Treating Conjuctival Ocular Surface Squamous Neoplasia

Treating Conjuctival Ocular Surface Squamous NeoplasiaINTERFERONTopical MMC and 5-fluorouracil substantiate been used to curb payoff rates when used as an adjunct to working(a) undercut and as a primary intercession however, their use can be associated with mark opthalmic surface toxicity. Topical (1.000.000 IU/ ml/ four-spot times a day) or subconjuctival INF alfa 2b (3 million IU/ml/ weekly) have been employed to treat CIN. In general, local INF important-2b is well tolerated. Subconjunctival administration presents more than side effects as flu-like symptoms ( wear out, fever, myalgias, malaise) and mild liver disturbancesi. Local conjunctival jibe and follicular conjunctivitis are the just about frequently reported side effects 17 after local administration. Redness and increase of CIN volume without optic discomfort have been reported in a caseii. Fine, diffuse, devolve epithelial microcysts in the cornea after instillation of local interferon a-2b have recentl y documented in other caseiii Topical INF alpha 2-b, sometimes combine with subconjunctival INF alpha 2-b, seems to be effective as primary treatment for CIN, in recurrent cases, and also in retreatment after takings when INF has been used antecedently for a short power point of time. Approximately, 9% of CIN interact with subconjunctival and/or local INF alpha 2b showed recurrences, and 33 % of them were successfully retreated with local IFN alpha 2b91. For INF alpha 2b topical treatment, the average time to pick up tumor response is 11 weeks (range 2-59). For INF alpha 2b subconjunctival and topical treatment, the average time to complete tumor response is 5.5 weeks (range 2-12),91. Previous studies plant the same observationiv.The time to clinical resolution using topical INF alpha 2-b was longer (11.6 weeks) that the combined intralesional and topical interferon (4.5 weeks), but that INF alpha 2b treatment involved few side effects. In general, it seems that the disadv antage with topical treatment is the long duration. We must emphasize the importance of long term follow-up for CIN patients because recurrences can occur anyplace from 33 days to 11.5 yearsv, although most recurrent CIN occurs within 2 years of initial excisionvi. Many surgeons add adjunctive topical therapy to their surgical regimens for larger lesions100. However, entirely sizes of lesions could be treated with topical INF alpha as the primary treatment because it is an effective, non-invasive treatment alternative to surgery that increases quality of life with low costsvii. Actually, no clear consensus on the best federal agency to manage the disorder has been established, because long-term, well designed studies are still needed. However, two recent studies have addressed the above questions and support the effectiveness of this topical therapy for CIN. The first study 17 demonstrated total resolution of the tumor in 96.4% of cases treated with INF alfa 2b with a mean follo w-up of 42.4 months. The reciprocal ohm study viiidemonstrated that topical treatment with INF and surgical excision have the same effectiveness as primary treatment for CIN for a mean follow-up of 35.6 months. The authors cerebrate that topical IFN alfa-2b and aggressive surgical excision can be considered equally effective as first select for treating CIN. Topical INF alfa-2b has some advantages over established excision, including the reduction of risk to loose limbal stem cells secondary to surgical trauma and, thus, compromising the integrity of the ocular surface. This therapeutic mode can be recommended curiously for patients who reject any type of surgery, or mentally retarded patients in whom surgery is complicated as well as extended cases where an aggressive excision could cause the loss of limbal stem cells94. Topical INF or subconjunctival INF remains a controversial issue. A recent report 103 concluded that subconjunctival 0.5 ml injection of 3 million IU IFN alfa 2b is a viable medical alternative for the treatment of ocular surface squamous neoplasia (OSSN) with a mean duration of follow-up of 55 months. The authors state that the advantages of perilesional INF alfa 2b injection include more rapid tumor resolution, ensured compliance, and perhaps more direct deli very to the tumor site when compared with topical INF drops. However, some patients may be upset about receiving injections roughly the eye and may prefer eye drops. A single weekly injection of INF may have better compliance than 4 eye-drops per day dosing for a mean of three months in many patients. Direct delivery to the tumor site may occur in well-localized lesions, while ring-shaped lesions or multifocal disease requires injection over the entire involved area, Increasing the risk of conjunctival haemorrhage. By contrast, topical therapy is delivered to the entire ocular surface and has very good success rates. Topical therapy could be recommended for patients who reject a ny surgical procedure or those who are apprehensive about injections.. Weekly subconjunctival INF alpha 2b strength be an alternative in resistant cases of CIN or recurrent conjunctival papillomatosis avoiding a mutilating surgeryix x A low-molecular weight glycoprotein, produced by leukocytes, has antineoplastic and antiviral properties. It slows the cellular addition cycle and enhances the bodys immune response against tumor cells. The FDA has approved IFN-a2b for the treatment of several conditions, including hairy cell leukemia. IFN-a2b therapy can be utilized as topical drops or subconjunctival injections. With drops, clinical resolution usually takes place with a mean time of about 12 weeks. Subconjunctival injection in addition topical IFN-a2b helps to initiate non-invasive effective treatment for CCIN with faster resolution time i.e. 6 weeks. In one study, the overall response rate was 96.4 share, and the recurrence rate was 3.7 percent after one year. The regime for topi cal IFN-a2b drops with a concentration of 1 million IU/mL (1 M.I.U) or 3 million IU/mL (3 M.I.U), applied four times daily or through subconjunctival route via injections as 3M.I.U million IU/0.5 mL, administered weekly. No significant clinical impact has been demonstrated on window pane difference. When tending(p) in topical form, IFN-a2b is generally well tolerated and has minimum side effects. However the systemic effects reported so far include, mild fever, myalgia and fatigue especially after subconjunctival injections. This s can be well managed with ibuprofen. Topical IFN-A2b therapy is somehow gentle to ocular surface in terms of minimum do drugs epitheliopathy and patients have better compliance to IFN-A2b drops when compared to other topical chemotherapeutic agents , even if used for 12 weeks or more. No punctal plugs are needed.In summary, interferon -2b is better alternative alternative for topical chemotherapy that has been used in patients with CCIN .This therapy ap pears to provide results similar to topical chemotherapy but may be less toxic to the normal epithelium or the cornea and conjunctiva. early(a) TREATMENT OPTIONSOther treatment options in the forethought of conjuctival OSSN include topical retinoids,cidofovir and photodynamic therapy (PDT). Topical unguent of trans-reinoic acid (0,01%)showed complete resolution of CIN in 20% of cases, whereas 40% showed only partialresponsexi. This treatment may be then only adjuvant to surgery Regression of diffuse conjunctival CIN was demonstrated following a 6 week course of topical cidofovir eye drops (2.5 mg/ml) with later residual lesion after surgical excisionxii.Following PDT, using verteporfin, a complete clinical CIN regression, support with angiographic evidence, has been reported at 1 month, without any recurrence for a mean follow-up of 8.6 monthsxiii. Likewise, histopathological evidence showing tumor regression following treatment with PDT in a patient with in situ CIN has been repor tedxiv.MATERIALS AND METHODSOur study is a single centered descriptive case series and was carried out at department of ophthalmology, Lahore General Hospital, a tertiary care hospital affiliated with Post Graduate Medical Institute (PGMI) Lahore from March 2014 to August 2014. A total of 150 cases were operated upon during the study period and all the cases were reviewed for at least six months to look for signs of recurrence. All the patients were pre operatively examined on slit lamp and those patients with either a pterygium or inflamed eyes or with previously excised and treated suspicious growths were excluded from the study. The risks and benefits of the study were discussed with the patients. Personal profile of the patients along with the contact numbers of the patients was noted. All the data was recorded on a pre-designed proformaDISCUSSIONOcular surface squamous neoplasia (OSSN) is a spectrum of disease, on which few of the large series have been documented to address th e role of chemotherapy and immunotherapy for the treatment of ocular surface squamous cell neoplasia, none in particular from the Pakistan, especially the role of interferon therapy in management of OSSN.As the CCIN is highly recurrent tumors, many queryers have made efforts to set out a treatment modality with minimum invasive therapy and side effects to treat OSSN. In our study the rate of recurrence was which is quiet similar to the results in achieved in one study105 i.e rate of recurrence was 10.9% and and 5-year recurrence rate was 18.5%xv and the most significant factors found to result recurrence were tumor size and first treatment given. However, surprisingly grading invasiveness of disease and positive margins for tumor were found less statistically significant in tumor recurrence. In contribution with ongoing research as the primary treatment therapy to treat OSSN, the interferon has proved to be most reliable drug in terms of controlling the tumor growth, preventing i ts recurrence and preserving the ocular surface with minimal side effects. The mitomycinC (MMC) 0.02%-0.04% is still being used for the treatment of OSSN as a part of topical therapy because of its role in lowering the recurrence rate. The standard treatment for CCIN is surgical. Due to the risk of recurrence and depending on the tumor free margins, adjuvant treatment like chemotherapy, cryotherapy and even radiotherapy has been used. Topical 5-fluorouracil and MMC have been used to minimize recurrence when used as an adjunct to surgical excision however, their use even in the topical formulation can be associated with ocular surface toxicity. Thus, intervention with interferon alpha 2b to treat the tumor established medical regime and thus alternative to surgical procedures for the treatment of CIN with more benefits, especially in reducing tumor recurrence, and multiple surgies can be avoided. This new chemotherapeutic drug is being used to avoid visits of the operation theatre an d is effectual in decreasing the potential risk of stem cell loss and scarring of limbal area. Till to date, there are no comparative studies of this topical regime combined with surgical resection, cryotherapy and additional chemotheray in the literature. This therapy is especially recommended in conditions where patients deny undergoing any surgical procedure, patient is mentally retarded and also in patients with extensive engagement of tumor ,when to perform a surgery seems difficult, and in advanced cases where a surgical procedure may result in limbal stem cell depletion. As the role of interferon in previous studies to reduce recurrence is demonstrated, it has a substantial advantage in excising new tumor. The clinician and patient should outweigh the, duration of treatment, cost of therapy and manageable side effects while deciding to initiate the primary treatment of CIN with INF alpha 2b. Topical interferon is well tolerated in terms of lower epithelial toxicity. Howeve r, via Subconjunctival route, encounters more side effects. In a study, four of seven patients reported local conjunctival injection and follicular conjunctivitis but It was established, however, the folliculitis most likely resulted from vehicle, which contained glycerol benzyl alcohol 0.09%,, and human albumin, and not the INF alpha 2b itselfxvi. Topical INF alpha 2b, added with subconjunctival INF alpha 2b, seems to be effective as primary treatment for CIN, in recurrent cases but also in recurrent cases where interferon has been used previously for a short time.six patients out of 66 treated with subconjunctival and/or topical INF alpha 2b had recurrences. Two of them were successfully retreated with topical INF alpha 2b. Another one achieved complete remission after intra- and perioperative MMC.For INF alpha 2b topical treatment, the average time to complete tumor response was 11weeks (range, 2-59). The average follow-up was 13.3months (range, 3-40), and only three patients ou t of 45 had recurrences. One of them was successfully retreated with topical INF alpha 2b.For INF alpha 2b subconjunctival and topical treatment, the average time to complete tumor response was 5.5weeks (range, 2-12). The average follow-up was 22.5months (range, 7.2-91), and only three patients out of 21 had recurrences. One of them was successfully retreated with topical INF alpha 2b. Another one achieved complete remission after intra- and perioperative MMC.Karpet al.xviidescribed the time for clinical resolution using INF alpha 2b was much longer (11.6weeks) than in their take previous studyxviiiin which they combined intralesional and topical interferon (4.5weeks), and also reported that INF alpha 2b treatment resulted in fewer side effects. One recurrence after treatment with 2weeks of INF alpha 2b was newly treated with topical INF alpha 2b for 8months with successxix. In general, it seems that the disadvantage of this form of treatment is the long duration. The only safe met hod of gauging when to stop the treatment is the disappearance of the lesion in the slit lamp examination. However the latest modality to search for early recurrence is based on ultra high-resolution anterior segment opthalmic coherence tomography in the diagnosis and management of ocular surface squamous neoplasiaxx. Therefore, It is important to emphasize to council the patients for the importance of long-term follow-up for CIN patients because recurrences can occur anywhere from 33days to 11.5yearsxxi, although most recurrent CIN occurs within 2years of initial excisionxxii. The mode of onset of the tumor can even masquerade as pterygium without giving any clue of clinical suspicion and the biopsies of the recurrent pterygium have shown to be squamous cell carcinoma on histopathology. So, every specimen of pterygium should be investigated for histopathologic examination and biopsies where OSSN is found should be examined more frequently for suppuration of clinical signs of OSSN , hence identified and treated at an early stagexxiii. To determine the judicious dosage of using interferon relative to the tumor size, Vann and Karpxxivfound efficacy relationship which was dose dependent achieved with the cumulative administration of topical therapy and subconjunctival injection for the treatment of CIN. Chenet al.xxv suggested that additive therapy with INF alpha 2b may be needed for all lesions to lower the recurrence, particularly if surgical excision seems not to ensure tumor-free margins in large sized tumors, topical INF alpha 2b may result in limited tumor regression due(p) to lack of insufficient drug penetration. However instead of introducing large dose of intralesional INF alpha 2b, excisional biopsy to decrease tumor mass should be performed. The larger lesions require repeat subconjunctival/perilesional injections, but it is suggested that smaller or residual lesions can be managed with topical therapy alone. Other authors have described the effect of tumor size on the choice of therapyxxvi. Many surgeons advise additional topical therapy to their surgical regimens for larger lesionsxxvii and the topical IFN-alpha2b plays effective role for recurrent tumors as it avoids the risks of further destruction to stem cells around limbus as mostly other agents and surgical excision result .However, If biopsy exhibits invasiveness at any stage, topical therapy is contraindicated, surgical excision should be performedxxviii.However, when there is a recurrence after INF alpha 2b treatment, an alternative could be intraoperative MMC, as described by Hawkinset al xxix. In our experienceall lesion with large tumor size can be treated with topical interferon as the primary therapy because of its effectiveness, non-invasiveness, and an alternative regime avoiding surgery that enhances quality of life and is also cost effective. Today, no clear consensus on the best way to manage the disorder has been established, because long-term, well-desi gned studies are still needed.iiiiiiivvviviiviiiixxxixiixiiixivxv Maudgil A,Patel T,Rundle P,Rennie IG,Mudhar HS- Ocular surface squamous neoplasia analysis of 78 cases from a UK ocular oncology centre.Br J Ophthalmol 97 (12) 1520-4xvi Schechter BA, Schrier A, Nagler RS, SmithEF, Velasquez GE. Regression of presumed primary conjunctival and corneal intraepithelial neoplasia with topical interferon alpha-2b. Cornea, 2002216-11.xvii Karp CL, Moor JK, Rosa RH Jr. Treatment of conjunctival and corneal intraepithelial neoplasia with topical interpferon alpha-2b. Ophthalmology, 20011081093-8.xviii Vann RR, Karp CL. Perilesional and topical interferon alfa 2b for conjuntival and corneal neoplasia. Ophthalmology, 199910691-7.xix Morgenstern KE, Givan J, Wiley LA. Long-term adminstration of topical interferon alfa-2b in the treatment of conjunctival squamous papilloma. Arch Ophthalmol, 20031211052-3.xx Thomas BJ,Galor A,Nanji AA,El Sayyad F,Wang J,Dubovy SR,Joag MG,Karp CL- Ultra high-reso lution anterior segment optical coherence tomography in the diagnosis and management of ocular surface squamous neoplasia. Ocul Surf 12 (1) 46-58xxi Tabin G, Levin S, Snibson G, LoughnanM, Taylor H. Late recurrences and the necessity for long-term follow-up in corneal and conjunctival intraepithelial neoplasia. Ophthalmology, 1997104485-92.xxii Schechter BA, Nagler RS, Schrier A. Recurrent intraepithelial neoplasia treatment. Ophthalmology, 20051121319.xxiii Pterygium and associated ocular surface squamous neoplasia.Hirst LW,Axelsen RA,Schwab I- Arch. Ophthalmol. 127 (1) 31-2xxiv Vann RR, Karp CL. Perilesional and topical interferon alfa 2b for conjuntival and corneal neoplasia. Ophthalmology, 199910691-7.xxv Chen HC, Chang SW, Huang SF. Adjunctive treatment with interferon alpha-2b may decrease the risk of papilloma-associated conjunctival intraepithelial neoplasm recurrence. Cornea, 200423726-9.xxvi Stone DU, Butt AL, Chodosh J. Ocular surface squamous neoplasia. Cornea, 20052 4297-300xxvii Stone DU, Butt AL, Chodosh J. Ocular surface squamous neoplasia. Cornea, 200524297-300.xxviii Holcombe DJ,Lee GA- Am. J. Ophthalmol. opical interferon alfa-2b for the treatment of recalcitrant ocular surface squamous neoplasia 142 (4) 568-71xxix Hawkins AS, Yu J, Hamming NA, Rubenstein JB. Treatment of recurrent conjunctival papillomatosis with mytomycin C. Am J Ophthalmol, 1999128638-40.