FP281 : Treatment Outcome with Interferon Alfa-2b Therapy in Ocular Surface Squamous Neoplasia

Dr. Rachna Meel, R12970, Dr.Rebika, Dr. Vanathi M, Dr. Seema Sen

Introduction

Ocular surface squamous neoplasia (OSSN) is common in countries located close to the equator. The conventional treatment of OSSN is wide surgical excision with a “no-touch” technique ⁴ often combined with cryotherapy and/or chemotherapy. However, repeated surgery causes significant morbidity in cases of tumor recurrence, which is common in this tumor. ⁵Topical chemotherapeutic agents [mitomycin C (MMC), 5-fluorouracil (5-FU)] have been employed to avoid  repeated surgeries, but have their own set of problems like limbal stem cell deficiency, scleral melting and punctal stenosis, especially in larger tumors.⁶

More recently, interferons have been used successfully in the treatment of OSSN with minimal reported complications.^10-17Herein, we present our experience with the use of INFa2b in treatment of primary or recurrent OSSN.

Methodology

This was a  retrospective observational study conducted at a tertiary eye care center. The medical records of all patients clinically diagnosed with OSSN at our centre from March 2015 to March 2016 were reviewed. The treatment outcome of patients treated with IFNa2b eye drops and/or perilesional injection, were analyzed.

Demographic details and clinical data including previous treatment history, risk factors or any systemic associations, best corrected visual acuity (BCVA), laterality and clinical staging of tumor (7^th edition of AJCC)¹⁹ were noted. The clinical characteristics of tumor documented were tissues involved, location, size, height of tumor on ultrasound biomicroscopic examination (UBM), multiplicity, presence of feeder vessels, clinical appearance (gelatinous/  papilliform/ulcerative), growth pattern (nodular/sessile), presence of leukoplakia, presence of pigmentation, intraocular involvement, nodal or systemic metastasis. Based on the number of clock hours of limbal involvement tumor was classified as small (≤1 quadrant of conjunctival involvement or ≤3 clock hours of limbal involvement), large (≤ 2 quadrants of conjunctival involvement or ≤6 clock hours of limbal involvement) and diffuse (>2 quadrants of conjunctival involvement or >6 clock hours of limbal involvement). Histopathology/impression cytology details and imaging scans were reviewed for all cases.

The topical IFNa2b drops, in a concentration of 1 million IU/ml, were prepared by the ocular pharmacology department of our centre via dilution of the injectable recombinant form (Reliferon, 3 million IU/0.5 ml) using preservative-free balanced salt solution. The patients were instructed to refrigerate the eye drops and use it four times a day. For perilesional injection, the preparation (3 million IU/0.5 ml) was directly injected using a tuberculin syringe and a 30-gauge needle through the adjacent normal conjunctiva, avoiding the tumor, into the subconjunctival space to achieve ballooning of conjunctiva all around the tumor. No more than 10 million IU were injected in any case. The patients on eye drops were followed every 6 weekly. The injections were repeated at 1 to 3 weekly intervals and were followed accordingly. In case of no response to IFNa2b therapy on two consecutive follow-ups, the treatment was stopped and alternative treatment was advised. After the complete resolution of tumor, maintenance therapy was given in the form of topical drops for another 1 month.

Complete response was defined as total disappearance of tumor clinically and absence of dysplasia on impression cytology. Partial response was defined as reduction in tumor size without complete disappearance. No response was defined as no change in the size of the tumor on two consecutive visits. The response to treatment, duration of treatment, recurrence or relapse, side effects and period of follow-up were noted. The treatment advised in cases of no response or partial response was also documented.

 

Results

A total of 51 patients of OSSN who were treated at our centre in one year were identified. Out of these, 24 eyes of 24 patients who were managed with IFNa2b therapy were included in the study. The median age of presentation was 60 years (range – 10 – 80 years). There was a male preponderance with a male:female ratio of 3:1. The risk factors included sunlight exposure in 50% cases (n=11), ocular trauma in 9% (n=2), ocular surgery in 9% cases (n=2), cigarette smoking in 13.6% (n=3) and immunosuppression in 4.5% (n=1). Fifty four percent (n=13) cases had a left sided involvement. A previous treatment history was present in 40% cases (n=10). History of surgery was present in 7 cases (2 cases were operated for pterygium and 5 cases for OSSN). Histopathological reports were available in 4 out of 7 patients and revealed well-differentiated squamous cell carcinoma in 3 cases and moderately differentiated carcinoma in 1 case.

The mean duration of symptoms was 2 ± 4.36 years. The tumor characteristics of 24 cases have been described in Table 1. Majority of tumors had a gelatinous appearance (62.5%) and a nodular growth pattern (62.5%). Based on the clinical characteristics, the AJCC grading of tumor included 1 eye (4.2%) in T1 and 23 eyes (95.8%) in T3. None of the cases had a regional lymph node involvement or a distant metastasis at presentation. Impression cytology and UBM examination was done in all except one pediatric patient. Impression cytology showed dysplasia in 65.2% (n=15/23) cases. Mean tumor height on UBM was 1.47± 1.43 mm and it ruled out any intraocular involvement. Associated ocular pathologies seen in the affected eye were senile ptosis (n=2) and lagophthalmos (n=1).The systemic associations found were xeroderma pigmentosum (n=1), human immunodeficiency virus (HIV) (n=1) and Berger’s disease (n=1).

Of 24 cases, 16 were treated with topical drops of IFNa2b (1 million IU/ml), 4 cases with sub-conjunctival injection of IFNa2b (3-6 million IU/ml) and 4 with combined topical and subconjunctival therapy of IFNa2b. One case was lost to follow-up. Thus, the tumour response in 23 cases were – complete regression in 19 cases (82.6%), partial regression in 1 case (4.4%) and no response in 3 cases (13%). Topical IFNa2b therapy had to be discontinued after 1 month of initiation in a single patient due to severe ocular surface congestion, thus rendering her intolerant to IFNa2b. In this case, despite the discontinuation of interferon drops complete resolution of tumor was seen on subsequent follow-up clinically as well as on impression cytology. All cases with partial or no response were fresh cases of small (< 1 quadrant) OSSN, falling in the AJCC T₃ category, and showed complete resolution on further treatment with topical mitomycin C. None of the patients required surgery. The median time to complete resolution in cases treated with topical interferon therapy was 3 months (range – 1 to 11 months) and in cases managed with injections or a combination of the two was 2.5 months (range – 0.7 to 3 months). The median duration of follow-up was 6.3 months (range – 2.5 to 11 months).

No side effects were reported in 15 out of 16 cases being treated with topical therapy. Acute congestion of the eye was seen in one patient. Patients receiving perilesional injection complained of local pain at the site of injection and fever/chills that were controlled with medications.

Spearman’s correlation coefficient was calculated between the duration of treatment and various parameters like age, previous treatment history, duration of complains, extent of limbal involvement, extent of conjunctival involvement and tumor staging. No significant correlation was noted between these parameters.

 

Discussion

In this retrospective study, we analyzed treatment outcome in cases of T₁, T₂ and T₃ OSSN who were treated with IFNa2b as topical therapy  and/or perilesional injection.

Interferons are naturally occurring glycoproteins that have anti-viral, anti-microbial and anti-neoplastic activity.²⁰ Its anti-neoplastic activity has been attributed to anti-proliferative effects, anti-angiogenic effects, cytotoxic effects and its ability to enhance the host anti-tumour surveillance mechanism.²¹IFNa2b is the recombinant form of interferon-alpha, and its use in OSSN is off-label based on scientific evidence. This formulation has been shown to be effective, both topically and as perilesional injection, for treating OSSN.^10-14

At our centre, the mode of administration of IFNa2b as eye drops/perilesional injection is based on tumor characteristics and patient profile. Topical drops are given in cases of large and diffuse OSSN and in patients who can maintain the cold chain and are compliant. Perilesional injections were preferred in cases with questionable compliance to topical therapy and in cases with recurrent OSSN cases. For topical therapy we chose a dosage of 1million IU/ml, as was recommended by Galor and associates in their study. ²⁴

Majority of the  tumors (16/24, 67%) in our study were large/diffuse tumors. A complete resolution of tumor was seen in 82.6% cases, which is comparable to studies reported in literature. ^{10-13, 15,25, 26} Sheilds et al reported a resolution rate of (72.2%) in ‘giant OSSN’ defined as more than 180 degrees of limbal involvement/more than 15mm basal diameter (majority of patients having invasive disease; 58% regressed completely with topical IFN-a2b, 100% with IFN-a2b injection alone/in combination of topical therapy). They reported a reduction in tumor size in rest of the cases, allowing for complete resolution with excision in this series. ¹⁷ In our study, 100% (9/9) of diffuse tumors regressed completely with immunotherapy. None of the patients in our study needed surgery for residual tumor.

The tumor response to interferons was unrelated to the size of the tumor. All the tumors that did not respond were small in size (height <2.2mm), while much thicker and diffuse tumors completely vanished with immunotherapy. Average height of tumours that responded to treatment was 1.95mm. The tumors that did not respond to interferons regressed completely with subsequent administration of mitomycin C.

Shields et al, in a retrospective case series, used IFN-a2b for immunotherapy in 22 patients and immunoreduction in 7patients. As immunotherapy IFNa2b alone achieved complete response in 75% Tis, in 100% T1 and in 70% T3. When combined with surgery complete control was possible in 100% cases (immunoreduction).¹⁶

The reported median time to clinical resolution of OSSN with interferons ranges from 1.5 months to 9 months depending the mode of administration and the tumor grade. In our study it was 2.5 months for injections and 3 months for topical therapy, which is comparable to that reported in literature.

IFN-a2b is extremely well tolerated with few reported side effects being ocular irritation, discomfort, photophobia, follicular conjunctivitis, punctate keratitis andcorneal epithelial defects. ^{11, 15, 16, 17, 24, 22, 27, 28} Flu like symptoms are often reported in patients receiving perilesional IFN-a2b as also seen in our cases.^{10, 16}In our study, one patient developed severe acute congestion of eye following topical IFNa2b eye drops, for which the IFNa2b therapy had to be discontinued.. This has probably not been reported before. However, it is interesting that this patient showed a dramatic resolution of tumor with just 3 weeks of immunotherapy.

We could not evaluate the clinical variables that may affect the treatment response to interferons, as the number of cases with poor/no response was very few. However, the factors that may influence the duration of treatment were evaluated. No significant correlation was found with AJCC tumor grading, tumor size, or clinical features including pigmentation, keratinisation, or tumor morphology. It is thought that the interferons improve the response to chemotherapy. Our study outcome supports this.

To conclude, in our study a complete regression was achieved in 82 % primary/ recurrent cases of OSSN with immunotherapy alone. With subsequent use of mitomycin C complete regression was achieved in 100% cases, avoiding the need of any surgery.

 

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Table 1- Summary of clinical features of 24 cases of OSSN

Clinical characteristics	Number of cases (%) N=24
Clinical appearance –          Gelatinous –          Pappiliform –          Ulcerative –          Fungating	15 (62.5) 8 (33.4) 1 (4.1) 0 (0)
Growth pattern –          Nodular –          Sessile –	15 (62.5) 9 (37.5)
Multiplicity –          Single –          Multiple	24 (100) 0 (0)
Structures involved –          Limbus –          Bulbar conjunctiva –          Tarsal conjunctiva –          Fornices –          Cornea –          Lid	20 (91) 18 (81.2) 3 (13.6) 5 (22.7) 18 (81.2) 3 (13.6)
Feeder vessels –          Present –          Absent	24 (100) 0 (0)
Leukoplakia –          Present –          Absent	6 (25) 18 (75)
Pigmentation –          Present –          Absent	5 (20.8) 19 (79.2)
Impression cytology –          Positive –          Negative –          Not Done (Paediatric patient)	15 (62.5) 8 (33.3) 1(4.2)
Based on the quadrant involvement –          Small –          Large –          Diffuse	8 (33.3) 7 (29.2) 9 (37.5)
Fresh/Recurrent –          Fresh –          Recurrent	17 (70.8) 7 (29.2)