A significant proportion of the Indian subcontinent belong to the underserved rural areas. Firstly, there is a lack of proper medical infrastructure and social awareness regarding ocular tumors in this section of society. Secondly, evidence reveals an underutilization of already well-established eyecare services in these areas.11 Although the exact incidence of ocular surface tumors in India is unknown, the reported incidence from an Electronic medical record (EMR)-based data from a tertiary eyecare center is < 1%.1 This study was undertaken to recognize the demographic distribution, clinical presentation, management outcomes, and the referral patterns of OSSN reporting to a limited resource secondary eyecare unit in rural India.
Males comprised 76% of all cases in our cohort, which is similar to the reported average of 68 to 70%.8, 12 Although one may argue that males are more likely to involve in outdoor occupations leading to higher exposure to UV radiation, in rural areas there is considerable outdoor exposure to women as well. The male predominance can be attributed to the notion that males being the predominant breadwinners of the society, are twice as likely to seek health care than females in rural areas.11
Though surgical excision is the gold standard treatment for OSSN, wide excisional biopsy with cryotherapy to surgical margins and ocular surface reconstruction with amniotic membrane graft (AMG) is challenging in a limited resource healthcare setup in rural India. Also, pathology centers for processing of excised specimens do not exist in most parts of rural India. With the availability of AS-OCT which provides optical biopsy confirming the diagnosis of OSSN, medical treatment of OSSN with topical medications is an emerging trend. Amongst the topical medications, Interferon alfa 2b (IFN-a2b) has shown to be effective against OSSN and is known to be associated with least complications compared to Mitomycin-C (MMC) and 5-FU.13 However, utilization of IFN-a2b in a rural setup is challenging owing to lack of availability of a refrigerator for drug storage in most rural households. In 2021, the National Family Healthy Survey (NFHS) of India, revealed a stark urban-rural divide on refrigerator ownership, with 63% urban households owning a refrigerator as opposed to only 25% ownership in rural households. These limits the utility of topical IFN-a2b in rural areas, as it requires a robust cold chain storage. Another considerable limiting factor is the difference in the cost of one vial of IFN-a2b, which is atleast three times more expensive than a vial of 5-FU (250mg/5mL) in the Indian subcontinent.14 MMC is also effective for OSSN but has a relatively increased side-effect profile compared to IFN-a2b and also requires cold chain maintenance.15
Due to the above-mentioned challenges, all OSSN cases were being referred to tertiary care centers for confirmation of diagnosis and further management, till 2 years ago. At our secondary eyecare facility, though trained eyecare professionals are available, surgical excision was not possible due to lack of cryotherapy, AMG, and pathology setup; IFN-a2b and MMC were not ideal due to limitations with cold chain maintenance. Based on the published literature, topical 5-FU has shown encouraging results,16 is inexpensive compared to IFN-a2b and MMC, and the drug can be stored at room temperature. These factors encouraged us to initiate the use of topical 5-FU as the first line of management of OSSN in our rural setup. Also, AS-OCT was available at the rural setup at regular intervals through an advanced mobile diagnostic unit “Pashyantu”, aiding in confirmation of diagnosis of OSSN, prior to initiation of medical treatment.
The first usage of 5-FU for OSSN dates back to 1986, when de Keizer et al reported a case of intraepithelial neoplasia involving the cornea and conjunctiva, successfully managed with instillation of topical 5-FU.17 Since then, this chemotherapeutic agent has gained worldwide popularity as a primary monotherapy for OSSN. Venkateswaran et al in their direct comparison between primary topical 5-FU and IFN-a2b therapy showed comparable efficacy (96% in 5-FU versus 81% in IFN-a2b group) in the primary management of OSSN. In their study, although 5-FU showed superiority based on univariate analysis, multivariate regression showed no statistically significant difference between the two therapies.18 In our study, complete tumor resolution with topical 5-FU monotherapy was seen in 95% and is consistent with the published literature. The mean number of topical 5-FU cycles for complete tumor resolution was 2 cycles, indicating the mean duration to tumor resolution being 2 months. This reflects the relatively quicker time to resolution when compared to the published literature reporting mean duration to resolution as 4–6 months.16, 19 This could be related to referral bias in tertiary health care centers versus early diagnosis of smaller lesions in a rural setup.
Tumor recurrence was noted in 3 of the 36 eyes after complete tumor resolution with topical 5-FU monotherapy. Two of these recurrences were noted in the youngest case (13 years) of our cohort, who had bilateral multifocal OSSN with XP, a well-established association.20 XP was detected only when the patient had sought care at our eye center for the growing ocular surface mass. The sequential multifocal involvement and tumor recurrence despite topical 5-FU and the need for genetic testing led to referral to our tertiary eyecare center. Considering the proven association of XP with ocular, periocular, head and neck malignancies, and higher recurrence rates of OSSN, awareness regarding this condition amongst the general population as well as healthcare personnel, and the need for lifelong follow-up should be highlighted.21
Reported complications following topical 1% 5-FU therapy vary in severity, ranging from transient hyperemia, pain, eyelid edema, to rare sight-threatening complications such as perforated corneal ulcer and stromal melt. Tendency for causing keratopathy and eyelid edema is significantly more, when compared to IFN-a2b.18, 22, 23 However, recent long-term studies have shown reasonable side-effect profile of IFN-a2b with comparable rates of hyperemia between IFN-a2b and 5-FU (19% versus 23%, respectively).24 In our series, 5-FU related adverse effects were noted in 2 eyes (5%). One patient developed transient conjunctival hyperemia not warranting discontinuation of 5-FU therapy, and another case developed bacterial keratitis during the last cycle of 5-FU therapy, which resolved with fortified antibiotics. The authors recommend avoiding topical 5-FU in cases with pre-existing dellen or compromised cornea. None of the patients in our series had eyelid edema, periocular excoriation, or pigmentation, which may be due to adequate counselling of patients on the appropriate way of instilling these eye drops, avoiding exposure of the drug to the periocular surface.
Through this study, the authors advocate for topical 1% 5-FU as a safe and effective primary monotherapy for OSSN in limited resource settings of rural areas. However, topical chemotherapy should be judiciously used only in definitive OSSN cases. Whenever the diagnosis is uncertain, topical chemotherapy should be avoided and the patients should be referred to higher centers for an appropriate diagnosis and treatment. The authors propose the following referral guidelines for better overall success rates: a) Diagnostic dilemma with atypical AS-OCT features b) Scleral fixity of OSSN c) No or suboptimal response beyond 3 cycles of topical 5-FU d) Worsening of OSSN despite treatment initiation e) Tumor recurrence f) OSSN in a setting of corneal dellen, microbial keratitis or compromised ocular surface. A closer follow-up is recommended in patients of XP and HIV.