Abstract
Medical therapy for ocular malignancies is an expanding field with increasing options for ocular surface malignancies. Epithelial, lymphoproliferative, and pigmented lesions of the conjunctiva now all have pharmacologic therapeutic options at the clinician’s disposal. Topical chemotherapy drops of interferon alpha-2b (IFNα-2b), 5-fluorouracil, and mitomycin have shown promising results as a primary therapy for ocular surface squamous neoplasia (OSSN). They have also been used as adjuvants to surgical excision. While these agents are the main medical agents for OSSN, retinoic acid, aloe vera, cidofovir, and anti-vascular endothelial growth factor have been tried with some success.
Pharmacological therapy for ocular and adnexal lymphoma is dependent on whether the disease is localized (unilateral or bilateral) or systemic. Local therapy has traditionally been radiotherapy, but local injections of rituximab and interferon have shown some success in small series. Systemic disease is treated with systemic chemotherapies, including monoclonal antibodies and radio-tagged monoclonal agents.
Pigmented lesions of the conjunctiva are life threatening, and surgery remains the mainstay of treatment. In cases of unresectable disease, and as adjuvants, medical therapies are needed. Mitomycin has an effect against pigmented cells. While imperfect, it reduces ocular surface pigmentation. The use of IFNα-2b has been reported with less success. Novel checkpoint inhibitors targeting programed cell death 1 (PD-1), such as pembrolizumab, have shown early potential for pigmented lesions of the ocular surface, but additional data is needed to understand their role in conjunctival melanoma.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Pe’er J. Ocular surface squamous neoplasia. Ophthalmol Clin N Am. 2005;18(1):1–13, vii.
Murillo JC, Galor A, Wu MC, Kye NK, Wong J, Ahmed IO, et al. Intracorneal and intraocular invasion of ocular surface squamous neoplasia after intraocular surgery: report of two cases and review of the literature. Ocul Oncol Pathol. 2017;3(1):66–72.
McClellan AJ, McClellan AL, Pezon CF, Karp CL, Feuer W, Galor A. Epidemiology of ocular surface squamous neoplasia in a veterans affairs population. Cornea. 2013;32(10):1354–8.
Gichuhi S, Sagoo MS, Weiss HA, Burton MJ. Epidemiology of ocular surface squamous neoplasia in Africa. Tropical Med Int Health. 2013;18(12):1424–43.
Nanji AA, Mercado C, Galor A, Dubovy S, Karp CL. Updates in ocular surface tumor diagnostics. Int Ophthalmol Clin. 2017;57(3):47–62.
Sayed-Ahmed IO, Palioura S, Galor A, Karp CL. Diagnosis and medical management of ocular surface squamous neoplasia. Expert Rev Ophthalmol. 2017;12(1):11–9.
Sepulveda R, Pe’er J, Midena E, Seregard S, Dua HS, Singh AD. Topical chemotherapy for ocular surface squamous neoplasia: current status. Br J Ophthalmol. 2010;94(5):532–5.
Adler E, Turner JR, Stone DU. Ocular surface squamous neoplasia: a survey of changes in the standard of care from 2003 to 2012. Cornea. 2013;32(12):1558–61.
Pe’er J. Ocular surface squamous neoplasia: evidence for topical chemotherapy. Int Ophthalmol Clin. 2015;55(1):9–21.
Tsatsos M, Karp CL. Modern management of ocular surface squamous neoplasia. Expert Rev Ophthalmol. 2014;8(3):287–95.
Houglum JE. Interferon: mechanisms of action and clinical value. Clin Pharm. 1983;2(1):20–8.
Shah SU, Kaliki S, Kim HJ, Lally SE, Shields JA, Shields CL. Topical interferon alfa-2b for management of ocular surface squamous neoplasia in 23 cases: outcomes based on American Joint Committee on Cancer classification. Arch Ophthalmol (Chicago III: 1960). 2012;130(2):159–64.
Karp CL, Galor A, Chhabra S, Barnes SD, Alfonso EC. Subconjunctival/perilesional recombinant interferon alpha2b for ocular surface squamous neoplasia: a 10-year review. Ophthalmology. 2010;117(12):2241–6.
Vann RR, Karp CL. Perilesional and topical interferon alfa-2b for conjunctival and corneal neoplasia11The authors have no proprietary interest in the development or marketing of any drug mentioned in this article. Ophthalmology. 1999;106(1):91–7.
Galor A, Karp CL, Chhabra S, Barnes S, Alfonso EC. Topical interferon alpha 2b eye-drops for treatment of ocular surface squamous neoplasia: a dose comparison study. Br J Ophthalmol. 2010;94(5):551–4.
Rishi P, Shields CL. Intralesional and topical interferon therapy following incomplete primary excision of ocular surface squamous neoplasia. Indian J Ophthalmol. 2016;64(6):460–1.
Arnaud P. Different interferons: pharmacology, pharmacokinetics, proposed mechanisms, safety and side effects. Rev Med Interne. 2002;23(4):449s–58s.
Aldave AJ, Nguyen A. Ocular surface toxicity associated with topical interferon alpha-2b. Br J Ophthalmol. 2007;91(8):1087–8.
Yeatts PR, Engelbrecht N, Curry CD, Ford JG, Walter KA. 5-Fluorouracil for the treatment of tntraepithelial neoplasia of the conjunctiva and cornea. Am Acad Ophthalmol. 2000;107(12):2191–5.
Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3(5):330–8.
Joag MG, Sise A, Murillo JC, Sayed-Ahmed IO, Wong JR, Mercado C, et al. Topical 5-fluorouracil 1% as primary treatment for ocular surface squamous neoplasia. Ophthalmology. 2016;123(7):1442–8.
Parrozzani R, Lazzarini D, Alemany-Rubio E, Urban F, Midena E. Topical 1% 5-fluorouracil in ocular surface squamous neoplasia: a long-term safety study. Br J Ophthalmol. 2011;95(3):355–9.
Midena E, Angeli CD, Valenti M, de Belvis V, Boccato P. Treatment of conjunctival squamous cell carcinoma with topical 5-fluorouracil. Br J Ophthalmol. 2000;84:268–72.
Venkateswaran N, Mercado C, Galor A, Karp CL. Comparison of topical 5-fluorouracil and interferon alfa-2b as primary treatment modalities for ocular surface squamous neoplasia. Am J Ophthalmol. 2018.
Yeatts RP, Ford JG, Stanton CA, Reed JW. Topical 5-fluorouracil in treating epithelial neoplasia of the conjunctiva and cornea. Ophthalmology. 1995;102(9):1338–44.
Verweij J, Pinedo HM. Mitomycin C: mechanism of action, usefulness and limitations. Anti-Cancer Drugs. 1990;1:5–13.
Singh P, Singh A. Mitomycin-c use in ophthalmology. IOSR J Pharm. 2013;3(1):12–4.
Frucht-Pery J, Sugar J, Baum J, Sutphin JE, Pe’er J, Savir H, et al. Mitomycin C treatment for conjunctival—corneal intraepithelial neoplasia. Ophthalmology. 1997;104(12):2085–93.
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.
Blasi MA, Maceroni M, Sammarco MG, Pagliara MM. Mitomycin C or interferon as adjuvant therapy to surgery for ocular surface squamous neoplasia: comparative study. Eur J Ophthalmol. 2018;28(2):204–9.
Siganos CS, Kozobolis VP, Christodoulakis EV. The intraoperative use of mitomycin-c in excision of ocular surface neoplasia with or without limbal autograft transplantation. Cornea. 2002;21(1):12–6.
Prabhasawat P, Tarinvorakup P, Tesavibul N, Uiprasertkul M, Kosrirukvongs P, Booranapong W, et al. Topical 0.002% mitomycin C for the treatment of conjunctival corneal intraepithelial neoplasia and squamous cell carcinoma. Cornea. 2005;24(4):443–8.
Ballalai PL, Erwenne CM, Martins MC, Lowen MS, Barros JN. Long-term results of topical mitomycin C 0.02% for primary and recurrent conjunctival-corneal intraepithelial neoplasia. Ophthalmic Plast Reconstr Surg. 2009;25(4):296–9.
Quebbeman EJ, Hoffman NE, Ausman RK, Hamid AA. Stability of mitomycin admixtures. Am J Hosp Pharm. 1985;42(8):1750–4.
Chen C, Louis D, Dodd T, Muecke J. Mitomycin C as an adjunct in the treatment of localised ocular surface squamous neoplasia. Br J Ophthalmol. 2004;88:17–8.
Frucht-Pery J, Rozenman Y, Pe’er J. Topical mitomycin-C for partially excised conjunctival squamous cell carcinoma. Ophthalmology. 2002;109(3):548–52.
Abraham LM, Selva D, Casson R, Leibovitch I. Mitomycin: clinical applications in ophthalmic practice. Drugs. 2006;66(3):321–40.
Lichtinger A, Pe’er J, Frucht-Pery J, Solomon A. Limbal stem cell deficiency after topical mitomycin C therapy for primary acquired melanosis with atypia. Ophthalmology. 2010;117(3):431–7.
Tunc M, Erbilen E. Topical cyclosporine-a combined with mitomycin C for conjunctival and corneal squamous cell carcinoma. Am J Ophthalmol. 2006;142(4):673–5.
Billing K, Karagiannis A, Selva D. Punctal-canalicular stenosis associated with mitomycin-C for corneal epithelial dysplasia. Am J Ophthalmol. 2003;136(4):746–7.
Bushue N, Wan YJ. Retinoid pathway and cancer therapeutics. Adv Drug Deliv Rev. 2010;62(13):1285–98.
Klaassen I, Braakhuis BJM. Anticancer activity and mechanism of action of retinoids in oral and pharyngeal cancer. Oral Oncol. 2002;38:532–42.
Muindi JRF, Frankel SR, Huselton C, DeGrazia F, Garland WA, Young CW, et al. Clinical pharmacology of oral all-trans retinoic acid in patients with acute promyelocytic leukemia. Cancer Res. 1992;52:2138–42.
Herbort CP, Zografos L, Zwingli M, Schoeneieh M. Topical retinoic acid in dysplastic and metaplastic keratinization of corneoconjunctival epithelium. Graefes Arch Clin Exp Ophthalmol. 1988;226:22–6.
Krilis M, Tsang H, Coroneo M. Treatment of conjunctival and corneal epithelial neoplasia with retinoic acid and topical interferon alfa-2b: long-term follow-up. Ophthalmology. 2012;119(10):1969–73.
Nanji AA, Sayyad FE, Karp CL. Topical chemotherapy for ocular surface squamous neoplasia. Curr Opin Ophthalmol. 2013;24(4):336–42.
Skippen B, Tsang H, Assaad N, Coroneo M. Rapid response of refractory ocular surface dysplasia to combination treatment with topical all-trans retinoic acid and interferon alfa-2b. Arch Ophthalmol. 2010;128(10):1368–9.
Harlev E, Nevo E, Lansky EP, Ofir R, Bishayee A. Anticancer potential of aloes: antioxidant, antiproliferative, and immunostimulatory attributes. Planta Med. 2012;78(9):843–52.
Damani MR, Shah AR, Karp CL, Orlin SE. Treatment of ocular surface squamous neoplasia with topical aloe vera drops. Cornea. 2015;34(1):87–9.
Zabawski EJJ, Cockerell CJ. Topical and intralesional cidofovir: a review of pharmacology and therapeutic effects. J Am Acad Dermatol. 1998;39(5):741–5.
Snoeck R, Wellens W, Desloovere C, Ranst MV, Neaesens L, De Clercq E, et al. Treatment of severe laryngeal papillomatosis with intralesional injections of cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine]. J Med Virol. 1998;54:219–25.
Sherman M, Feldman K, Farahmand S, Margolis TP. Treatment of conjunctival squamous cell carcinoma with topical cidofovir. Brief Rep. 2002;134(3):432–3.
Asena L, Dursun Altinors D. Topical bevacizumab for the treatment of ocular surface squamous neoplasia. J Ocul Pharmacol Ther. 2015;31(8):487–90.
Kim LA, D’Amore PA. A brief history of anti-VEGF for the treatment of ocular angiogenesis. Am J Pathol. 2012;181(2):376–9.
Finger PT, Chin KJ. Refractory squamous cell carcinoma of the conjunctiva treated with subconjunctival ranibizumab (Lucentis): a two-year study. Ophthalmic Plast Reconstr Surg. 2012;28(2):85–9.
Paul S, Stone DU. Intralesional bevacizumab use for invasive ocular surface squamous neoplasia. J Ocul Pharmacol Ther. 2012;28(6):647–9.
Faramarzi A, Feizi S. Subconjunctival bevacizumab injection for ocular surface squamous neoplasia. Cornea. 2013;32(7):998–1001.
Pozarowska D, Pozarowski P. The era of anti-vascular endothelial growth factor (VEGF) drugs in ophthalmology, VEGF and anti-VEGF therapy. Cent Eur J Immunol. 2016;41(3):311–6.
Hartmann EM, Ott G, Rosenwald A. Molecular biology and genetics of lymphomas. Hematol Oncol Clin North Am. 2008;22(5):807–23, vii.
Sassone M, Ponzoni M, Ferreri AJ. Ocular adnexal marginal zone lymphoma: clinical presentation, pathogenesis, diagnosis, prognosis, and treatment. Best Pract Res Clin Haematol. 2017;30(1–2):118–30.
Shields CL, Shields JA. Conjunctival lymphoid tumors clinical analysis of 117 cases and relationship to systemic lymphoma. Ophthalmology. 2001;108:979–84.
Viani GA, Fendi LI. Adjuvant treatment or primary topical monotherapy for ocular surface squamous neoplasia: a systematic review. Arq Bras Oftalmol. 2017;80(2):131–6.
Blasi MA, Tiberti AC, Valente P, Laguardia M, Sammarco MG, Balestrazzi A, et al. Intralesional interferon-alpha for conjunctival mucosa-associated lymphoid tissue lymphoma: long-term results. Ophthalmology. 2012;119(3):494–500.
Lachapelle KR, Rathee R, Kratky V, Dexter DF. Treatment of conjunctival mucosa-associated lymphoid tissue lymphoma with intralesional injection of interferon alfa-2b. Arch Ophthalmol (Chicago, III: 1960). 2000;118:284–5.
Cerny T, Borisch B, Introna M, Johnson P, Rose A. Mechanism of action of rituximab. Anti-Cancer Drugs. 2002;13(Suppl 2):3–10.
Sein J, Stefanovic A, Karp CL. Diagnosis and treatment of conjunctival lymphoma. EyeNet. 2012;16(9):41-43. https://www.aao.org/eyenet/article/diagnosis-treatment-of-conjunctival-lymphoma.
Annibali O, Chiodi F, Sarlo C, Cortes M, Quaranta-Leoni FM, Quattrocchi C, et al. Rituximab as single agent in primary MALT lymphoma of the ocular adnexa. Biomed Res Int. 2015;2015:895105.
Tuncer S, Tanyildiz B, Basaran M, Buyukbabani N, Dogan O. Systemic rituximab immunotherapy in the management of primary ocular adnexal lymphoma: single institution experience. Curr Eye Res. 2015;40(8):780–5.
Ferreri AJ, Govi S, Colucci A, Crocchiolo R, Modorati G. Intralesional rituximab: a new therapeutic approach for patients with conjunctival lymphomas. Ophthalmology. 2011;118(1):24–8.
Demirci H, Kauh CY, Rajaii F, Elner VM. Intralesional rituximab for the treatment of recurrent ocular adnexal lymphoma. Ophthalmic Plast Reconstr Surg. 2017;33(3S Suppl 1):S70–S1.
Biotti D, Lerebours F, Bonneville F, Ciron J, Clanet M, Brassat D. Late-onset neutropenia and neurological relapse, during long-term rituximab therapy in myelin oligodendrocyte glycoprotein-antibody spectrum disorder. Mult Scler. 2018:1352458518765677.
Yi JH, Kim SJ, Ahn HK, Lee SJ, Chang MH, Kim WS. Rituximab-induced acute thrombocytopenia: a case report and review of the literature. Med Oncol. 2009;26(1):45–8.
Oellers P, Savar A, Samaniego F, Pro B, Esmaeli B. Second-line 90Yttrium-ibritumomab tiuxetan (Zevalin) in a patient with conjunctival mucosa-associated lymphoid tissue lymphoma refractory to rituximab. Ophthalmic Plast Reconstr Surg. 2012;28(6):e145–6.
Esmaeli B, McLaughlin P, Pro B, Samaniego F, Gayed I, Hagemeister F, et al. Prospective trial of targeted radioimmunotherapy with Y-90 ibritumomab tiuxetan (Zevalin) for front-line treatment of early-stage extranodal indolent ocular adnexal lymphoma. Ann Oncol. 2009;20(4):709–14.
Witzig TE, Flinn IW, Gordon LI, Emmanouilides C, Czuczman MS, Saleh MN, et al. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. J Clin Oncol. 2002;20(15):3262–9.
Wiseman GA, White CA, Stabin M, Dunn WL, Erwin W, Dahlbom M, et al. Phase I/II 90Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) radioimmunotherapy dosimetry results in relapsed or refractory non-Hodgkin’s lymphoma. Eur J Nucl Med. 2000;27(7):766–77.
Govi S, Dognini GP, Licata G, Crocchiolo R, Resti AG, Ponzoni M, et al. Six-month oral clarithromycin regimen is safe and active in extranodal marginal zone B-cell lymphomas: final results of a single-centre phase II trial. Br J Haematol. 2010;150:226–48.
Ferreri AJ, Sassone M, Kiesewetter B, Govi S, Scarfo L, Donadoni G, et al. High-dose clarithromycin is an active monotherapy for patients with relapsed/refractory extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT): the HD-K phase II trial. Ann Oncol. 2015;26(8):1760–5.
Peters DH, Clissold SP. Clarithromycin. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic potential. Drugs. 1992;44(1):117–64.
Griffin MO, Fricovsky E, Ceballos G, Villarreal F. Tetracyclines: a pleitropic family of compounds with promising therapeutic properties. Review of the literature. Am J Physiol Cell Physiol. 2010;299(3):C539–48.
Han JJ, Kim TM, Jeon YK, Kim MK, Khwarg SI, Kim CW, et al. Long-term outcomes of first-line treatment with doxycycline in patients with previously untreated ocular adnexal marginal zone B cell lymphoma. Ann Hematol. 2015;94(4):575–81.
Ferreri AJ, Ponzoni M, Guidoboni M, Resti AG, Politi LS, Cortelazzo S, et al. Bacteria-eradicating therapy with doxycycline in ocular adnexal MALT lymphoma: a multicenter prospective trial. J Natl Cancer Inst. 2006;98(19):1375–82.
Bryant SG, Fisher S, Kluge RM. Increased frequency of doxycycline side effects. Pharmacotherapy. 1987;7(4):125–9.
Jakobiec FA, Folberg R, Iwamoto T. Clinicopathologic characteristics of premalignant and malignant melanocytic lesions of the conjunctiva. Ophthalmology. 1989;96(2):147–66.
Damato BE, Coupland SE. Ocular melanoma. Saudi J Ophthalmol. 2012;26(2):137–44.
Shields CL, Shields JA. Tumors of the conjunctiva and cornea. Surv Ophthalmol. 2004;49(1):3–24.
Shields CL, Markowitz JS, Belinsky I, Schwartzstein H, George NS, Lally SE, et al. Conjunctival melanoma: outcomes based on tumor origin in 382 consecutive cases. Ophthalmology. 2011;118(2):389–95 e1–2.
Wong JR, Nanji AA, Galor A, Karp CL. Management of conjunctival malignant melanoma: a review and update. Expert Rev Ophthalmol. 2014;9(3):185–204.
Kurli M, Finger PT. Topical mitomycin chemotherapy for conjunctival malignant melanoma and primary acquired melanosis with atypia: 12 years’ experience. Graefes Arch Clin Exp Ophthalmol. 2005;243(11):1108–14.
Pe’er J, Frucht-Pery J. The treatment of primary acquired melanosis (PAM) with atypia by topical Mitomycin C. Am J Ophthalmol. 2005;139(2):229–34.
Finger PT, Czechonska G, Liarikos S. Topical mitomycin C chemotherapy for conjunctival melanoma and PAM with atypia. Br J Ophthalmol. 1998;82:476–9.
Chalasani R, Giblin M, Conway RM. Role of topical chemotherapy for primary acquired melanosis and malignant melanoma of the conjunctiva and cornea: review of the evidence and recommendations for treatment. Clin Exp Ophthalmol. 2006;34(7):708–14.
Huerva V, Traveset AE, Vilardell F. Topical interferon alpha-2b for diffuse conjunctival primary acquired melanosis with atypia. Ocul Immunol Inflamm. 2017;25(2):284–6.
Finger PT, Sedeek RW, Chin KJ. Topical interferon alfa in the treatment of conjunctival melanoma and primary acquired melanosis complex. Am J Ophthalmol. 2008;145(1):124–9.
Garip A, Schaumberger MM, Wolf A, Herold TR, Miller CV, Klingenstein A, et al. Evaluation of a short-term topical interferon alpha-2b treatment for histologically proven melanoma and primary acquired melanosis with atypia. Orbit. 2016;35(1):29–34.
Herold TR, Hintschich C. Interferon alpha for the treatment of melanocytic conjunctival lesions. Graefes Arch Clin Exp Ophthalmol. 2010;248(1):111–5.
Oellers P, Karp CL. Management of pigmented conjunctival lesions. Ocul Surf. 2012;10(4):251–63.
Bratton EM, Knutsen-Larson S, Durairaj VD, Gregory DG, Mellette JR. Combination topical therapy for conjunctival primary acquired melanosis with atypia and periocular lentigo maligna. Cornea. 2015;34(1):90–3.
Kini A, Fu R, Compton C, Miller DM, Ramasubramanian A. Pembrolizumab for recurrent conjunctival melanoma. JAMA Ophthalmol. 2017;135(8):891–2.
Dalvin LA, Shields CL, Orloff M, Sato T, Shields JA. Checkpoint inhibitor immune therapy systemic indications and ophthalmic side effects. Retina. 2018;38:1063–78.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Al Bayyat, G., Arreaza-Kaufman, D., Galor, A., Pe’er, J., Karp, C.L. (2019). Pharmacotherapy for Conjunctival Malignancies. In: Pe'er, J., Singh, A., Damato, B. (eds) Clinical Ophthalmic Oncology. Springer, Cham. https://doi.org/10.1007/978-3-030-06046-6_20
Download citation
DOI: https://doi.org/10.1007/978-3-030-06046-6_20
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-06045-9
Online ISBN: 978-3-030-06046-6
eBook Packages: MedicineMedicine (R0)