Description of the condition

Laser in situ keratomileusis (LASIK) is the most common surgical procedure for the treatment of refractive errors. However, some disadvantages are associated with LASIK including flap striae, epithelial ingrowth, and corneal ectasia (Gimbel 1998; Tuli 2007). Furthermore, patients with thin corneas can be at risk for corneal ectasia postoperatively, because the structural stability of the cornea can be compromised due to inadequate residual stromal bed thickness. Patients with steep corneal curvatures or suspicious topographies are at risk for complications during or after LASIK and may be better candidates for surface ablation procedures such as photorefractive keratectomy (PRK), laser epithelial keratomileusis (LASEK), or, recently, epithelial laser in situ keratomileusis (epi‐LASIK) (Gamaly 2007).

PRK has proven to be a safe and effective procedure to correct low to moderate myopia, hyperopia, or astigmatism (O'Connor 2006). It continues to represent a good alternative to LASIK for many patients, and in some situations, PRK remains the procedure of choice (Diakonis 2007; Lee 2005; Pallikaris 1994). PRK is associated with side effects including increased postoperative pain, a stronger healing response, and most significantly, the possibility of subepithelial corneal opacity following corrections for high myopia (Kuo 2004).

PRK alters the natural matrix structure of the extracellular corneal tissue. The procedure also results in changes in cellular density and generation of cells producing scar‐tissue, myofibroblasts. The end result may be decreased transparency of the cornea associated with subepithelial corneal haze, which is clinically significant in some patients. In most cases, corneal haze appears within a few weeks as a mild, diffuse, white, anterior stromal opacity that increases in severity for two to four months and fades thereafter. The reported incidence of haze after PRK is between 0.6% and 4.9% (Kuo 2004). Several different clinical factors are likely to contribute to haze formation including ablation depth, delayed epithelial healing, and the smoothness of the stromal surface after ablation. Recent studies have confirmed that postoperative smoothness of the stromal surface is an important factor to subepithelial haze formation (Netto 2006). In addition, different modulators of the corneal wound healing response and potential medications have been suggested for prophylactic treatment of haze (Netto 2006).

LASEK was developed to reduce some of the complications associated with PRK, such as postoperative pain and haze. In this procedure, an epithelial flap is detached after application of a diluted alcohol solution, and after stromal ablation, the flap is repositioned (Ambrósio 2003). LASEK is safe, efficacious, and predictable. Claringbold et al. reported 222 consecutive LASEK cases with 11.00 diopters (D) myopia, and concluded that LASEK is an effective and safe alternative to LASIK (Claringbold 2002). However, there is no standardized procedure for this surgical technique, and concerns about the effect of alcohol on the epithelium remain (Taneri 2004).

Epi‐LASIK is a surface procedure that automates the separation of the epithelium mechanically. Pallikaris and colleagues (Pallikaris 2003) developed the epikeratome as an alternative method for separating corneal epithelial cells before surface ablation. The epithelium is cleaved below its basement membrane and lifted to expose Bowman’s membrane. Unlike LASEK, alcohol is not required with epi‐LASIK, and up to 85% of the epithelium remains viable (Pallikaris 2003).

Description of the intervention

The mitomycins are potent antibiotics that belong to the family of anti‐tumor quinolones. In 1956, mitomycin A and B were isolated from the broth of Streptomyces caespitosus, and shortly thereafter mitomycin C (MMC) was discovered. In 1991, Talamo et al. (Talamo 1991) suggested the use of topical MMC as a modulator of the corneal wound healing response after excimer laser photoablation. These investigators reported that rabbits treated with MMC following laser ablation had markedly reduced formation of subepithelial collagen. Majumdar et al. (Majumdar 2000) first proposed the use of MMC to treat patients with subepithelial fibrosis secondary to previous PRK and radial keratotomy. These authors reported improvement in corneal clarity with a single, two‐minute intraoperative application of 0.02% MMC. Other studies have reported decreased subepithelial haze and better refractive outcomes after PRK following prophylactic use of MMC (Carones 2002). An exposure time of two minutes was also initially proposed, but many investigators are now shortening this exposure to 30 seconds or even 12 seconds to reduce potential toxicity, while maintaining clinical efficacy (Bedei 2006; Goldsberry 2007; Netto 2006).

However, concerns for sub‐clinical toxicity to cellular structures in the cornea (keratocytes and endothelium) and anterior segment still exist, leading to an uncertainty regarding long‐term effects. Among these, corneal endothelial cell dysfunction and intraocular toxicity remain of the greatest importance, although to date only a single case of corneal edema has been reported following phototherapeutic keratectomy (PTK) using the standard MMC concentration of 0.02% (Thornton 2008). This standard dose following high myopic surface ablation was empirically proposed based on its historical use in glaucoma filtering procedures and pterygium excision. However, several questions regarding the optimal dosage and exposure time and the long‐term safety and efficacy of topical MMC treatment remain unanswered.

Thornton et al. (Thornton 2008) retrospectively compared the safety and efficacy of lower dose MMC (0.002%) to that of the standard dose (0.02%) in eyes treated with PRK for myopia –3.00 D or worse. The standard concentration of topical MMC (0.02%) was more effective than low dose MMC (0.002%) in preventing postoperative haze formation following surface ablation for myopia –6.0 D or worse and deeper ablation depth more than 75 µm. The duration of application of MMC appears to be less important than its concentration.

Argento et al. (Argento 2006) analyzed the results of prophylactic intraoperative use of MMC (0.02%) in patients who underwent LASEK. The patients were divided in to a MMC group and no MMC group. The haze intensity was 0 in the MMC group and 0.25 ± 0.36 in the no MMC group. The difference between both groups values was statistically significant (P<0.001).

Gamaly et al. (Gamaly 2007) demonstrated that epi‐LASIK and PRK were similar in efficacy and predictability in reducing myopia with or without astigmatism. Moreover, epi‐LASIK reduced the risk of corneal haze, was less painful, and provided faster visual recovery than PRK. The absence of haze in the majority of eyes that underwent epi‐LASIK indicates that the use of MMC may not be warranted with this procedure.

How the intervention might work

Mitomycin C binds with deoxyribonucleic acid (DNA) and inhibits DNA synthesis (Kim 2006). At high concentrations, cellular ribonucleic acid (RNA) and protein synthesis can also be suppressed. As a consequence, MMC is believed to trigger apoptosis or cell death and inhibit proliferation of virtually all cells that it enters in sufficient concentrations, including corneal epithelial cells, stromal cells, endothelial cells, and conjunctival cells (Kim 2004). However, the primary mechanism of action of MMC in the cornea remains uncertain (Netto 2006).

Why it is important to do this review

Although laser in situ keratomileusis (LASIK) has surpassed surface ablation procedures (PRK, LASEK, epi‐LASIK) in popularity because of faster visual recovery, less patient discomfort, lower regression rate, and a lower likelihood of significant haze in highly myopic eyes, there are several indications in which surface ablation procedures are preferred over LASIK. These include patients with inadequate residual corneal stromal thickness to perform LASIK, and patients at increased risk for ocular trauma. Patients with anterior basement membrane dystrophy are considered poor candidates for LASIK; a surgeon might therefore consider performing PRK, LASEK or epi‐LASIK on such patients to avoid epithelial defects in the flap and the potential for diffuse lamellar keratitis and epithelial in‐growth. There is a published Cochrane review on PRK versus LASIK (Shortt 2006) and another one underway comparing PRK versus LASEK. It is unclear whether use of MMC results in better outcomes after PRK and LASEK. For these reasons, it is important to keep studying medications such as MMC in order to improve the surface ablation procedures outcomes as well as avoiding long‐term complications.