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Clinical and Experimental Ophthalmology 2014; 42: 307–308 doi: 10.1111/ceo.12349

Editorial Ocular surface squamous neoplasia: to cut or not to cut The goal of treating ocular surface squamous neoplasia (OSSN) is to eliminate all neoplastic squamous epithelium and prevent recurrence without causing complications or side effects. There are several recognized pathways of trying to achieve this goal but no universally accepted gold standard of treatment. Surgical excision with adjunctive cryotherapy or topical chemotherapy has been used for years with good success. Surgical excision removes the clinically macroscopic disease and confirms the histological degree of neoplasia. Adjunctive cryotherapy and chemotherapy can reduce the recurrence rate compared with surgery alone. Large tumours, however, are best not treated with surgery because of the side effects induced by large areas of limbal and conjunctival epithelial removal. Surgery and cryotherapy also fail to address clinically undetectable and sometimes widespread microscopic disease. More recently, there has been a paradigm shift to the use of topical chemotherapy as adjuncts to surgery or as primary therapy alone.1,2 The rationale for topical chemotherapy as primary treatment is that the entire ocular surface is treated, and surgical complications are prevented. The costbenefit ratio may also favour topical treatment.3 Mitomycin C (MMC), Interferon alpha-2b (IFN) and 5-Flurouracil (5FU) have all been reported as successful, and can be used alone or in combination depending on individual patient response and side effect profiles.3,4 Retinoic acid has also been reported to work synergistically with IFN.5 The concentration, dose and treatment cycles of these agents differ between studies, together with a mixed range of follow-up. As a consequence, the reported rates of success and recurrence vary widely. Recurrence of OSSN is a surrogate measure of treatment success. It is a result of inadequate elimination of primary disease or could be the growth of new disease interpreted as a recurrence. This may occur within weeks or as long as 12 years after treatment.6 Recurrence rates are likely to be dependent on length of follow-up, adjunctive therapy and

tumour-related characteristics such as size, location, phenotype and histopathological grade.7 It has recently been reported that recurrence is equally as likely to occur after surgical or topical IFN treatment.8 In this issue, Bahrami et al. present their data on the outcome of treatment of 153 eyes of 150 patients with non-invasive OSSN.9 The cases are limited to lesions that are considered by the authors to be surgically excisable as this is their preferred method of treatment. Large lesions (more than five clock hours in limbal extent), invasive squamous cell carcinoma and lesions treated with chemotherapy alone are excluded. Cryotherapy was used as an adjunct to surgery except in 12 early cases. After epithelial healing, eyes were treated over non-overlapping time periods with either topical MMC 0.04% or 5FU 1% as adjunctive chemotherapy. The median follow-up was just short of 3 and 5 years for the 5FU and MMC treated eyes, respectively. The primary outcome measure was clinical recurrence and was low in both cohorts by comparison to other studies. The side effect rates were high, but not vision threatening. These results are commendable and replicate what others have shown if surgery is used as the primary therapy. Galor et al reported a large series that confirmed adjuvant cryotherapy significantly decreases the risk of recurrence, and also showed that postoperative adjuvant IFN in patients with positive histopathological margins reduced the recurrence to that of patients with negative excision margins.7 So what is the best treatment protocol? Unfortunately making comparisons between studies is confounded by selection and treatment bias along with variable follow-up. Most treatment protocols eventually achieve high tumour clearance rates, and recurrence is a risk regardless of the initial treatment or pathology. If toxicity is a common issue with chemotherapy, then perhaps clinical studies should explore doses and concentrations that avoid toxic side effects yet still achieve the same outcomes. Lower concentrations and shorter durations of exposure to topical

Conflict/competing interest: No stated conflict of interest. Funding sources: No stated funding sources. © 2014 Royal Australian and New Zealand College of Ophthalmologists

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MMC10 and 5FU11 have resulted in fewer or less severe side effects. Finger noted in 2006 that what is needed to advance the management of OSSN is a method of standardized tumour grading and treatment that allows comparisons between multiple centres.10 This still appears to be the case, and furthermore the time is right to compare medical versus surgical protocols in randomized clinical trials. Complimentary to this should be more basic research to improve our understanding of tumour genetics, cellular biology and immunology in OSSN.12 As a consequence, better and more targeted therapies may be designed that can help patients achieve the goal of tumour eradication with no recurrences or side effects and at minimal expense and inconvenience. Richard AD Mills FRANZCO PhD Flinders Medical Centre, Flinders University of South Australia, Adelaide, Australia

REFERENCES 1. Stone D, Butt A, Chodosh J. Ocular surface squamous neoplasia. A standard of care survey. Cornea 2005; 24: 297–300. 2. Adler E, Turner J, Stone D. Ocular surface squamous neoplasia: a survey of changes in the standard of care from 2003 to 2012. Cornea 2013; 32: 1558–61. 3. Besley J, Pappalardo J, Lee G, Hirst L, Vincent S. Risk factors for ocular surface squamous neoplasia recurrence after treatment with topical mitomycin C and interferon alpha-2b. Am J Ophthalmol 2014; 157: 287–93.

4. Nanji A, Sayyad F, Karp C. Topical chemotherapy for ocular surface squamous neoplasia. Curr Opin Ophthalmol 2013; 24: 336–42. 5. Krilis M, Tsang H, Coroneo M. Treatment of conjunctival and corneal epithelial neoplasia with retinoic acid and topical interferon alfa-2b: long-term followup. Ophthalmology 2012; 119: 1969–73. 6. Tabin G, Levin S, Snibson G, Loughnan M, Taylor H. Late recurrences and the necessity for long-term follow-up in corneal and conjunctival intraepithelial neoplasia. Ophthalmology 1997; 104: 485–92. 7. Galor A, Karp CL, Oellers P et al. Predictors of ocular surface squamous neoplasia recurrence after excisional surgery. Ophthalmology 2012; 119: 1974–81. 8. Nanji A, Moon C, Galor A, Sein J, Oellers P, Karp C. Surgical versus medical treatment of ocular surface. A comparison of recurrences and complications. Ophthalmology 2014; 121: 994–1000. doi: 10.1016/ j.ophtha.2013.11.017; [Epub ahead of print]. 9. Bahrami B, Greenwell T, Muecke J. Long-term outcomes after adjunctive topical 5-flurouracil or mitomycin C for the treatment of surgically excised, localized ocular surface squamous neoplasia. Clin Experiment Ophthalmol 2014; 42: 317–22. 10. Finger P. Topical mitomycin chemotherapy for malignant conjunctival and corneal neoplasia. Br J Ophthalmol 2006; 90: 807–9. 11. Yeatts RP, Engelbrecht NE, Curry CD, Ford JG, Walter KA. 5-Fluorouracil for the treatment of intraepithelial neoplasia of the conjunctiva and cornea. Ophthalmology 2000; 107: 2190–5. 12. Nagata M, Nakamura T, Sotozono C, Inatomi T, Yokoi N, Kinoshita S. LRIG1 as a potential novel marker for neoplastic transformation in ocular surface squamous neoplasia. PLoS ONE 2014; 9: e93164. doi: 10.1371/ journal.pone.0093164; eCollection 2014.

© 2014 Royal Australian and New Zealand College of Ophthalmologists

Ocular surface squamous neoplasia: to cut or not to cut.

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