FP1560 : Subconjuctival Perilesional Interferon Alpha 2b in Treatment of Ocular Surface Squamous Neoplasia.

Dr.Kiran Kumar, K19195, Dr. Suresh Babu G., Dr.Shilpa S Reddy

Ocular surface squamous neoplasia (OSSN) refers to the varied spectrum of disease involving abnormal growth of dysplastic epithelium on the ocular surface. The term was first described by Lee and Hirst. It consists of the entire spectrum of corneal and conjunctival lesions ranging from benign to pre-invasive to invasive carcinoma.

The management of OSSN has been constantly changing over the past decade with the better understanding of the disease pathogenesis and emerging diagnostic and treatment modalities. The treatment of choice for OSSN has been wide surgical excision ensuring free margins with cryotherapy of margins¹.The approach has slowly shifted from a more aggressive surgical management to a primary medical therapy utilizing chemotherapeutic agents and immunotherapy so as to ensure minimal cosmetic and anatomical disfigurement. Also the topical chemo and immune- therapy helps deal with microscopic tumour extension which may not be otherwise visible. Impression cytology as a diagnostic modality has helped bring this shift in the treatment patterns in view of better diagnostic capabilities to recognise ocular surface pathologies in terms of high sensitivity.

The management protocols have further been revamped with the recent introduction of interferon therapy. Though limited research is available these agents are slowly gaining popularity as both chemo-reductive and therapeutic agents.

Interferons (IFNs) are a diverse family of pleotropic cytokines ² that have a role in innate immunity. These are natural multifunction proteins that inhibit viral replication, inhibit cellular proliferation, have anti-angiogenic activity and act as immune-modulators. They act by binding to specific cell surface receptor and initiate a cascade of intracellular signals. The properties of IFNs that have been utilized and exploited in the field of ophthalmology are its immune-modulatory, anti-proliferative and anti-angiogenic actions.

One such area is the management of ocular surface squamous neoplasia. Interferon alpha2b (IFN-a2b) is a naturally occurring glycoprotein. Its role in treatment to OSSN can be justified by the fact that the Human Papilloma Virus has a possible role in the etio-pathogenesis. Though not FDA approved it is being used off label in certain group of patients with OSSN and studies have shown favourable outcomes.

Patients and Methods

Study Population

Sequential patients who were treated with perilesional subconjunctival IFN 2b injections for OSSN at Minto Regional Insitute of Ophthalmology were included in the study. With these criteria, 20 eyes of 19 patients were identified; All eyes had a confirmed histologic diagnosis.

Technique for Subconjunctival/Perilesional Injection.

After obtaining informed consent, patients were given 0.5% topical proparacaine (Alcon Laboratories, Fort Worth, TX). The patients then were given a perilesional subconjunctival injection of 3 million international units (MIU) of recombinant IFN2b in 0.5 ml of solution.

• It should be given using a 30 gauge needle sub-conjunctivally at the junction of neoplastic lesion and normal conjunctiva under direct visualisation.
• Ensure ballooning of the conjunctiva.
• The drug may be administered at a single site in case of small lesions or at multiple sites in case of extensive lesion.
• The injection should be perilesional and not intralesional to avoid seeding.
• Avoid sub-conjunctival haemorrhage as this may hamper postoperative monitoring of the extent of the lesion

Results

Study Population at Presentation

Twenty eyes (19 patients) were treated with perilesional subconjunctival injections of 3 MIU in 0.5 ml of recombinant IFN 2b. The median age at the time of initial treatment was 58 years (range, 35– 71 years).  The initial cohort of patients treated in this study was injected with IFN 2b once weekly. patients received weekly injections until clinical disease resolution. After resolution, patients were seen every 3 months in the first year, every 6 months for the second year, and then yearly thereafter.

Treatment Information

Interferon injections successfully eliminated disease in all eyes. The median number of injections was 5 (range, 2–10 injections). The median time to OSSN resolution in the successfully treated eyes was 1.5 months (range, 1–2.5 months; Fig 3). The median follow-up time was 9 months (range, 2-15 months; Table 1). Local side effects of the injections included stinging and irritation in 2 of 20 eyes and systemic reports of fever and malaise after injection in 4 of 20 eyes. Clinical resolution of tumor occurred in all 100 % (20/20) of cases.

Discussion

Ocular surface squamous neoplasia is managed most commonly with surgery using a wide excision and cryotherapy. However, this treatment option can lead to limbal stem cell deficiency and high rates of recurrence. This is especially problematic in patients with recurrent disease or large annular lesions of the limbus. The approach has slowly shifted from a more aggressive surgical management to a primary medical therapy utilizing chemotherapeutic agents and immunotherapy so as to ensure minimal cosmetic and anatomical disfigurement. Also the topical chemo and immune- therapy helps deal with microscopic tumour extension which may not be otherwise visible.

In the study using perilesional subconjunctival interferon injections, the median time to tumor resolution was 1.5 months (range, 1 –2.5 months). This is similar to an initial study in which the median time to resolution was 1.1 months. As described previously, this treatment time is much shorter than the average time to resolution reported in the literature for treatment with topical drops of approximately 3 months.

The ideal dose and frequency of IFN 2b injections for OSSN is not yet known. The injection was given subconjunctivally, adjacent to the lesion. Perilesional/subconjunctival injections of IFN 2b can be considered for both primary and recurrent OSSN. Medical treatment is especially advantageous in diffuse, multifocal lesions, annular lesions of the limbus, and recurrent disease where extensive surgery would be needed and would be accompanied by the risk of limbal stem cell deficiency. Medical therapy also has the theoretical advantage of possibly treating subclinical, invisible disease.

Advantages of perilesional subconjunctival IFN2b injections include more rapid tumor resolution, ensured compliance, and perhaps more direct delivery of IFN2b to the tumor site when compared with topical IFN2b drops.

Systemic use of IFN2b intravenously, intramuscularly, and subcutaneously is known to cause some systemic side effects, including fever, malaise, and flulike symptoms. These systemic side effects were seen in 15% of patients (3/20 eyes) receiving subconjunctival IFN2b injections in this study. As with the systemic use of IFN2b, the intensity of the side effects often is reduced with subsequent injections, as patients habituate to the drug and its side effects. Additionally, acetaminophen at the time of injection and a few hours after can help to reduce these symptoms.

This study demonstrated that perilesional/subconjunctival interferon (with or without concomitant topical therapy) was effective in the treatment of OSSN, future studies will be needed to determine the ideal treatment regimen with respect to the dosing and frequency of injections and to the need for topical medication.

References:

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3. Galor A et al. Topical interferon alpha 2b eye-drops for treatment of ocular surface squamous neopla sia: a dose comparison study. Ophthalmology 2010.
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