. Most surgeons require that their nomogram be adjusted to allow for some reduction in this setting. Realistically, a pre-existing nomogram or some arbitrary value may be used to adjust the treatment plan initially. However, because the technique of MMC application as well as the type of surface ablation procedure may differ, each individual surgeon will more than likely end up with a personally modified version of the initial nomogram.

    As for the concentration and exposure time, it is common practice to apply MMC 0.02% (0.2 mg/dl) to the corneal stroma following laser ablation via a saturated corneal light shield for 2 minutes. However, based on a study by Seldomridge et al that showed no differences in haze scores or refractive outcomes among 3 groups where MMC was applied for 12 seconds, 60 seconds, or 120 seconds, the trend appears to be heading toward less exposure time (Seldomridge et al, Cornea Society, October 23, 2004) . In addition, there are reports demonstrating success using lower concentrations of MMC, as low as 0.002%. However, lower concentrations of MMC did not appear as effective in treating pre-existing corneal haze.

    Conclusion

    The role of MMC in ophthalmology is varied and continues expand. In particular, MMC has proven to be an invaluable tool for the refractive surgeon in achieving excellent results with a variety of surface ablation procedures. The risk of ectasia has certainly fueled the resurgence of surface ablation; however, without the haze-preventing property of an agent like MMC, surface ablation undoubtedly would have been limited to a smaller subset of refractive candidates. In addition, MMC has allowed safer re-treatments of patients who have undergone previous procedures such as LASIK and RK as well as allowing successful treatment of patients who have suffered complications of buttonholed flaps or scarring. Current studies indicating the safety and effectiveness of MMC have validated its use in surface ablation procedures. In addition, a healthy respect for potential long-term toxicity has led to the current trend toward a more judicious use of the agent, which may very well help ensure that MMC continues to play a significant role in refractive surgery.

    References

    1. Carones F, Vigo L, Scandola E, Vacchini L. Evaluation of the prophylactic use of mitomycin-C to inhibit haze formation after photorefractive keratectomy. J Cataract Refract Surg. 2002;28(12):2008–2095.
    2. Gambato C, Ghirlando A, Moretto E, et al. Mitomycin C modulation of corneal wound healing after photorefractive keratectomy in highly myopic eyes.Ophthalmology. 2005;112(2):208–218.
    3. Hashemi H, Taheri SM, Fotoluhi A, et al. Evaluation of the use of mitomycin-C to inhibit haze formation after photorefractive keratectomy in high myopia: a prospective study.BMC Ophthalmol. 2004;4:12.
    4. Kim TI, Pak JH, Lee SY, Tchah H. Mitomycin C-induced reduction of keratocytes and fibroblasts after photorefractive keratectomy.Invest Ophthalmol Vis Sci. 2004;45(9):2978–2984.
    5. Camellin M. Laser epithelial keratomileusis with mitomycin-C: indications and limits.J Refract Surg. 2004;20(5 suppl):S693–S698.
    6. Muller LT, Candal EM, Epstein RJ, et al. Transepithelial phototherapeutic keratectomy/photorefractive keratectomy with adjunctive mitomycin-C for complicated LASIK flaps.J Cataract Refract Surg. 2005;31(2):291–295.
    7. Chalita MR, Roth AS, Krueger RR. Wavefront-guided surface ablation with prophylactic use of mitomycin C after a buttonhole laser in situ keratomileusis flap.J Refract Surg. 2004;20(2):176–181.
    8. Solomon R, Donnenfeld ED, Thimons J, et al. Hyperopic photorefractive keratectomy with adjunctive topical mitomycin C for refractive error after penetrating keratoplasty for keratoconus.Eye Contact Lens. 2004;30(3):156–158.
    9. Torres RM, Merayo-Lloves J, Daya SM, et al. Presence of mitomycin-C in the anterior chamber after photorefractive keratectomy.J Cataract Refract Surg. 2006;32(1):67–71.
    10. Morales AJ, Zadok D, Mora-Retana R, et al. Intraoperative mitomycin and corneal endothelium after photorefractive keratectomy.Am J Ophthalmol. 2006;142(3):400–404.
    11. Lee D. Long-term follow-up of patients treated with PRK and mitomycin C. Paper presented at: Annual Meeting of the American Academy of Ophthalmology; November 10, 2006; Las Vegas, NV.
    12. Midena E. Long-term safety of mitomycin C in haze prevention: a confocal microscopy evaluation. Paper presented at: Annual Meeting of the American Academy of Ophthalmology; November 10, 2006; Las Vegas, NV.
    13. Seldomridge D, Klein SR, Epstein RJ, et al. A comparison of application times of mitomycin C for haze prophylaxis following photorefractive keratectomy. Paper presented at: Annual Meeting of the Cornea Society; October 23, 2004; New Orleans, LA.

    Author Disclosure

    The author states that he has no financial relationship with the manufacturer of any product discussed in this article or with the manufacturer of any competing product.