Interferon alpha-2b, a naturally occurring low molecular weight glycoprotein, is known for its antiviral and antineoplastic properties, and has been shown to be effective in the treatment of OSSN. Its antineoplastic effects include inducing apoptosis, inhibiting angiogenesis, and extending the cell cycle duration in cancer cells [15]. The drug, IFNα-2b is available in concentrations of 1 MIU, 3 MIU, 5 MIU, and 5 MIU. A study comparing different concentrations of IFNα-2b found no statistically significant difference in the efficacy or treatment duration between the various drug concentrations [16]. There is no difference in efficacy of IFNα-2b based on tumor configuration (flat or dome-shaped) [17]. A study of 98 eyes by Nanji ete al. compared topical IFNα2b to surgical excision, and showed similar tumor recurrence rates between the groups: 3% in the IFNα-2b group and 5% in the surgery group, with comparable side effect rates [5]. In our previous study on use of INFα2b in 30 eyes with OSSN, the tumor recurrence rate was 0% and side-effects were noted in 5% patients [18]. In the current study, the tumor recurrence rate with INFα2b was 5% and side-effects were noted in 13% patients. We also analysed the cost-effectiveness of INFα2b for the treatment of OSSN in our previous study and showed that the mean cost for treatment of tumors < 5 mm was INR 9607 ($143) and for tumors > 5 mm was INR 10985 ($164) [18]. In our current study including tumors with a mean tumor diameter of 10 mm, the average cost for complete tumor regression with INFα2b was INR 9763 ($ 117).

A pyrimidine analogue, 5-FU is another effective agent for OSSN. It inhibits thymidylate formation from uracil, leading to the inhibition of DNA and RNA synthesis and cell death. It is typically administered as a 1% solution [19]. Various regimens are described, including 4 times/day for one week followed by three weeks of a drug-free interval, continuous administration three to four times a day for four weeks, or administration for two to four days followed by a 30 to 45-day drug-free period [20]. The efficacy of 5-FU ranges from 40 to 100% in the literature [21, 22], with a tumor recurrence rate of 7.3% to 10% within three months of treatment discontinuation [19, 23]. In our study, tumor recurrence rate after discontinuation of 5-FU for OSSN was noted in 2% eyes. A vial of 5% 5-FU costs 29 INR, which can be diluted to prepare five vials of 1% drug, offering the advantage of stability at room temperature, eliminating the need for refrigeration [6]. In our study, the average cost of treatment per patient for complete resolution of tumor was INR 12 ($ < 1). In comparison to INFα2b, topical 5-FU is an inexpensive treatment option for OSSN and does not require special storage precautions.

In our study, the mean age at diagnosis of OSSN was 58 years in the IFNα2b group and 52 years in the 5-FU group, consistent with the reported mean age of 56 years in the literature [24], with a male predominance. The mean conjunctival basal diameter in the IFNα2b group (10 mm) was significantly larger than in the 5-FU group (5 mm), explained by the evolving criteria for the management of OSSN at our institute. Previously, smaller tumors were being managed by surgical excision and medical treatment was offered to placoid diffuse tumors. Currently, medical treatment is offered to patients with smaller tumors as well. In this study, the number of sessions/cycles for achieving complete tumor control was higher in IFNα2b group at 3 versus 2 cycles in the 5-FU group. This could be related to larger tumors in the IFNα2b group compared to 5-FU group. Also, it is reported that the treatment response is quicker with topical 5-FU compared to IFNα2b [18,19,20,21,22,23].

A comparative study of 48 eyes with OSSN primarily treated with IFNα2b monotherapy versus 54 eyes treated with topical 5-FU by Venkateswaran et al., revealed a statistically significant difference in the tumor resolution rate between 5-FU (96.3%) and IFNα2b (81.3%) (p = 0.01) on univariate analysis, though no difference was found on multivariate analysis, with ethnicity being the only confounding factor [25]. Another study compared the outcomes of adjuvant INFα2b versus 5-FU post-surgical excision of OSSN, and showed that there was no statistical difference between the rates of tumor resolution (94.11% versus 94.6%, respectively) [26]. In our study, complete tumor resolution was noted in 80% OSSN eyes treated with IFNα2b versus 83% treated with topical 5-FU, with no statistical difference in the outcomes.

Venkateswaran et al. found more adverse effects with topical 5-FU compared to INFα2b, such as eyelid edema and pain [25]. San Román Llorens et al. also found a significant difference between the side effect profiles between INFα2b and 5-FU (19% versus 59%, p = 0.015) [26]. Most studies report predominantly mild side-effects associated with 5-FU 1% treatment. Joag et al. observed side effects in 61% of patients, primarily pain (39%) and tearing (23%), with one case of infection [19]. Parrozzani et al. documented mild to moderate side-effects in 48% of patients with 5-FU, with no severe adverse events or treatment discontinuation [23]. Wylegala et al. noted mild hyperemia (26%) and pain (23%) as the most common side-effects, while sight-threatening complications, such as limbal stem cell deficiency, occurred in only 3% of cases [27]. In contrast, in our study, the side-effects with INFα2b was 13% and 5-FU group displayed side-effects in 6%. However, more serious complications like limbal stem cell deficiency and punctal stenosis were noted only in the 5-FU group which correlates with the existing literature. The lower side-effect profile in the topical 5-FU group in our study could be related to the judicious instillation of topical lubricants during and after use of topical 5-FU. Higher incidence of adverse effects (flu-like symptoms and hyperemia) in INFα2b group can also be attributed to administration of subconjunctival injections in 80% patients as compared to only topical therapy in 5-FU group.

Comparing the cost of the two treatments, there is a significant difference between the average cost of treatment of OSSN with INFα2b versus topical 5-FU. Treatment with INFα2b costed 813 times more than 5-FU therapy. Lower cost and lack of necessity for refrigeration makes topical 5-FU a more affordable and convenient modality of treatment for OSSN, especially in developing countries.

The limitations of our study include its retrospective nature, shorter follow-up, and differences in the tumor morphology and staging between the groups. Though the tumor dimensions were different in the two groups, there were comparable outcomes in both groups, indicating the effectiveness of both treatment modalities. Although no clear guidelines exist on the indications for these medications, this study provides perspective on selecting suitable treatment for patients. Especially, with the recent limited availability of IFNα2b, this study highlights the comparable efficacy and safety of topical 5-FU, which is easily available. Future prospective studies with comparable tumor dimensions in the two groups and larger sample size can help us to understand the efficacy and effectiveness of the two topical drugs, INFα2b and 5-FU. Moreover, prospective study will also ensure standardized protocol for treatment in the two groups.

In conclusion, both IFNα2b and topical 5-FU are effective, non-invasive treatments for OSSN, exhibiting comparable side-effect profiles. If IFNα2b is readily available and the patient is likely to be complaint to the treatment and its storage specifications, IFNα2b is a good treatment modality for OSSN. However, topical 5-FU aligns well with the healthcare infrastructure and economic constraints commonly found in developing countries, offering a practical solution for managing OSSN, without compromising on quality of patient care.