Treatment of CIN with Retinoic Acid and Topical Interferon Alfa-2b

I have read with interest the recent report from Krilis et al about topical treatment of conjunctiva-cornea intraepithelial neoplasia (CIN) using a combination of 1 million IU/ml topical interferon (INF)-α2b drops 4 times daily and 0.01% retinoic acid once every second day. They concluded that 0.01% topical transretinoic acid once every second day and INF-α2b may act synergistically and that a combined treatment of INF-α2b and retinoic acid may offer a superior alternative to INF-α2b alone when treating CIN. This combination resulted in quicker clinical resolution of CIN than that of topical INF alone. However, the authors did not compare the time of resolution with the use of subconjunctival INF for CIN treatment. Surgical excision offers a fast and definitive approach for patients; however, because of the high recurrence rates, the existence of nonresectable lesions, and the risk of damage to limbal stem cells, it may not be the ideal option and chemotherapeutic agents may be superior. A major advantage of topical treatment is that the therapeutic agent comes into contact with most of the ocular surface. Topical mitomycin-C and 5-fluorouracil have been used to reduce recurrence rates when used as an adjunct to surgical excision and as a primary treatment; however, their use can be associated with marked ocular surface toxicity. Topical (1 million IU/ml 4 times per day) or subconjunctival INF-α2b (3 million IU/ml weekly) have been used to treat CIN. Topical INF-α2b is generally well-tolerated, whereas subconjunctival administration presents more side effects, such as flu-like symptoms (fatigue, fever, myalgia, and malaise) and mild liver disturbances. Other treatment options to manage CIN include topical retinoids, cidofovir, and photodynamic therapy. Topical applications of transretinoic acid (0.01%) may result in complete resolution of CIN in 20% of cases, whereas 40% may show only a partial response. This single topical treatment has been considered previously only as an adjuvant to surgery. However, the study by Krilis et al showed that a combined treatment of retinoic acid and topical INF-α2b is an effective and efficient treatment for primary or recurrent CIN, and successful clinical regression was demonstrated in 97.75% of CIN cases. The mean time to resolution was 1.69 months (7.2 weeks; range, 19 days to 6.5 months). We performed a retrospective study of the reported CIN series treated with topical or subconjunctival INF until 2008. The time to complete clinical resolution of CIN using topical INF-α2b was longer (11.6 weeks; range, 2–59) than that of a combined intralesional and topical INF treatment (4.5 weeks; range, 2–12). A later report showed that the median time to resolution using topical INF alone is 2 months (8.6 weeks). In general, it seems that the disadvantage of topical treatment is the long duration needed for resolution. Actually, no clear consensus on the best way to manage this disorder has been established, because long-term, well-designed studies are still needed. Topical INF or subconjunctival INF remains a controversial issue. One report concluded that an 0.5-ml subconjunctival injection of 3 million IU of IFN-α2b is a viable medical alternative to treat ocular surface squamous neoplasia. The authors stated that the advantages of perilesional INF-α2b injection include more rapid tumor resolution, ensured compliance, and perhaps more direct delivery to the tumor site compared with those of topical INF drops. However, some patients may be apprehensive about receiving injections around the eye and may prefer eyedrops. A combined treatment of IFN-α2b and retinoic acid may offer a superior alternative to IFN-α2b alone owing to faster clinical resolution compared with the referred studies that used INF-α2b alone or with subconjunctival injections. This treatment may be another alternative for patients who reject any operative procedure or those who are apprehensive about injections. Furthermore, systemic side effects such as flulike symptoms can be avoided. The mean time to clinical resolution of 7.2 weeks using this combination is in the range (2–12 weeks) for subconjunctival INF treatment for CIN. I think that this second point, which was not discussed by the authors, is very important and gives greater value to the report.