Discussion

To our knowledge, this is the largest series of primary and recurrent CCIN lesions treated with MMC as adjuvant or sole therapy. The authors note that better control is achieved for localised compared with diffuse disease (recurrence rate 0% vs 30%). For localised disease, the best control is achieved with excision and cryotherapy followed by topical MMC (no recurrences in 73 eyes).

Excision remains an important step in management of localised CCIN. The authors prefer primary excision where possible, as it allows an immediate histopathological diagnosis and excludes life-threatening invasive malignancies such as SCC or amelanotic malignant melanoma.3 It also helps to exclude masquerading lesions such as viral papilloma, where MMC is not effective, and keratoacanthoma and solar keratosis, where MMC is not necessary. Surgical debulking of the lesion makes adjuvant treatment more effective, as MMC is being utilised against a lower tumour load.

The disadvantage of primary excision alone is the high recurrence rate, which ranges from 15% to 52%.1 CCIN may also be a multifocal disease. Impression cytology studies have revealed that areas of clinically normal limbus remote from the tumour may be positive for dysplasia. Localised surgery does not address these areas of possible preclinical dysplasia;15 therefore, numerous topical adjuvant treatments have been described in an attempt to decrease the rate of recurrence. The authors believe that the combination of excision (with or without adjuvant cryotherapy) followed by MMC has resulted in the absence of recurrences seen in their series of cases with localised excisable disease.

When treating disease involving more than five clock hours of limbus, excision is potentially hazardous due to the risk of limbal stem cell failure,21 and so is avoided by the authors. MMC is used as sole therapy for cases with diffuse limbal involvement. There have been no cases of complicating limbal stem cell failure in this series. However, the lack of prior surgical debulking resulted in the higher persistence and recurrence rates noted in cases with diffuse disease. Fortunately, all but one of these cases responded to subsequent treatment with topical 5FU or excision and have remained free of further recurrences.

Intraoperative cryotherapy is commonly used as adjuvant therapy,1–3 as it is known to decrease the recurrence rate by destruction of any residual tumour tissue beyond the horizontal or deep surgical margins of the wound.22 Chen and Muecke,3 however, found no difference in the recurrence rate of localised CCIN in patients who received cryotherapy compared with those who did not, when MMC was also used as adjuvant treatment. The authors continue to use cryotherapy to the limbal base because of the possibility of invasive disease deep to the excision margin.

Topical MMC provides an alternative to extensive and repeated surgery for CCIN, and its use has also been reported in a number of smaller studies. The results have been summarised in table 3 and compared with the current study. These studies all support a role for utilising MMC in the treatment of CCIN.

One of the major limitations of topical MMC therapy is the lack of a recommended optimal dose and duration of treatment. Previous studies have used 0.02 or 0.04% concentrations for durations of 1–5 weeks (results outlined in table 3). The strength of this study lies in the fact that it is largest reported cohort of patients all treated with a standard dose of MMC of 0.04%. The lack of major complications is supportive of this treatment regime.

The rationale for the authors' regimen of adjuvant MMC is to use the highest tolerable concentration of chemotherapy (0.04%) against the lowest possible residual tumour load. Limbal toxicity from MMC has been reported;23 hence, a week-on week-off regime is used to minimise toxicity to normal healthy ocular surface and periocular tissues, especially limbal stem cells. In a previously published study by Khong and Muecke,24 there were no serious complications noted in a similar number and spectrum of patients.

Other topical chemotherapy agents have been used such as 5-FU16 17 and IFA 2B.18–20 Yeatts et al17 evaluated the efficacy of pulse dosing of 5-FU in the treatment of CCIN in a prospective, non-comparative case series. Seven patients were treated with 5-FU 1% for an average of 3.75 cycles (range 2 to 5 cycles). Three patients had disease recurrence with a mean follow-up period of 18.5 months.17 Some studies have shown success with 5-FU in cases refractory to MMC.16 The success of 5-FU in these studies and in ours (when treating persistent or recurrent disease) suggests effectiveness of 5-FU due to a difference in the mechanism of cytotoxicity of the two agents.16

IFA 2B has been used with favourable outcomes in primary and recurrent cases of CCIN. The above studies, however, indicate that IFA 2B requires a longer duration of treatment (1–10 months)18–20 than is required with MMC, which may be a disadvantage. However, IFA 2B may be useful in cases resistant to MMC or 5FU.

In conclusion, this is the largest study evaluating the treatment of CCIN where MMC has been used in the regimen. There were few recurrences and no serious complications. MMC treatment following surgical excision of primary or recurrent localised CCIN appears to decrease the recurrence rate. A higher incidence of persistent or recurrent disease is noted when MMC is used as sole therapy for diffuse disease. However, to avoid potential damage to limbal stem cells from extensive excision, MMC may be used as sole therapy but close ongoing follow-up is recommended in view of the significant risk of recurrence.