Ocular Surface Squamous Neoplasia

Ocular Surface Squamous Neoplasia: Comparison

Please note this is a comparison between Version 2 by Rita Xu and Version 1 by Jerome Lee.

Ocular surface squamous neoplasia (OSSN) encompasses a broad spectrum of neoplastic changes involving the squamous epithelium of the conjunctiva, cornea and limbus ranging from mild dysplasia, intraepithelial neoplasia (carcinoma in situ) to squamous cell carcinoma (SCC) [1].

ocular surface squamous neoplasia
management
topical chemotherapy

1. Introduction

Exposure to ultraviolet (UV) B radiation is the primary risk factor for OSSN [2]^[1]. Non-modifiable risk factors include age and male gender [3,4,5]^[2][3][4]. Modifiable risk factors include smoking, chronic trauma or inflammation, exposure to chemicals, vitamin A deficiency and local immunosuppression [1,2,4,6]^[1][3][5][6]. Human papilloma virus (HPV) and human immunodeficiency virus (HIV) are strongly associated with OSSN [7,8,9,10,11]^{[7][8][9][10][11]}. Human papilloma virus serotypes 16 and 18 are thought to be cofactors in the development of OSSN [12^[12][13],13], while OSSN may be the first presentation of HIV [14,15,16,17,18]^{[14][15][16][17][18]}. Screening for HIV should be performed in atypical cases such as younger patients with OSSN, especially those with risk factors such as having multiple sexual partners and/or a history of sexually transmitted diseases. Interestingly, a separate study ^[19] found that HPV does not appear to play a significant role in the etiology of OSSN in India. Instead, it is suggested that other factors listed above, such as ultraviolet radiation and immunodeficiency, played a more important role.

Although rare, OSSN is the most common non-pigmented tumour of the ocular surface ^[20], with a worldwide age-standardised rate of 0.26 cases per 100,000 per year. There is a higher incidence in African countries of 3–3.4 per 100,000/year [2]^[1]. Ocular surface squamous neoplasia is becoming more common in Africa, which can be partly attributed to increased survival of HIV-infected patients [2]^[1]. A study conducted in Canada also found an increasing incidence of malignant OSSNs, likely in part due to an aging population ^[21].

OSSN occurs with equal frequency in both men and women in Africa [2]^[1] and in parts of Asia including Saudi Arabia ^[22]. However, in most of the rest of the world, OSSN is more common in men [2]^[1]. This is partly due to differing risk factors, with a higher prevalence of HIV and HPV in Africa contributing to the increased risk of developing OSSN in women [2]^[1]. Malignant OSSNs generally follow the same epidemiological pattern, with studies finding that they are more common in males in Canada, Iran, and the United States [21^[21][23][24],23,24], and equally common among both genders in Africa [2]^[1].

Although no causative genetic mutations have been identified ^[25], several mutations including the tumour suppressor gene p53 ^[26], the telomerase reverse transcriptase (TERT) gene promoter ^[27], a disintegrin and metallopeptidase domain 3 (ADAM3) [28^[28][29],29], matrix metalloproteinase 9 (MMP-9), matrix metallopeptidase 11 (MMP-11) and clusterin ^[30] have been associated with the pathogenesis of OSSN. Further, DNA hypomethylation at the DNA methyltransferase 3-like (DNMT3L) promoter has been identified in OSSN, however its physiologic significance remains unclear ^[31].

Clinically, OSSN typically presents as a unilateral vascularized mass, with bilateral or multifocal presentations being less common [1]^[5]. Lesion morphology ranges from gelatinous, leukoplakic, papillary, nodular to nodulo-ulcerative ^[32]. Nodular and papillomatous lesions are associated with higher histopathologic grade ^[33]. Nodulo-ulcerative lesions are rare, aggressive variants which have been described in a case series of six patients with four having intraocular extension suggesting that they may be more invasive compared to other morphologies ^[32].

Diagnosis of OSSN is more challenging when associated with other ocular surface lesions sharing risk factors of UV exposure such as pterygia and pinguecula ^[34]. Histopathological evaluation following an incisional or excisional biopsy is the gold standard for the diagnosis of OSSN ^[33]. Less invasive modalities include impression ^[35] or exfoliative cytology [36^[36][37],37], in vivo confocal microscopy (IVCM) [38,39]^[38][39] and high-resolution or ultra-high-resolution anterior segment optical coherence tomography (HR-OCT) ^[40].

Surgical excision is the gold standard for the management of OSSN. Excision via Shields’ no touch technique with 4 mm margins, followed by intraoperative cryotherapy with the double freeze-and-slow-thaw technique achieved a low rate of recurrence ^[41], Surgical management can be associated with the development of complications such as limbal stem cell deficiency, symblepharon formation, conjunctival hyperaemia and conjunctival scarring [6,42,43,44]^{[6][42][43][44]}. Limbal stem cell deficiency may arise as OSSN typically involve the limbal region. In cases with orbital extension resulting from late presentation, delayed or missed diagnosis, and/or incomplete excision, orbital exenteration may be required ^[45].

Recently, there has been a shift towards medical management including topical chemotherapy drugs and immunomodulatory agents such as 5-fluorouracil (5-FU), mitomycin C (MMC), and interferon alfa-2b (IFNα−2b). Such agents have been used in combination with surgical excision but also as monotherapy due to their ability to treat the entire ocular surface ^[46].

A combination of surgical and medical methods has also shown to be effective in cases with high recurrence risk. Topical chemo-reduction with MMC may allow for less extensive surgical resection and tissue reconstruction ^[47]. Post-operative topical IFNα−2b therapy lowered the recurrence rate in patients with positive margins to a level similar to that of negative margins ^[48]. Topical chemotherapeutics such as IFNα−2b and MMC have been used preoperatively for tumour reduction, especially for extensive tumours which may be less amenable to monotherapy with such topical agents [47,49]^[47][49].

Topical IFN alfa-2a (IFNα−2a) has been used both as primary therapy and tumour reduction prior to surgical management [50,51]^[50][51]. Subconjunctival IFNα−2b has also been used as adjuvant therapy to reduce the risk of recurrence ^[52]. However, it is less commonly used compared to IFNα−2b. The two drugs differ by an amino acid present at position 23 of the protein. Lysine is present in IFNα−2a in this position, while IFNα−2b has arginine ^[53].

Adjunctive treatments reported to be in use include radiotherapy, topical anti–vascular endothelial growth factor (anti-VEGF) agents [54^[54][55],55], topical cidofovir [56^[56][57],57], topical retinoic acid ^[54] and photodynamic therapy ^[58].

2. Surgical Management

Surgical excision is the gold standard for the management of OSSN. The primary method of excision has been described by the Shields group ^[41]. This technique recommends macroscopic tumour-free margins of at least 4 mm during surgery to increase the likelihood of complete tumour resection ^[41]. This is followed by intraoperative cryotherapy applied to conjunctival and limbal margins via the double freeze-and- slow- thaw technique to rupture tumour cell membranes and occlude associated feeding blood vessels [59,60]^[59][60]; this further reduces the risk of recurrence ^[48]. Keratoepitheliectomy can be performed in cases of corneal involvement. Absolute alcohol is applied for 1 min before excision with tumour-free margins of at least 2 mm ^[41]. For scleral invasion, a partial lamellar sclerectomy can be performed ^[61]. In rarer cases of intraocular invasion, enucleation ^[62] should be considered while orbital invasion requires exenteration ^[63]. Primary wound closure may be performed for small wounds while amniotic membrane coverage is preferred for larger wounds to aid healing and to minimise inflammation and scarring. Despite amniotic membrane closure, extensive excision of the conjunctiva may lead to symblepharon and conjunctival scarring [64,65]^[64][65]. Surgical management can also be associated with other complications such as limbal stem cell deficiency (LSCD) [6,42,43,44]^{[6][42][43][44]}. Surgically induced scleral necrosis (SINS) is a relatively rare but well-documented post-operative complication that is more likely to occur following adjuvant therapy. This can occasionally lead to devastating complications such as scleral melt and perforation ^[66]. A modified Mohs micrographic excision technique with intraoperative cryotherapy has been proposed to allow for maximal conservation of healthy tissue ^[61] while concomitant limbal epithelial transplantation has been useful in preventing LSCD [67,68,69]^[67][68][69]. However, these techniques are time-intensive and require specific surgical expertise. Surgical excision alone may lead to tumour recurrence due to the presence of residual microscopic disease. Erie et al. ^[70] found that recurrence of conjunctival intraepithelial neoplasia and squamous cell carcinoma did not correlate with cell type or degree of atypia, but with the presence or absence of positive margins. Recurrence rates with positive margins can be as high as 56% and were reduced to 33% with negative margins ^[71]. Recently, lower recurrence rates of 0–21% have been reported, likely due to the use of intraoperative cryotherapy, adjunctive postoperative topical MMC and postoperative topical INFα−2b in patients with positive margins [48,72,73]^[48][72][73]. Thus, to reduce recurrence rates, adjunctive topical chemotherapy with IFNα−2b, 5-FU or MMC should be performed if histopathological evaluation shows positive margins. Although surgical management potentially shortens the overall treatment period compared to medical treatment, the complications highlighted above may limit its wider application. As proposed by Karp ^[74], surgery may be preferred for small (<4 clock hours (Shields) ^[41] or ≤5 mm (American Joint Committee on Cancer (AJCC)) ^[75]), unifocal lesions, lesions with an uncertain diagnosis and first presentations of OSSN. Considerations of factors such as accessibility and affordability of health services and medications, tolerance of and compliance with treatment, patient comorbidities and preferences also influence the choice between surgical and medical management.

3. Medical Management

To avoid the complications of surgery, there has been a shift towards medical management ^[76] which uses both topical chemotherapy drugs and immunomodulatory agents such as 5-fluorouracil (5-FU) [77,78^{[77][78][79][80]},79,80], mitomycin C (MMC) [47^{[47][81][82][83][84][85][86][87]},81,82,83,84,85,86,87], and interferon alfa (IFNα) [44,88,89,90,91,92]^{[44][88][89][90][91][92]} as monotherapy. These agents can treat the entire ocular surface, thus treating subclinical and microscopic disease ^[46]. The utility of topical chemotherapy ranges from chemo-reduction prior to surgery [47,89]^[47][89], primary treatment, to adjunctive treatment after surgery to reduce the risk of recurrence ^[6]. As primary therapy, topical chemotherapy has been shown to be comparable to surgery with similar efficacy and recurrence rates ^[44]. Karp ^[74] has suggested that topical chemotherapy may be preferred for large (>4 clock hours (Shields) ^[41] or ≥5 mm (AJCC) ^[75]), multifocal and recurrent lesions [88,89]^[88][89].

3.1. 5-Fluorouracil (5-FU)

5-FU is a pyrimidine analog that inhibits thymidine synthase, impairing DNA and RNA synthesis preferentially in cancer cells, thus preventing DNA replication and their proliferation. This mainly affects cells in the S stage of mitosis [42,93]^[42][93]. 5-FU is typically applied as a topical ophthalmic formulation. Subconjunctival and perilesional injections have also been used in limited studies ^[94]. The most widely used protocol recommends 1% 5-FU drops four times daily for 1 week, followed by 3 weeks off as one cycle, for a total of 4 cycles ^[6]. Table 1 below summarises the effectiveness of different protocols where 5-FU was used as primary therapy.

Table 1. Summary of study protocols using 5-Fluorouracil (5-FU) as sole treatment of ocular surface squamous neoplasia (OSSN).

Study	Protocol	Outcomes
Topical 1% 5-fluorouracil in ocular surface squamous neoplasia: a long-term safety study ^[95]	Study location:	Italy	Number of patients:	22	Dose:	1% 5-FU topical QDS for 4 weeks, adjunctive courses administered after 3 months of chemotherapy-free interval Eye ointment applied to inferior eyelid to minimise skin contact, and inferior lacrimal punctum briefly occluded	Endpoint:	Until clinical and cytological tumour regression	Response:	22 (100%)	Time to response:	Not specified	Recurrence:	3 (14%)	Side effects:	not reported
Topical 5-Fluorouracil 1% as Primary Treatment for Ocular Surface Squamous Neoplasia ^[80]	Study location:	United States	Number of patients:	44	Dose:	1% topical 5-FU QDS for 1 week followed by a drug holiday of 3 weeks No punctal plugs	Endpoint:	Until clinical resolution or failure to respond within 4 or more cycles	Response:	36 (82%)	Time to response:	3.8 cycles (median: 4, range: 2–9)	Recurrence:	4 (6% at 1 y, 15% at 2 y)	Side effects:	pain (17, 39%), tearing (10, 23%), photophobia (6, 14%), itching (4, 9%), swelling (2, 5%), infection (1, 2%), no long-term complications
Topical 1% 5-fluoruracil as a sole treatment of corneoconjunctival ocular surface squamous neoplasia: long-term study ^[96]	Study location:	Italy	Number of patients:	41	Dose:	1% 5-FU topical QDS for 4 weeks, adjunctive courses administered after 1 month of chemotherapy-free interval Eye ointment applied to the inferior eyelid skin to minimise skin contact, no punctal occlusion	Endpoint:	Until clinical resolution or clinical evidence of lack of further tumour response	Response:	34 (83%)	Time to response:	11 ± 9 weeks (range: 3–22 weeks)	Recurrence:	4 (9%) 2 were treated with topical MMC and 2 were treated with topical MMC + surgery, all responded completely.	Side effects:	photophobia (20, 51%), conjunctival hyperemia (19, 48%), irritation (17, 43%), pain (14, 36%), superficial punctate keratitis (11, 28%), lid erythema (4, 8%)
Comparison of Topical 5-Fluorouracil and Interferon Alfa-2b as Primary Treatment Modalities for Ocular Surface Squamous Neoplasia ^[97]	Study location:	United States	Number of patients:	54	Dose:	1% topical 5-FU QDS for 1 week followed by a drug holiday of 3 weeks	Endpoint:	Until clinical resolution or failure to respond within 2 cycles	Response:	52 (96%)	Time to response:	6.6 ± 4.5	Recurrence:	6 (12%), mean of 7.7 ± 9.1 months	Side effects:	pain (12, 22%), tearing (12, 22%), redness (11, 20%), eyelid edema (5, 93%), keratopathy (4, 7%), no long-term complications

Studies have shown 5-FU to be very effective as primary therapy for OSSN, with high-resolution rates of 82–100% and low recurrence rates of 6–14%. Its effectiveness has not been affected by patient age, gender, and ethnicity [80,96]^[80][96]. Compared to topical IFNα−2b, rates of tumour resolution, recurrence and time to response were similar with 5-FU [80,97,98]^[80][97][98]. 5-FU is generally well tolerated with mostly mild side effects reported, including pain, redness, eyelid edema, tearing, keratopathy and superficial stromal melting ^[97]. Many of these adverse effects can be managed through regular use of preservative free artificial tears throughout the course of treatment and short-term use of topical steroids as needed. Punctal and canalicular stenosis have not been reported to arise from topical treatment, although they have resulted from systemic administration of 5-FU for other cancers [96,99]^[96][99]. Although topical 5-FU has fewer reported side effects compared to MMC [96^[96][97],97], it is associated with more side effects compared to IFNα−2b as it also affects the proliferation of normal rapidly dividing epithelial cells and fibroblasts [89,100]^[89][100]. However, 5-FU generally costs less than IFNα−2b, despite the need for compounding ^[42]. While 5-FU can be stored at room temperature, refrigeration is recommended [80,101,102]^{[80][101][102]}.

3.2. Mitomycin C (MMC)

MMC is an antimetabolite and alkylating agent that exerts its antineoplastic and antibiotic properties through inhibiting DNA synthesis and fibroblast migration as well as by inducing apoptosis. Compared to 5-FU, which mainly affects cells in the S stage of mitosis, MMC affects both proliferating and non-proliferating cells ^[89]. MMC is typically applied as topical eye drops. The most widely used protocol is 0.04% MMC drops four times daily for 1 week followed by 2–3 weeks off until the eye is quiet, for a total of 3 cycles, sometimes with punctual occlusion during administration [47,73,86,103,104]^{[47][73][86][103][104]}. However, various protocols have been reported with varying efficacies, as summarized in Table 2 below.

Table 2. Summary of study protocols using Mitomycin C (MMC) as sole treatment of OSSN.

Study	Protocol	Outcomes
Randomized controlled trial of topical mitomycin C for ocular surface squamous neoplasia: early resolution ^[87]	Study location:	Australia	Number of patients:	26 with MMC vs. 22 with placebo	Dose:	MMC 0.4 mg/mL QDS for 3 weeks Advised punctal plugs or manual occlusion	Endpoint:	Until resolution by slit lamp examination or failure to regress by 6 weeks	Response:	24 (92%)	Time to response:	121 days (range: 73–169)	Recurrence:	Not specified	Side effects:	redness, irritation
Long-Term Results of Topical Mitomycin C 0.02% for Primary and Recurrent Conjunctival-Corneal Intraepithelial Neoplasia ^[103]	Study location:	Brazil	Number of patients:	18	Dose:	0.02% topical MMC QDS for 14 days, followed by 14 more days if no resolution Manual punctal occlusion for 3 min	Endpoint:	For 28 consecutive days	Response:	18 (100%)	Time to response:	28 days	Recurrence:	0 (0%)	Side effects:	conjunctival hyperemia, tearing, corneal epithelial erosions (2, 11%)
Retrospective Comparative Study of Topical Interferon α2b Versus Mitomycin C for Primary Ocular Surface Squamous Neoplasia ^[105]	Study location:	India	Number of patients:	25	Dose:	MMC 0.4 mg/mL QDS in 1 week on and 1 week off cycles Advised punctal occlusion for 5 min during treatment course	Endpoint:	Until clinical resolution or failure to regress after 2 cycles	Response:	23 (92%)	Time to response:	1.5 ± 0.54 (median 1.5)	Recurrence:	0 (0%)	Side effects:	Conjunctival hyperemia (11, 44%), hyperemia with burning sensation (9, 36%), corneal epitheliopathy (3, 12%), photophobia with blepharospasm (2, 8%), punctal stenosis (1, 4%)

As primary therapy, studies have shown MMC to be very effective in treating OSSN, with high-resolution rates of 92–100% and low recurrence rates. Although the rates of tumour resolution were similar compared to IFNα−2b, MMC had a faster time to resolution of 1.5 months compared to 3.5 months ^[105]. However, use of MMC is limited by its toxicity. MMC has more frequent and severe ocular side effects compared to 5-FU and IFNα−2b [96,97,105]^{[96][97][105]}. These include ocular pain, redness, allergic conjunctivitis, tearing, epitheliopathy, conjunctival hyperaemia, punctate staining of the cornea, punctal stenosis and LSCD [81,82,87,103,105,106,107,108,109,110,111]^{[81][82][87][103][105][106][107][108][109][110][111]}. Topical preservative free tears and steroids are commonly used throughout the course of treatment to alleviate toxicity while punctal plugs may be used to prevent punctal stenosis [84,89,107,112]^{[84][89][107][112]}. Additionally, ancillary management with hyaluronic acid eye drops results in improvements in both subjective and objective ocular parameters, reducing MMC induced adverse effects ^[113]. Careful monitoring is needed for early identification of any signs of toxicity, as MMC administration should be halted if epitheliopathy occurs to minimise its toxic effects. Other disadvantages of MMC include its need for compounding and refrigeration. Although it may be more costly than 5-FU, it is generally cheaper than IFNα−2b.

3.3. Interferon Alfa (INFα)

Interferon Alfa-2b (INFα-2b)

IFNα−2b is a leukocyte derived low molecular weight glycoprotein that functions as an immunomodulatory cytokine. It exerts its anti-proliferative, anti-angiogenic and cytotoxic effects through activating pathways involved in the alteration of gene expression, apoptosis, inhibition of protein synthesis and inducing host anti-tumour immunosurveillance [114,115,116,117]^{[114][115][116][117]}. IFNα−2b also enhances the production of IL-2 and IFN-γ mRNA by the immune system and lowers the production of IL-10 which aids in the recognition and targeting of neoplastic cells ^[118]. Thus, immunocompetency is required for efficacious use of IFNα−2b [119,120]^[119][120]. The use of non-immunomodulating agents like 5-FU or MMC may be preferred in immunosuppressed patients. IFNα−2b can be used as a topical eye drop or a subconjunctival perilesional injection. The most widely used protocol for topical drops is 1 million international units (MIU)/mL four times daily until resolution followed by at least one to three more months after resolution with a mean time to resolution of 4 months [6,42,121,122]^{[6][42][121][122]} while subconjunctival perilesional injections are typically given at a dose of 3MIU/0.5cc weekly ^[121] or 10 MIU/0.5cc monthly until resolution ^[123]. Table 3 below summarises the effectiveness of different protocols where IFNα−2b was used as primary therapy.

Table 3. Summary of study protocols using Interferon alfa-2b (IFNα−2b) as sole treatment of OSSN.

Study	Protocol	Outcomes
Topical
Regression of presumed primary conjunctival and corneal intraepithelial neoplasia with topical interferon alpha-2b ^[124]	Study location:	United States	Number of patients:	7	Dose:	1 MIU/mL IFNα−2b 4–6 times daily	Endpoint:	Until 1 month beyond complete clinical resolution via slit-lamp biomicroscopy	Response:	7 (100%)	Time to response:	median: 54 days, mean: 77 days, range: 28–188 days	Recurrence:	0 (0%)	Side effects:	conjunctival hyperemia and follicular conjunctivitis (4, 57%)
Topical Interferon α-2b as a Single Therapy for Primary Ocular Surface Squamous Neoplasia ^[125]	Study location:	India	Number of patients:	24	Dose:	1 MIU/mL topical IFNα−2b QDS	Endpoint:	Until clinical resolution or failure to regress within 3 months	Response:	22 (92%)	Time to response:	median: 3.25, range: 2–4	Recurrence:	0 (0%)	Side effects:	intratumoural bleeding (2, 8%), conjunctival congestion (1, 4%), foreign body sensation (1, 4%)
Retrospective Comparative Study of Topical Interferon α2b Versus Mitomycin C for Primary Ocular Surface Squamous Neoplasia ^[105]	Study location:	India	Number of patients:	26	Dose:	1 MIU/mL topical IFN IFNα−2b QDS	Endpoint:	Until clinical resolution or failure to regress after 2 months	Response:	23 (89%)	Time to response:	3.1 ± 0.73 (median 3.5)	Recurrence:	1 (4%) at 18 m	Side effects:	conjunctival hyperemia (2, 8%), hyperemia with burning sensation (1, 4%)
Comparison of Topical 5-Fluorouracil and Interferon Alfa-2b as Primary Treatment Modalities for Ocular Surface Squamous Neoplasia ^[97]	Study location:	United States	Number of patients:	48	Dose:	1 MIU/mL topical IFNα−2b QDS	Endpoint:	Not specified	Response:	39 (81%)	Time to response:	5.5 ± 2.9	Recurrence:	2 (5%), mean of 9.9 ± 11.4 months	Side effects:	pain (9, 20%), redness (6, 13%), blurred vision (6, 13%), tearing (2, 4%), no long-term complications
Primary treatment of ocular surface squamous neoplasia with topical interferon alpha-2b: Comparative analysis of outcomes based on original tumor configuration ^[126]	Study location:	United States	Number of patients:	61	Dose:	1 MIU/mL topical IFNα−2b QDS	Endpoint:	Until biomicroscopic evidence of tumour resolution or until the time a secondary treatment was deemed necessary due to poor response	Response:	59 (95%) complete response; 2 (3%) had partial response; additional treatment required for complete response in 7 (11%)	Time to response:	5.8 (median: 5, range: 1–17.8)	Recurrence:	2 (3%)	Side effects:	follicular reaction (4, 6%), corneal epithelial defect (2, 3%), irritation (1, 2%)
Recombinant Interferon Alpha-2b as Primary Treatment for Ocular Surface Squamous Neoplasia ^[127]	Study location:	Iran	Number of patients:	92 * Data was combined with perilesional IFNα−2b used in some patients as second line	Dose:	3 MIU/mL topical IFNα−2b QDS	Endpoint:	Until 1 month beyond complete tumour resolution then tapered to BD for 2 months, or until failure to regress tumour in 2 subsequent monthly visits	Response:	89 (97%); 8 required perilesional IFNα−2b	Time to response:	4.64 ± 1.92 months (median: 5, range: 1–10)	Recurrence:	Not specified	Side effects:	conjunctival hyperemia (4, 4%), follicular reaction (2, 2%), punctate epithelial erosions (1, 1%), chemosis (1, 1%)
Subconjunctival
Management of Ocular Surface Squamous Neoplasia with Topical and Intralesional Interferon Alpha 2B in Mexicans ^[128]	Study location:	Mexico	Number of patients:	6	Dose:	3 MIU/0.5 mL intralesional IFNα−2b once weekly	Endpoint:	Until resolution	Time to response:	6.5 months, range: 4–11 months	Recurrence:	0 (0%)	Side effects:	None reported
Subconjunctival/Perilesional Recombinant Interferon α2b for Ocular Surface Squamous Neoplasia: A 10-Year Review ^[121]	Study location:	United States	Number of patients:	15 * Some eyes were recurrences of OSSN	Dose:	3 MIU/0.5 mL perilesional subconjunctival IFNα−2b weekly (10 eyes had concomitant topical IFN, but the study found no difference in resolution)	Endpoint:	Until resolution	Response:	13 (87%)	Time to response:	median: 1.4 months, range 0.6–5.7	Recurrence:	1 (7%)	Side effects:	stinging and irritation (4, 27%), fever and malaise (5, 33%)
Perilesional and topical interferon alfa-2b for conjunctival and corneal neoplasia ^[92]	Study location:	United States	Number of patients:	6 * All eyes had concomitant topical IFNα−2b	Dose:	3 MIU/0.5 mL perilesional subconjunctival IFNα−2b once followed by 1MIU/mL topical IFNα−2b QDS	Endpoint:	Until 1 month after clinical resolution	Response:	6 (100%)	Time to response:	within 6 weeks	Recurrence:	0 (0%)	Side effects:	fever and myalgia (2, 33%)

As primary therapy, both forms are highly effective in treating OSSN, with high rates of disease resolution of 81–100% and 87–100% and remarkably low recurrence rates of 0–5% and 0–7% for topical eye-drops and subconjunctival injections, respectively. A study comparing doses of topical IFNα−2b drops found that the 1 MIU/mL formulation is equally effective as the 3 MIU/mL dose with fewer side effects ^[122]. The effectiveness of both topical and subconjunctival IFNα−2b has not been affected by patient demographics ^[129]. Compared to 5-FU, the rates of tumour resolution, recurrence and time to response were similar [80,97,98]^[80][97][98]. When compared to MMC, rates of tumour resolution were also similar. However, time to response was longer for IFNα−2b, with median time to resolution of 3.5 months compared to 1.5 months for MMC. Regardless, IFNα−2b may be preferable to MMC as it is associated with significantly lower adverse effect rates of 12% compared to 88% ^[105]. Topical IFNα−2b drops are the best tolerated among the topical therapies for OSSN available [89,100,105]^{[89][100][105]}. Side effects of topical IFNα−2b are largely limited to mild irritation, conjunctival hyperaemia ^[52], reactive lymphoid hyperplasia ^[130] and follicular conjunctivitis ^[123] as it is an endogenous molecule as opposed to an external chemotherapeutic agent [125,131]^[125][131]. Most side effects resolve with discontinuation of treatment.

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