Conjunctival tumors include a large spectrum of disease involving

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1 REVIEW ARTICLe Pharmacotherapy and Immunotherapy of Conjunctival Tumors Edoardo Midena, MD, PhD,* Luisa Frizziero, MD,* and Raffaele Parrozzani, MD, PhD* Abstract: Conjunctiva and cornea tumors represent a large spectrum of conditions ranging from benign lesions to aggressive and life-threatening malignancies. Topical pharmacotherapies and immunotherapies have recently acquired a relevant role in the management of conjunctival tumors and, in the past decades, there has been a shift from surgery alone toward the use of these agents, both as a sole therapy or as adjunct to surgery (before or after surgery). The main agents that have been used for topical medical treatment of conjunctival tumors are mitomycin C, -fluorouracil, and interferon-αb. Advantages of topical pharmacotherapies and immunotherapies include the ability to treat the entire ocular surface and prevention of surgical side effects and complications. The aim of this review is to summarize the current use of topical pharmacotherapy and immunotherapy in the management of conjunctival tumors. Key Words: conjunctiva, cornea, management of conjunctival tumors, topical pharmacotherapies, immunotherapy (Asia-Pac J Ophthalmol ;6: ) Conjunctival tumors include a large spectrum of disease involving the ocular surface (the conjunctiva and the cornea), characterized by different biological and clinical characteristics and behavior. Although surgical excision remains the standard treatment modality for most conjunctival malignancy, in the past decades the introduction of topical chemotherapy has rapidly changed the therapeutic approach to these lesions. Topical chemotherapy has several advantages when compared with standard surgical excision, including treatment of the entire ocular surface, targeting of the tumor cells, simplicity of treatment, reduced cost associated with avoidance of the surgical approach, and reduced patient morbidity. Topical chemotherapy is actually used as an adjuvant treatment (after surgery, to reduce the risk of recurrences), as a neoadjuvant treatment (before surgery, to reduce the dimension of the tumor before its surgical excision), or as a sole treatment., Three main drugs are currently used for topical chemo- and immunotherapy of conjunctival tumors: mitomycin C (MMC), used for both pigmented [conjunctival melanoma and From the *Department of Ophthalmology, University of Padova, Padova; and G.B. Bietti Foundation, IRCCS, Ocular Oncology and Toxicology Research Unit, Rome, Italy. Received for publication February, ; accepted March,. F. B. was supported by Ministry of Health and Fondazione Roma. The authors have no other funding or conflicts of interest to declare. Reprints: Edoardo Midena, MD, PhD, Department of Ophthalmology, University of Padova, Via Giustiniani,, Padova, Italy. E mail: edoardo.midena@ unipd.it. Copyright by Asia Pacific Academy of Ophthalmology ISSN: 6-99 DOI:.6/APO. primary acquired melanosis (PAM)] and nonpigmented [ocular surface squamous neoplasia (OSSN)] epithelial tumors; -fluorouracil (-FU), whose use is reserved for nonpigmented epithelial lesions (OSSN); interferon-αb (IFN-αb), used for both pigmented (conjunctival melanoma, PAM) and nonpigmented (OSSN) epithelial tumors, and also for conjunctival mucosaassociated lymphoid tissue (MALT) non-hodgkin lymphoma. The aim of this review is to summarize the current trend in the use of topical pharmacotherapy and immunotherapy for the treatment of conjunctival tumors. MATERIALS AND METHODS To identify potentially relevant articles in the medical literature, we searched MEDLINE for English language articles published from January 9 to December, 6. MEDLINE was queried using the following search terms (used both individually and in combination for advanced research): pharmacotherapy, chemotherapy, immunotherapy, topical chemotherapy, local chemotherapy, mitomycin C (MMC), -fluorouracil (-FU), interferon (IFN), conjunctival neoplasm, conjunctival tumor, primary acquired melanosis, conjunctival melanoma, conjunctival squamous cell carcinoma (SCC), ocular surface squamous neoplasia, conjunctival lymphoma, conjunctival mucosa-associated lymphoid tissue lymphoma, conjunctival dysplasia, and conjunctival intraepithelial neoplasia (). Additional articles were identified by reviewing the references of examined publications. To identify potentially relevant articles to include in this review, investigators reviewed each paper. Case series were preferred to single-case reports. Articles included in the reference list were fully examined by the authors. TOPICAL CHEMOTHERAPY OF CONJUNCTIVAL TUMORS Mitomycin C Mitomycin C is an antibiotic isolated from Streptomyces caespitosus acting as an alkylating agent, affecting the cells during all phases of the cell cycle. Mitomycin C binds to nuclear D leading to irreversible cross-linking and inhibition of nucleotide synthesis. Mitomycin C seems to be toxic to both proliferating and nonproliferating cells. It is soluble in water and organic solvents and in aerobic conditions, as in topical application, MMC can also generate free radicals, causing direct cytotoxicity by D and protein damage via lipid peroxidation., Its biologic effect on conjunctival tumors is enhanced by D(P)H quinone oxidoreductase (NQO), a bioactivating enzyme for MMC that is present in conjunctival and corneal epithelial tumors, mainly in OSSN., Mitomycin C eyedrops need light protection and

2 Midena et al Table. Summary of Selected Clinical Studies on the Use of Topical MMC as a or Treatment of Conjunctival PAM MMC Dosage Frucht-Pery et al 6 Finger et al * Salomao et al Demirci et al 9 Kemp et al Shields et al Kopp et al Kurli et al Pe er et al Khong et al Hung et al 6 Lichtinger et al Russel et al Ghassemi et al 9 9 primary adjuvant primary 6 6 adjuvant primary 6 6 adjuvant 69 primary adjuvant..6 (means) 6 primary neoadjuvant, successive treatment with IFN-αb.%.%.%.%.% QID for weeks : QID, weeks : no response (MM), progression to MM (PAM) : QID, week : no recurrences QID for weeks or weeks ( ) : QID, weeks on, weeks off () : QID, week QID, weeks on, weeks off, weeks on QID, week on, week off (6) QID, weeks (up to 6 cycles) QID, weeks on, weeks off () QID, weeks on, weeks off ( ) QID, week on, week off () QID, days on, days off () QID, weeks on, weeks off () QID, weeks on, weeks off, no response, weeks on recurrences QID, weeks on, week off, weeks on, week off, week on, month off () MM indicates malignant melanoma;, not applicable; QID, quater in die, times a day. *Histological diagnosis of malignant melanoma versus primary acquired melanosis not fully delineated. Cycle duration modified from original plan due to ocular surface toxicity. Two patients received only a partial treatment with.% MMC. should be stored at room temperature ( C) for up to week or refrigerated ( C) for up to months with preservation of 9% of activity. The Use of Mitomycin C in Acquired Melanosis Several authors reported the use of MMC in melanocytic premalignant (Table ) and malignant (Table ) lesions of the conjunctiva, both as sole therapy or as neoadjuvant or adjuvant treatment, along with in the treatment of recurrences. 6 The most common dose and therapeutic regimen consists of MMC eye drops (. mg/ml) used times per day for consecutive days ( cycle), with or without or weeks of therapy-free interval between each cycle., The first case reports describing the use of topical MMC in the treatment of PAM with atypia were published in the 99s by Frucht-Pery et al (996, a single case), 6 Finger et al (99, cases), and Salomao et al (999, cases). After these encouraging results many other case series were reported. 9 Finger et al,9, published several papers describing their clinical experience with the use of MMC for conjunctival melanocytic lesions and in reported a case series of eyes affected by PAM and treated with MMC for cycles ( days per cycle) as a sole and primary treatment. All patients showed a clinical regression of the lesions, but patients showed a recurrence of the disease in long-term follow-up (mean, months). Pe er et al reported a series of 9 patients affected by PAM with atypia and treated by topical MMC as a primary treatment ( days per cycle; range, to cycles; -week intervals) until disappearance or stabilization of the remnant pigmentation. Shields et al also reported the effectiveness of topical MMC () on corneal melanosis in patient, avoiding the need for surgery and its relative side effects. In, Russel et al reported the treatment of patients affected by PAM with atypia with topical MMC (). Of these, 6 patients were treated as a primary treatment, whereas a single patient as a neoadjuvant therapy. The authors reported cases of lack of response and recurrences during follow-up. Other authors reported the use of topical MMC in a lower concentration (.%). 6,,,6, This reduced dosage was introduced to reduce MMC-related side effects. Hung et al 6 reported the use of.% MMC in patients affected by conjunctival PAM, with no recurrences during follow-up. However, one of these patients experienced temporary drug toxicity similar to those treated by the concentration. When using topical MMC for the treatment of PAM, in a consistent proportion of treated eyes the conjunctival pigmentation Asia-Pacific Academy of Ophthalmology

3 Therapy for Conjunctival Tumors Table. Summary of Selected Clinical Studies on the Use of Topical MMC as a Treatment of Conjunctival Melanoma MMC Dosage Finger et al Demirci et al 9 Shields et al Kemp et al Kopp et al Kurli et al Pe er et al Khong et al Rudkin et al Russel et al Ditta et al Balci et al Salazar Mendez et al 9 Neoadjuvant primary adjuvant primary 6 adjuvant primary neoadjuvant adjuvant Neoadjuvant weeks QID, consecutive days and -second sponge application on weekdays : QID, weeks on, weeks off () : QID, week QID, week on, week off () QID, weeks on, weeks off, weeks on QID, for weeks (up to 6) : QID, weeks on, weeks off ()* : week QID, weeks on, weeks off ( ) QID, week on, week off () QID weeks on, week off, weeks on QID, weeks on, weeks off, weeks on QID, weeks on, week off () QID, week on, week off () QID, weeks (after surgery) (primary), (adjuvant) (/ primary) no response, recurrences (after surgery) *Cycle duration modified from original plan due to ocular surface toxicity. does not resolve completely after the treatment. Nevertheless, this pigment persistence is not a sign of lack of response to the therapy, as this usually represents a grouping of normal melanocytes with increased pigmentation and extracellular pigment deposition in the area of the pre-existing lesion., Moreover, the aspect of treated lesions is characterized by a progressive pigment degranulation, clinically characterized by a reorganization of the pigmentation in small clusters separated by areas of absence of pigmentation (Fig. ). Regular observation appeared adequate to evaluate eventual progression of the pigmentation and the necessity of retreatment in these cases. The Use of Mitomycin C in Conjunctival Melanoma Finger et al first reported a single case of recurrent conjunctival melanoma treated with topical MMC as a neoadjuvant treatment, obtaining a decrease of the pigmentation and thinning of the nodular part of the lesion. Kurli et al reported early tumor recurrence in patients (%) affected by conjunctival melanoma figure. Anterior segment photograph of a flat pigmented multifocal corneo-conjunctival lesion located in the temporal limbus in a case of primary acquired melanosis with atypia, before (A) and month after (B) the end of topical chemotherapy with MMC eye drops (. mg/ml), used times per day for consecutive days ( cycles) with a -week therapy-free interval between the cycles. The pigment degranulation inside the lesion, clinically characterized by remnant pigmentation organized in small clusters (black points) separated by small areas of absence of pigmentation, is clearly evident after the treatment (B). Asia-Pacific Academy of Ophthalmology

4 Midena et al Table. Summary of Selected Clinical Studies on the Use of Topical MMC as a Treatment of Conjunctival Intraepithelial Neoplasia MMC Dosage Frucht-Pery et al 6 Heigle et al Wilson et al Frucht-Pery et al 9 Akpek et al Rozenman et al McKelvie et al Kemp et al Daniell et al Shields et al * Billing et al * Dogru et al 6 Chen et al Dudney et al Prabhasawat et al 9 Singh et al Khong et al Hirst et al Zaki et al Gupta et al Ballalai et al Russel et al Besley et al * Bahrami et al 6 Rudkin et al Pe er et al * ( + IFN-αb) 6 9 / neoadjuvant primary recurrent primary recurrent primary adjuvant Neoadjuvant 9 primary adjuvant + CSA (.%) primary adjuvant primary recurrent primary neoadjuvant adjuvant /recurrent %.%.%.%..%.%.%.% QID, days QID, week () QID, week ( ) QID,.% or (for retreatment) weeks ( ) TID, weeks QID,.% or (for retreatment) weeks ( ) QID, week on, week off (up to ) QID, weeks on, weeks off, weeks on QID,.% or week on, week off ( ) QID, week ( ) QID, week () TID, 6 days QID, week ( ) QID, week on, week off () QID, week ( ) QID, week on, week off () QID, week on, week off () QID, weeks QID, weeks QID, week on, week off ( ) QID, consecutive days QID, weeks on, weeks off, weeks on QID, week on, weeks off ( 6) QID, week on, week off ( ) QID, week on, week off ( ) QID, weeks (postsurgery) partial response no response (recurrent group) (recurrences or persistence) partial response CSA indicates cyclosporine A; TID, ter in die, times a day. *Histological diagnosis of conjunctival intraepithelial neoplasia versus squamous cell carcinoma not fully delineated. Cycle and holiday durations modified from original plan due to ocular surface toxicity. and treated with cycles of MMC as a primary treatment. The other 6 patients were treated using a reduced cycle of MMC ( days), used as adjuvant therapy after surgical tumor removal starting within weeks of the surgery. Three of these patients ( treated with MMC as a primary treatment and a single patient as an adjuvant treatment) developed orbital recurrences requiring orbital exenteration. Successful primary treatment with MMC was obtained in conjunctival melanoma by Pe er et al in of the reported cases. Nevertheless, these authors emphasized that these patients presented with only minor extensions of PAM that minimally broke through the basement membrane. In another series described by Ditta et al, including eyes affected by conjunctival melanoma and treated with a -week cycle of MMC after surgery, patients developed recurrences after a median of 9 months. These authors also described a correlation between tumor recurrences and a delay in starting the topical therapy. Metastatic disease was subsequently diagnosed in patients, with of Asia-Pacific Academy of Ophthalmology

5 Therapy for Conjunctival Tumors Table. Summary of Selected Clinical Studies on the Use of Topical MMC as a Treatment of Conjunctival Squamous Cell Carcinoma MMC Dosage Heigle et al Frucht-Pery et al 9 Shields et al Frucht-Pery et al Kemp et al Prabhasawat et al 9 Shields et al 9 Rahimi et al Zaki et al Russel et al 6 Neoadjuvant Neoadjuvant + CSA (.%) neoadjuvant adjuvant 9..%.%.%.% QID, week ()* QID, weeks QID, week ( ) QID,.% or weeks ( ) QID, weeks on, weeks off, weeks on QID, week () QID, week on, week off ( 6) QID, week on, week off ( ) QID, weeks (CSA and MMC) QID, weeks on, weeks off, weeks on* no response, recurrences *Cycle duration and/or dosage modified from original plan due to ocular surface toxicity or limited response. them needing orbital exenteration because of concurrent orbital recurrence. The largest series of conjunctival melanoma treated by topical MMC was reported in by Russel et al, including consecutive eyes. Among them, patients were treated as a primary treatment, as neoadjuvant treatment, and for adjuvant purposes. The authors reported a single case of complete lack of response and recurrences during follow-up. The Use of Mitomycin C in Conjunctival Intraepithelial Neoplasia Several authors reported the use of MMC in the treatment of noninvasive (Table ) and invasive (Table ) OSSN.,,,,6 The first paper describing the use of topical MMC in the treatment of patients affected by was published in 99 by Frucht-Pery et al. 6 These authors obtained complete tumor control in all enrolled cases using topical MMC.%. After this first report, the same group published several papers describing the efficacy of both.% and MMC, used times daily for consecutive weeks in noninvasive OSSN. 9, Mitomycin C () was also used by Wilson et al in a short case series of patients with diffuse, who were considered poor surgical candidates or who had experienced recurrences despite prior surgical treatment. A single patient required subsequent surgical excision and adjunctive cryotherapy for a partial response. Gupta et al, in, reported a case series of patients affected by localized noninvasive ( cases) or recurrent ( cases). These patients were treated with surgical excision and cryotherapy, followed by to -week cycles of adjuvant topical MMC (). Another patients affected by diffuse were also included, receiving to -week cycles of topical MMC () as sole and primary treatment. After a mean follow-up of 6. months (range,. to 9.) no recurrences were documented in the group of localized tumors treated with MMC as a sole and primary therapy. A single case of tumor persistence and recurrences were reported in the group of diffuse tumors treated with MMC as a sole and primary therapy. A single recurrence was also documented in the group of recurrent tumors. Bahrami et al, 6 comparing MMC and -FU in the adjuvant treatment of noninvasive and localized OSSN, reported no recurrence in 6 eyes treated with MMC applied times a day on a week-on week-off basis for to cycles. Rudkin et al in a larger series ( patients) of diffuse pre-invasive lesions (defined as extended over or more clock hours of limbus, or characterized by extensive central or paracentral corneal spread) reported a recurrence rate of %, slightly higher than those usually reported for nondiffuse lesions. A single randomized controlled trial was performed for of any dimension or clock hours of limbal involvement, using MMC times a day for weeks. The authors reported a complete resolution in of 6 patients. The Use of Mitomycin C in Conjunctival Squamous Cell Carcinoma Mitomycin C seems to be most frequently used as adjuvant or neoadjuvant therapy for SCC and rarely used as a sole therapy for invasive OSSN (Table ). The dosage of MMC used as adjuvant treatment for previously excised SSC ranges from.% through.% to., The largest group was reported by Rahimi et al ( patients). Using topical MMC at as an adjuvant treatment, these authors reported recurrences (9%) during follow-up. Other authors reported their experience with MMC as a neoadjuvant chemotherapy agent for tumor reduction before the surgical resection (at least weeks) of thick extensive conjunctival SCC, obtaining interesting results.,,9 However, most authors recommended the use of MMC as a primary therapy only if excision is not possible, as in extensive or diffuse lesions., The Use of Mitomycin C in Other Tumors Rare case reports in the literature analyze the use of MMC in the treatment of sebaceous carcinoma, as a pre-, intra-, and postoperative therapy, obtaining promising results. Chemotherapy with MMC seems to be suitable for treating these lesions because of the ill-defined and multifocal nature of the intraepithelial involvement. Both and.% dosages were used., Ocular Toxicity of Mitomycin C Tissue side effects secondary to the use of topical MMC can persist for many years after the cessation of treatment, similar to Asia-Pacific Academy of Ophthalmology

6 Midena et al Table. Summary of Selected Clinical Studies on the Use of Topical -FU % as a Treatment of OSSN Diagnosis De Keizer et al Yeatts et al Midena et al Yeatts et al Midena et al 6 Yamamoto et al Al-Barrag et al 9 Parrozzani et al 6 Rudkin et al 6 Bahrami et al 6 Nutt et al 6 Kenawy et al 6 Rudkin et al Joag et al 6 Parrozzani et al 6 SCC SCC /SCC /SCC /SCC /SCC (diffuse) /SCC /SCC , adjuvant, adjuvant, recurrent Recurrent, neoadjuvant, adjuvant, salvage, adjuvant (if refractive to MMC) TID /day, weeks TID or QID, weeks on, months off ()* QID, weeks QID, days on, days off ( 6) QID, weeks ( ) QID, weeks () and week () QID, days on, days off (6) QID, weeks ( ) QID, weeks* QID, weeks QID, week ( )* QID, days on, weeks off () QID, week on, week off ( ) QID, week on weeks off ( 9) QID, weeks on, weeks off ( ) partial response, no response no response, recurrences recurrences, partial response indicates conjunctival intraepithelial neoplasia, including corneal-conjunctival intraepithelial neoplasia and carcinoma in situ. *Cycle duration modified from original plan due to ocular surface toxicity or loss to follow-up. those caused by ionizing radiation. Topical MMC toxicity occurs in a predictable and dose-dependent pattern and is usually more severe than that caused by -FU and IFN., Patients receiving shorter courses and lower drug concentrations (.%) seem to experience fewer severe adverse effects than those receiving longer or multiple courses, or using topical MMC at higher concentrations (). Patients usually experience transient adverse effects, such as conjunctival hyperemia and chemosis, tearing, punctate epithelial keratopathy, and/or toxic keratoconjunctivitis. These adverse effects are managed by adding topical steroid or nonsteroidal anti-inflammatory drugs (NSAIDs) or stopping the topical chemotherapy.,,,, Different cases of treatment discontinuation secondary to MMC adverse effects were reported. Punctal stenosis secondary to the use of topical MMC has been also reported.,, The incidence of this adverse effect should be reduced by occluding the lower punctum for a few minutes after instilling the drug.,, Other rare adverse effects include corneal haze, cataract, epithelial defects, disciform keratitis, and periocular dermatitis., Rare cases of limbal stem cell deficiency were also reported.,, When used as adjuvant chemotherapy to surgical excision, postoperative MMC does not prevent wound closure or cause corneo-conjunctival melting, if instituted after epithelial healing has occurred. -Fluorouracil Five-fluorouracil is a cell-cycle-specific pyrimidine analog, an antimetabolite that inhibits thymidylate synthetase, preventing D and R synthesis., Five-fluorouracil exerts its toxicity in active proliferating cells and the main mechanism of action is limited to cells in the S-phase of the cell cycle. Dormant cells are able to proliferate after treatment has been discontinued. Fivefluorouracil is effective against rapidly dividing tumor cells in the epithelium but does not seem to affect normal cells or corneal stem cells., Therefore, -FU seems to have a selective cytotoxicity to the dysplastic epithelium. Five-fluorouracil is soluble in water and when prepared in aqueous solution remains stable for at least weeks. Compared with MMC, -FU does not require refrigeration or light protection., The Use of -Fluoruracil in OSSN De Keizer et al first reported, in 96, the use of % -FU as sole treatment of noninvasive OSSN with successful results. Subsequently, Yeatts et al and Midena et al,6 reported other successfully treated cases using the same drug dosage (%). This dosage still remains the standard one, but it is used in variable therapeutic regimens. Compared with MMC and IFN-αb, relatively few papers have been published about the use of topical -FU (Table ). 6,,, 6 Joag et al 6 recently reported the use of % -FU ( times daily for week followed by weeks of suspension, for an average of cycles) as a primary treatment of eyes affected by OSSN. These authors reported a lack of response in cases. Moreover, cases were switched to a different therapy for various reasons, and cases recurred during followup ( at. years after the treatment). These authors also noted that the presence of nodularity increased the risk of recurrence approximately -fold. Unfortunately, a limit of this study is Asia-Pacific Academy of Ophthalmology

7 Therapy for Conjunctival Tumors that histopathology was reported only for 6 patients. In, Parrozzani et al 6 reported OSSN cases retrospectively analyzed for detecting long-term side effects of -FU. Of these, patients were affected by intraepithelial dysplastic lesions treated with topical % -FU times per day for weeks as primary or adjuvant treatment. In this case series, a single case of tumor recurrence was documented. Bahrami et al 6 recently reported the largest series of patients affected by noninvasive and localized OSSN treated by -FU as adjuvant treatment (as a part of a larger study comparing MMC and -FU as adjuvant treatment for OSSN), using % -FU times per day continuously for a period of weeks. These authors reported a single case of recurrence in a patient who had not completed the protocol. Rudkin et al, using a regime of weeks of continuous therapy of % -FU, described the effectiveness of -FU in primary and recurrent OSSN, also in selected cases refractory to topical MMC. In a recent paper, Parrozzani et al 6 reported a response rate of 9% and % in cases of low-grade and high-grade dysplasia, respectively, using % -FU as sole treatment (Fig. ). No correlation was found between late recurrences (% and %, respectively) and primary incomplete response to chemotherapy or number of treatment courses. Furthermore, multivariate analysis showed that the major limitations of topical chemotherapy with -FU were tumor thickness (more than. mm) and multifocality. Five-fluorouracil seems to be most frequently used as adjuvant or neoadjuvant therapy for SCC and rarely used as a sole therapy. 9,6,6 Our group has recently reported cases of SCC treated with -FU as a sole treatment, obtaining a response rate of % with a mean follow-up of ± months. 6 Three other patients affected by SCC were treated with % -FU as sole treatment by Joag et al. 6 One patient showed full resolution after cycles of -FU, a single patient did not respond to treatment after 6 cycles, and another patient was switched to a different treatment. Ocular Toxicity of -Fluorouracil The adverse effects of -FU are mild and transient, consisting of hyperemia and superficial keratitis. Transient keratoconjunctivitis is present in most patients treated continuously for days during the third or fourth week of treatment and can be easily controlled with topical steroid. Conversely, Yeatts et al did not find significant side effects using a pulsed dosing regimen. Five-fluorouracil toxicity seems to be less severe than that caused by MMC, with rarer cases of corneal epithelial defects, erythema of the eyelid skin, and epiphora. Rare cases of treatment interruption because of transient superficial toxicity were also reported.,6,,6,6 Furthermore, Parrozzani et al 6 already demonstrated (by in vivo confocal microscopy) that topical chemotherapy with % -FU is a safe treatment in the long-term for all corneal layers, revealing no long-term differences between the treated and control (fellow) eyes. IMMUNOTHERAPY OF CONJUNCTIVAL TUMORS Interferon-αb Interferons are a group of glycoproteins with antiviral, antimicrobial, and antineoplastic activities. They act at cell surface receptors prolonging the length of the cell cycle, downregulating oncogenes, and promoting tumor suppressor genes., Their systemic use is established for the treatment of hairy cell leukemia, condyloma acuminate, Kaposi sarcoma in AIDS, and hepatitis C., Interferon-αb is the recombinant form of interferon-α, and it was applied both topically and in subconjunctival/perilesional injections to conjunctival tumors (Table 6). Its antiproliferative proprieties seem to be related to the promotion of the immune response through an activation of host cytotoxic effector cells. Even if comparable rates of resolution were reported with both treatment modalities, topical application is preferred due to its better safety profile and avoidance of systemic effects. Interferonαb needs refrigeration to ensure -month stability. Although the costs vary widely, IFN-αb is the most expensive agent compared with -FU and MMC.,,66 The Use of IFN-αb in Conjunctival Pigmented Lesions Published data on the use of IFN-αb for the treatment of pigmented lesions are limited. The regimen of million IU/mL times a day as adjuvant therapy was reported in series of conjunctival melanomas by Finger et al. 6 Four of these patients who had failed previous excision or topical MMC had resolution of the lesion. Herold et al 6 reported a series of 9 patients affected by PAM with atypia and treated by IFN-αb, million IU/mL times a day in 6-week cycles. Of these, showed complete figure. Anterior segment photograph of a dyskeratotic nonpigmented corneo-conjunctival lesion located in the temporal limbus in a case of ocular surface squamous neoplasia (high-grade dysplasia), before (A) and month after (B) the end of topical chemotherapy with % -FU eye drops, used times per day for consecutive weeks ( cycle). Asia-Pacific Academy of Ophthalmology

8 Midena et al Table 6. Summary of Selected Clinical Studies on the Use of Topical IFN-αb Used as and Therapy for Conjunctival Tumors Diagnosis Dosage Finger et al 6 Herold et al 6 Garip et al 69 Maskin et al Galor et al Holcombe et al Sturges et al Nanji et al MM PAM MM PAM MM SCC OSSN* OSSN* OSSN* 9 9, adjuvant, adjuvant, salvage, salvage million IU/mL million IU/mL million IU/mL million IU/mL or million IU/mL million IU/mL million IU/mL or or million IU/mL million IU/mL or million IU/. ml QID, months /d, 6 weeks ( ) /d, 6 weeks ( 6) BID, months QID, months QID, 6 weeks QID or TID, months Drop: QID or TID month ( ) or/and injections/wk no response no response (/ SCC), recurrences no response no response ( ) Blasi et al MALT 6. million IU/mL, then million IU/mL injections/wk, weeks ( ) BID indicates bis in die, twice a day. *Histological diagnosis of invasive and preinvasive disease not fully delineated. Cycle duration modified from original plan due to ocular surface toxicity. regression, patients required a second cycle, and patient needed a third cycle. One patient required both a fourth cycle of therapy and additional surgery to control the disease. Recently, Garip et al 69 reported patients with biopsy-proven PAM with atypia and patients affected by conjunctival melanoma that were treated with topical IFN-αb. Compared with pretreatment lesion dimension, the mean decreases in tumor size were 66% after the first cycle, % after the second cycle, and % after the third cycle. The Use of IFN-αb in Conjunctival OSSN A large number of papers were published on the use of IFNαb in the treatment of OSSN after the first report by Maskin et al in 99. Interferon-αb may be effective as a primary treatment and also as a salvage treatment, especially when prior surgical excision has failed., Different regimens were found to be effective, and the most common dosages range from to million IU/mL, times daily, used at least until complete clinical resolution of the lesion., Karp et al 66, published several reports about the use of IFN-αb in OSSN and, in, Galor et al reported a comparison between eyes treated with million IU/mL and eyes with million IU/mL. No statistical differences in clinical resolution of primary versus recurrent (% and 9%, respectively) were reported. The same authors reported comparable average time of resolution (. and.9 months, respectively) using these different drug concentrations. Interferon-αb has been shown to be effective, with clinical resolution of around % of the cases in the larger series reported. For example, Holcombe et al reported clinical resolution of of cases of recalcitrant OSSN with topical IFN-αb ( million IU/mL) times a day until clinical resolution. All patients had been previously treated with topical MMC with lack of response. Unfortunately, of the enrolled patients developed orbital invasion and underwent orbital exenteration. Thus, the authors conclude that IFN-αb may be a valid option for extensive or recurrent lesions, but invasive disease should not be managed with IFN-αb alone, as this could delay definitive surgical intervention and extension of the malignancy. Sturges et al and Nanji et al, analyzing respectively 9 and 9 patients, reported no significant differences in the disease control using surgery or IFN-αb. Unfortunately, the lack of histology in conservatively treated patients may be a potential bias of these studies. However, a recent literature-based decision analysis identifies surgical excision followed by topical IFN-αb for cases with positive surgical margins as the most effective strategy for minimizing persistence or recurrence of OSSN. 6 The Use of IFN-αb in Conjunctival Non-Hodgkin Lymphoma The majority of conjunctival lymphomas are B-cell non-hodgkin lymphomas (9%). Of these, the most frequent subtypes are MALT lymphoma (%), followed by follicular lymphoma (%), diffuse large B-cell lymphoma (%), and mantle cell lymphoma (%). At present, external beam radiotherapy is the treatment of choice for MALT and follicular lymphoma, whereas diffuse large B-cell lymphoma, mantle cell lymphoma, and T-cell lymphomas are mainly treated with chemotherapy. The use of local immunotherapy with IFN-α, injected subconjunctivally, was reported as a promising treatment of conjunctival MALT lymphoma. Blasi et al, in, reported the largest series ( eyes of 6 patients) of histologically proven conjunctival MALT lymphoma. These authors used. million IU of IFN-α subconjunctivally injected inside the lesion, times weekly for weeks. If there was even a minimal response, a further cycle of,, IU times weekly for weeks was administered. A complete response was obtained in eyes (%) at the end of the first cycle and in eyes (%) after further cycles. Seventeen eyes (%) showed no local recurrence after a median follow-up of 6 months. Three eyes (%) demonstrated recurrence at variable points after treatment. Asia-Pacific Academy of Ophthalmology

9 Therapy for Conjunctival Tumors Ocular and Systemic Toxicity of IFN-αb Topical interferon has fewer adverse effects, compared with other topical chemotherapeutic agents, such as mild chemical conjunctivitis and corneal punctate epithelial erosions.,, A relatively higher frequency of adverse effects occurs when using a dose of million IU. When injected subconjunctivally, transient local adverse effects were common, including injection, irritation, corneal punctate epithelial erosions, and corneal and eyelid edema. Local adverse effects are associated with mild systemic adverse reactions, such as flu-like symptoms, fever, and myalgia.,66 No fatal or carcinogenic adverse effects have been reported with subconjunctival or topical use of IFN-αb., OTHER DRUGS AND COMBITION THERAPIES Immunotherapy with monoclonal antibodies, particularly rituximab and daclizumab, has been proposed as a treatment option for patients with conjunctival lymphoma. The existing studies suggest that intralesional rituximab is well tolerated and produces a good response, with approximately % of patients being progression- or recurrence-free during a -year follow-up period. Bevacizumab is a full-length humanized monoclonal antivascular endothelial grow factor (VEGF) antibody that was initially approved by the US Food and Drug Administration (FDA) for the treatment of patients with colorectal cancer. A case series of 6 eyes affected by conjunctival intraepithelial neoplasia and treated with topical bevacizumab was recently published, suggesting the possible efficacy of this drug as neoadjuvant therapy. A dose of mg/ml bevacizumab was administered times daily for a period of weeks. All lesions were responsive to treatment and surgery was not necessary in cases. Moreover, no recurrences were observed during a follow-up period of 6 months. No systemic and local side effects were documented. 9 Unfortunately, after analyzing other case reports on the use of topical anti-vegf for the treatment of recalcitrant OSSN, resolution of the disease seems to occur in a minority of cases. Other agents were proposed to treat pigmented and nonpigmented conjunctival epithelial tumors, such as retinoic acid, urea, the immunologic adjuvant dinitrocholorbenzene, and cidofovir. Unfortunately, no data are available to better address their efficacy and safety in the treatment of conjunctival tumors. A peculiar case of a patient with a clinical diagnosis of OSSN who refused traditional therapies and obtained complete resolution of the lesion using a commercially available aloe vera preparation was reported by Damani et al. Many cases of combination therapy were reported in the attempt to have a synergic therapeutic effect with fewer side effects. Interferon was administered after a marked size reduction of PAM with atypia induced by MMC to complete treatment limiting MMC local toxicity. 9 Zaki et al reported the use of MMC.% combined with cyclosporine A.% times a day for weeks after surgery for conjunctival intraepithelial neoplasia involving the cornea in 6 eyes and SCC in eyes. No recurrence was reported. The use of this combination may provide a synergic effect leading to an effective result limiting MMC side effects. CONCLUSIONS Growing evidence shows a more prominent use of topical therapies for conjunctival tumors, both as a sole treatment or in Asia-Pacific Academy of Ophthalmology conjunction with surgery. 6 The reasons for this trend are the possibility to treat the entire ocular surface, potentially eliminating subclinical tumor cells at sites different from the clinically evident tumor and to avoid the complications of surgical excision. Topical chemotherapy results are particularly attractive in diffuse, multifocal lesions involving the limbus and the cornea, or when positive margins are detected after surgery., Nevertheless, a standard protocol for the use of different drugs in different conjunctival tumors has not yet been identified. The rarity of these diseases limits our possibility to have comparable study results, and clinical decisions are still left to the single physician on the basis of personal experience in different patient populations. However, some conclusions can be drawn from the current literature. Mitomycin C proved to necessitate a shorter period of administration compared with others and some patients may prefer a particular regimen ( or treatment weeks per month with MMC and -FU is easier than the daily dosing of IFN for months). Five-fluorouracil does not require refrigeration, unlike the others drugs, and presents fewer side effects than MMC. Interferon has the best safety profile (when topically administered) but a longer period of administration., At present, a larger series on OSSN reported similar response frequency to topical -FU, IFN ( % for both), and MMC (6 %), even if distinction between invasive and preinvasive lesions is not always clear and in several series patients underwent different previous treatments because of the retrospective design of most studies.,,6 With regard to pigmented lesions, most series underline that MMC should be considered the chemotherapeutic agent of choice for PAM, but IFN seems to be an effective alternative. Patients that present with inadequate or incomplete response to one agent may respond to another drug (MMC or IFN). Recently a preliminary correlation between mutant genes and a history of lack of response to a specific topical therapy (in particular IFN-αb) has been reported, suggesting a possible new way to decide the best therapy in advance. 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