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  5. FP357 : Treating OSSN with Drops: An Analysis of Different Options.

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Dr. Rakhi Kusumesh, K11392, Dr. Nazia Imam, Dr. Bibhuti Prassan Sinha, Dr. Anita Ambastha

ABSTRACT

Introduction

Ocular surface squamous neoplasia (OSSN) encompasses the entire spectrum of dysplastic and carcinomatous lesions of the ocular surface. 1,2 Medical treatment alone or as an adjuvant has been used increasingly for OSSN. Possible advantages of medical therapy include the ability to treat the entire ocular surface and the potential to avoid the stem cell deficiency associated with extensive surgical excisions.4, 5 Various topical agents have been advocated, including topical treatment such as mitomycin C (MMC), 5-fluorouracil (5- FU), and interferon alfa 2b (IFN a2b). In this study, we have evaluated and compared the efficacy and safety of all three topical therapies available for OSSN.

Material and Methods

Medical records of 65 patients who received topical therapy (IFN a2b 1 Million IU/ml four times a day or mitomycin 0.04% 1 week off and on cycle or 5- FU 1% 1 week on and 3 weeks off cycle) for primary OSSN were reviewed at the Regional Institute of Ophthalmology fromJune 2013 to January 2017. The diagnosis of OSSN was primarily clinical, based on the thorough examination with slit-lamp biomicroscopy. OSSN was diagnosed from  its characteristic macroscopic appearance and classified into papillomatous, gelatinous, and leukoplakic. Topical therapy was stopped as the lesion resolved.  Pretreatment findings included the diagnosis with all tumor characteristics, pretreatment and post treatment tumor size as measured by the greatest linear diameter and  limbal involvement in number of clock hours. Treatment information comprised the dose, frequency, duration and adverse effects of treatment and post treatment clinical course were also noted. The primary outcome measure was frequency of clinical resolution of tumors along with failure and recurrence rates after treatment. Statistical analysis was performed using Epi Info 7 (CDC, Atlanta, GA).

Results:

A total of 66 eyes of 65 patients with primary OSSN received topical medications. 26 eyes were treated with 1 million IU/ ml of topical IFNa2b; 25 eyes were treated with .04% of topical MMC and 15 eyes were treated with 1% of topical 5-FU. There was no statistical difference in macroscopic appearance, greatest linear dimension, limbal involvement, location of tumors and risk factors between threestudy medication groups. In all included eyes (IFNa2b, 26; MMC, 25; 5-FU, 15), complete response was achieved in 23 (89%), 23 (92%) and 13 (87%) with topical IFNa2b, MMC and 5-FU respectively (P = 0.854).  The median time to lesion resolution was significantly different between the groups (median 3.5 months in IFNa2b group, 1.5 months in MMC group and 2 months in 5-FU group) with average difference of 1.71 and 2 months among all (95% CI (1.35 to 2.079). Seven (9.8%) of 66 patients failed or partially responded to topical therapy; subsequently, they underwent surgical excision. Adverse effects occurred in (12%, IFNa2b; 88% MMC; 60% 5-FU) (P, 0.001).

Discussion:

Keeping in view the high recurrence rate of surgical excision in OSSN, there has been a paradigm shift in the treatment approach of OSSN over the past few years. MitomycinC is an alkylating agent. It acts preferentially on rapid dividing cells by inhibiting deoxyribonucleic acid (DNA) synthesis and produces cell death by apoptosis and necrosis. 5-Fluorouracil is a structural analog of thymine that inhibitsDNA formation by blocking the enzyme thymidylate. Interferons are a family of glycoproteins. They act by binding to cell surface receptors to promote antiviral and antitumor properties by activating immune cells, as well as they increase the recognition of tumor cells by up-regulating antigen presentation to T-lymphocytes. Though all three groups of patients had similar tumor characteristics and mean greatest linear dimension, we found significantly prolonged time to lesion resolution with average difference of 1.71 and 1.89 month (95% CI, p<.005) in eyes treated with IFNa2b in comparision to MMC and 5-FU respectively. For topical INFa2b treatment, the reported average time to complete tumor response was 11 weeks (range 2-59). In conjunction with previous knowledge of MMC action, we can suggest that MMC has faster action on tumor cells in comparison to INFa2b probably, due to MMC having direct action on rapidly proliferating tumor cells. As far as 5-FU is concerned, it also acts on rapidly multiplying cells, such as tumor cells, require more DNA and ribonucleic acid (RNA) than normal cells, and therefore take up larger amounts of 5-FU, allowing selective targeting of cancerous lesions. In the present study, out of 66 eyes, three eyes (4.5%) failed to respond with topical MMC whereas two eyes (3 %) each did not respond to topical IFNa2b and 5-FU. These  cases underwent surgery and on histopathology were proven to be squamous cell carcinoma  (SCC).

Timeto-tumor resolution depends on the type, size, and mode of therapy. In this study, topical MMC treated lesions took 1.48±.54 months (median 1.5) to resolve completely which is less than the documented case series of Shields CL et al 3 who reported 100% success in three median cycles (1-4 cycles), which could be because all of his cases had extensive, recurrent conjunctival-corneal squamous cell carcinoma. Topical 5-FU treated lesions took 2.06±.59 months (median 2.0) to resolve completely.  On the other hand, lesions treated with IFNa2b in our study took 3.19±.73 months (Median 3.5) to resolve completely.  Besley J et al 4 noted that lesion size and location, gender, age, treatment duration and treatment type did not significantly influence recurrence of OSSN. Our study demonstrated significantly higher ocular adverse effects in MMC  and 5-FU treated cases (88% and 60% respectively) in comparison to IFNa2b (11.5% ) (P < .001). Most common adverse effect was conjunctival hyperemia followed by burning sensation associated with hyperemia with  these eye drops.

In conclusion, all three drops had comparable efficacy. IFNa2b exhibited greater ocular tolerability.

References 

  1. Lee GA, Hirst LW. Incidence of ocular surface epithelial dysplasia in metropolitan Brisbane. A 10-year survey. Arch Ophthalmol. 1992 ; 110(4):525-7
  2. Hirst LW. Randomized controlled trial of topical mitomycin C for ocular surface squamous neoplasia: early resolution. Ophthalmology. 2007; 114:976Y982.
  3. Shields CL, Naseripour M, Shields JA. Topical mitomycin C for extensive, recurrent conjunctival-corneal squamous cell carcinoma. Am J Ophthalmol.2002; 133(5):601-6.
  4. Besley J, Pappalardo J, Lee GA, et al. Risk factors for ocular surface squamous neoplasia recurrence after treatment with topical mitomycin C and interferon alpha-2b. Am J Ophthalmol. 2014; 157:287Y293.

 

 

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