Ocular surface squamous neoplasia (OSSN) is the most common malignancy of the ocular surface and comprises a spectrum of diseases ranging from dysplasia to invasive carcinoma. Intraepithelial carcinoma refers to superficial disease in the epithelium only, which is generally categorized as mild, moderate, or severe (in situ/full thickness) intraepithelial disease. When cancerous cells invade through the basement membrane it is described as squamous cell carcinoma [1,2]. Significant risk factors include a prolonged history of sun exposure, smoking, and immunosuppression. In addition, human papillomavirus (HPV) may also play a role in the pathogenesis of the disease [3,4].

Historically, the gold standard treatment for OSSN has been surgical excision with a no-touch technique and adjuvant cryotherapy; however, surgical excision has been associated with sequelae such as symblepharon, conjunctival scarring, conjunctival hyperemia, and limbal stem cell deficiency [2,[5], [6], [7]]. Recently, the tide has turned to favor topical chemotherapy as an alternative to surgery for OSSN [8,9]. Topical chemotherapies offer the advantage of treating the entire ocular surface, thus addressing subclinical disease that can lead to up to 56% recurrence frequency if surgically excised with resultant positive margins [10].

Topical chemotherapeutic agents used to treat OSSN include interferon α-2b (IFN), mitomycin C (MMC), and 5-fluorouracil (5FU). IFN is a recombinant form of interferon α-2b, a naturally occurring cytokine with antiviral, antimicrobial, and antineoplastic properties [[11], [12], [13], [14], [15], [16]]. It has been used to treat OSSN topically since 1994 and has been shown to have minimal side effects and high resolution rates [[11], [12], [13], [14], [15], [16], [17]] However, it has become increasingly expensive and now very difficult to obtain in the United States.

MMC is an alkylating agent with antibiotic and antineoplastic properties [18,19]. It has been used as an adjunct therapy in glaucoma, pterygium, and OSSN excision surgeries and has been used to treat OSSN topically since 1994 [6,20]. While it offers high-resolution rates, MMC subjects the ocular surface to significant toxicity and has an unfavorable side effect profile [20,21].

5FU is a pyrimidine analog of uracil that inhibits the enzyme thymidine synthase, impairs DNA and RNA synthesis, and thus results in an antineoplastic effect [22,23]. It is an antimetabolite that has been used to treat skin, colon, and breast cancers [23]. Tumors treated with 5FU demonstrate cytoplasmic vacuolation and pyknotic nuclei in the keratinocytes [24,25]. 5FU can also decrease fibrosis and scar formation by way of its anti-inflammatory effect [26]. Using in-vivo confocal microscopy, one study observed that 5FU is selective for OSSN, demonstrating no long-term pathological change in corneal cells, including endothelium, epithelium, stroma, and sub-basal nerve parameters [27]. 5FU has applications in ophthalmology as an adjuvant therapy in glaucoma, vitreoretinal, and pterygium surgeries and has been used to treat OSSN topically since 1986 [28]. Additionally, it is more cost-effective than IFN and MMC, averaging about $50 per month of treatment at our center. As such, 5FU is an attractive choice for topical chemotherapy of OSSN.

Previous studies of 5FU as topical chemotherapy for OSSN have shown high-resolution rates, low recurrence rates, and generally tolerable side effects [[29], [30], [31]]. However, these data were generated by examining a small number of patients, the largest series including 54 patients with a mean follow-up of 474 days [29]. Furthermore, studies reported contradictory results regarding risk factors for tumor non-resolution and recurrence [29,30]. To fill this knowledge gap, our study examined a large population of patients treated with 5FU as a primary modality for OSSN and examined treatment outcomes.