- Email: [email protected]
Topical Interferon Alfa-2b for the Treatment of Recalcitrant Ocular Surface Squamous Neoplasia
Topical Interferon Alfa-2b for the Treatment of Recalcitrant Ocular Surface Squamous Neoplasia DAVID J. HOLCOMBE, BSC, AND GRAHAM A. LEE, MD, FRANZCO
● PURPOSE: To evaluate topical interferon alfa-2b (IFN␣2b) for the treatment of recalcitrant ocular surface squamous neoplasia (OSSN). ● DESIGN: Prospective, noncomparative, interventional consecutive case series. ● METHODS: Ten patients with recalcitrant OSSN were treated with topical IFN-␣2b (1 million IU/ml) four times a day until clinical resolution of the lesion or until the lesion appeared nonresponsive—that is, treatment failure. Progress was assessed by clinical examination and photographic records, with a minimum follow-up of six months. ● RESULTS: Eight of 10 patients achieved clinical resolution from topical IFN-␣2b treatment. One patient developed invasive squamous cell carcinoma and underwent exenteration. The other patient required further mitomycin C therapy to achieve clinical resolution. The mean duration to clinical resolution for the eight patients treated with IFN-␣2b was 21.9 weeks (range six to 59 weeks). There have been no recurrences for any of the nine patients during follow-up (mean 55.0 weeks; range 26 to 84 weeks). ● CONCLUSIONS: Topical IFN-␣2b is an important treatment modality for recalcitrant OSSN; it avoids the risks of further limbal stem cell destruction from other agents and surgical excision. If invasive disease is diagnosed at any stage, topical therapy is contraindicated, necessitating surgical excision. (Am J Ophthalmol 2006;142:568 –571. © 2006 by Elsevier Inc. All rights reserved.)
T
HE TREATMENT OF RECURRENT OCULAR SURFACE
over the whole ocular surface while relatively conserving the limbal stem cell population. Interferon alfa-2b (IFN␣2b) as a topical preparation has recently been used successfully in the treatment of primary OSSN.1– 8 The efficacy of topical IFN-␣2b as a treatment for recalcitrant OSSN—that is, recurrent OSSN after previously unsuccessful standard treatment—is not as well established, and thus the aim of this study was to further investigate its role as a treatment modality.
METHODS TEN CONSECUTIVE PATIENTS WITH RECALCITRANT BIOPSY-
proven OSSN, who presented between 2002 and 2005 at the Royal Brisbane Hospital, Queensland, Australia, were treated with topical IFN-␣2b (Table). All patients provided informed consent. The topical IFN-␣2b was prepared by diluting 18 mol/l IU/1.2 ml injectable recombinant IFN-␣2b (Intron A; Schering Plough, Kenilworth, New Jersey, USA) with a balanced salt solution. Approval for the use of topical IFN-␣2b in the treatment of OSSN was obtained from the Royal Brisbane Hospital Drug and Ethics Committee. Patients were supplied with one month’s course divided into three bottles (one bottle/10 days). Treatment consisted of one drop (1 million IU/ml) four times a day until clinical resolution of the lesion or until lesion regression appeared to be unresponsive—that is, treatment failure. Progress was assessed by clinical examination and photographic records. Minimum follow-up was six months.
squamous neoplasia (OSSN) is associated with high rates of failure as a result of insufficient eradication of neoplastic cells. Topical therapy has an advantage over surgical excision in that it potentially treats abnormal cells
Supplemental Material available at AJO.com. Accepted for publication May 22, 2006. From the University of Queensland (D.J.H., G.A.L.) and Royal Brisbane Hospital (G.A.L.), Brisbane, Queensland, Australia. Inquiries to Graham A. Lee, MD, FRANZCO, City Eye Centre, 135 Wickham Tce, Brisbane Q 4000, Australia; e-mail: [email protected]
568
©
2006 BY
RESULTS TEN EYES OF 10 PATIENTS (SEVEN MEN AND THREE WOMEN)
were enrolled onto this study. The mean age of patients was 73.4 years (range 60 to 84 years). Six patients had at least one attempted excision before interferon therapy, and all had previously been treated with mitomycin C (MMC).
ELSEVIER INC. ALL
RIGHTS RESERVED.
0002-9394/06/$32.00 doi:10.1016/j.ajo.2006.05.058
TABLE. Recalcitrant Ocular Surface Squamous Neoplasia Treated With Topical INF-␣2b Patient
Age (years)
Gender
Previous Excision
Previous MMC Courses
INF-␣2b Treatment (weeks)
Clinical Resolution (weeks)
Follow-up (weeks)
1 2 3* 4 5 6† 7 8 9 10 Mean
72 69 84 80 61 60 73 81 79 75 73.4
F M F M M M F M M M 7M:3F
0 6 0 4 2 1 0 2 0 1 1.6
3 11 2 2 2 1 2 6 6 2 3.7
20 23 43 19 28 8 6 18 28 51 24.4
20 15 — 19 19 14 6 9 28 59 21.0
71 35 NA 26 58 68 84 42 72 39 55.0
MMC ⫽ mitomycin C. *Patient progressed to invasive squamous cell carcinoma with eye and orbital contents exenterated. † Patient discontinued interferon alfa 2b (INF-␣2b) therapy and commenced topical MMC 0.04% to achieve clinical resolution.
After IFN-␣2b therapy, eight of the 10 patients obtained clinical resolution after a mean duration of 21.9 weeks (range six to 59 weeks) (Table). In these patients, there have been no recurrences of OSSN after a mean follow-up of 53.4 weeks (range 26 to 84 weeks). The topical IFN-␣2b was well tolerated, with only one patient reporting minor irritation; this irritation resolved after cessation of the treatment. Patient 2: an 69-year-old man who presented with a 12-month history of right eye epiphora and foreign body sensation. At his nasal limbus was a raised lesion measuring 6.5 ⫻ 6.5 mm. Impression cytology diagnosed carcinoma in situ, and the lesion was excised with additional cryotherapy to the base and wound edges. Recurrences occurred over the next five years, with the patient undergoing five further excisions with cryotherapy and 11 courses of topical MMC (Figure 1). Therapy with topical IFN-␣2b four times a day was commenced. Fourteen weeks later, the lesion had resolved, and after a further two weeks, IFN-␣2b treatment was stopped (Figure 2). The patient has been observed without recurrence for two years since the topical IFN-␣2b was ceased. Patient 3: an 84-year-old woman who presented complaining of a red eye. Excision biopsy was performed and severe dysplasia diagnosed. After recurrence, she was treated with topical MMC 0.04% for three weeks. Residual dysplasia was present one month later, and an additional three week course of topical MMC 0.04% was given. The lesion did not resolve, and four months later, she initiated therapy with topical IFN-␣2b four times a day (Figure 3). At follow-up three months later, there was no resolution, and the dose was increased to six times a day. After a further four months, including 3 ⫻ 0.8-ml intralesional injections of IFN-␣2b, the lesion showed progression (Figure 4). Analysis of a biopsy sample of the lesion showed invasive squamous cell carcinoma. Although the VOL. 142, NO. 4
TOPICAL IFN-␣2B
FOR
FIGURE 1. Recurrent carcinoma in situ of limbus recalcitrant to previous excision and topical mitomycin C (MMC).
patient was reluctant to undergo surgery, extensive excision, including removal of the underlying scleral wall, was undertaken, but surgery failed to fully remove the OSSN. The eye and orbital contents were subsequently exenterated. Patient 6: an 60-year-old male presented with a recurrent OSSN of his left medial limbus. He had undergone previous excisions with cryotherapy as well as a previous course of topical MMC 0.04%. He was commenced on topical IFN-␣2b qid and two months later, the area of dysplastic epithelium had enlarged to involve both the superior and inferior cornea (Supplementary Figure 5 at AJO.com). The topical IFN-␣2b was ceased, and topical MMC 0.04% qid for seven days was repeated. Two months later, the lesion showed improvement (Supplementary Figure 6 at AJO.com), and a second course of MMC for seven days was administered with full resolution after one TREATMENT
OF
NEOPLASIA
569
FIGURE 2. Resolution of recurrent carcinoma in situ of limbus after 16 weeks of topical interferon alfa-2b (IFN-␣2b).
FIGURE 4. Progression of dysplasia to invasive squamous cell carcinoma of conjunctiva after failure of four months of topical and intralesional interferon alfa-2b (IFN-␣2b).
impression cytology and/or biopsy confirmation of the grade of the OSSN is highlighted by patient 3 of our series. Invasive squamous cell carcinoma cannot be managed by topical treatment alone, with persistence of topical therapy delaying definitive surgical treatment. For lesions that are extensive, involve the visual axis, or are residual, recurrent, multifocal or diffuse, surgery is not the ideal treatment. Topical preparations have advantages in the treatment of such lesions. There is no requirement to ensure clear tissue margins because the medication contacts the entire ocular surface, thus enabling treatment of multifocal or diffuse lesions with targeting of tumor cells.4,10 Furthermore, the increased cost, stress, pain, and trauma associated with a surgical procedure are avoided.4,10 Topical MMC, and to a lesser degree 5-fluorouracil, can resolve lesions when used alone and can reduce recurrence rates when used as an adjunct to surgical excision; however, their use can be associated with marked ocular surface toxicity with side effects including corneal edema, punctate epithelial keratoplasty, transient conjunctival injection, tearing, photophobia, ocular pain, and, potentially, limbal stem cell failure.11,12 In contrast, topical IFN-␣2b appears to be associated with few or no side effects. Schechter and associates4 reported local conjunctival injection and follicular conjunctivitis in four (57.1%) of seven patients. It was proposed, however, that the folliculitis was likely to be due to the vehicle that contained benzyl alcohol 0.09%, glycerin, and human albumin, and not the IFN-␣2b itself. Subconjunctival injections of IFN-␣2b have been associated with transient fevers and myalgias.6,8 The efficacy of IFN-␣2b in treating OSSN may be explained by its dual antiviral and antitumor effects. The onocogenic link between human papilloma virus (HPV) and squamous neoplasia of the uterine cervix is well established
FIGURE 3. Recurrent dysplasia of limbus and conjunctiva recalcitrant to previous excision and topical mitomycin C (MMC).
month. The patient has been observed for 68 weeks without recurrence.
DISCUSSION IFN-␣2B HAS BEEN REPORTED IN THE LITERATURE TO BE
effective as a primary treatment for OSSN, but its use as a chemotherapeutic agent for recalcitrant OSSN is not as well established.1,6 – 8 Boehm and Huang9 reported six cases of recurrent OSSN that were treated successfully with topical IFN-␣2b with a mean duration to resolution of 16.4 weeks (range five to 28 weeks). The cases in our report were specifically recalcitrant, having failed previous standard treatments, including surgical excision with or without cryotherapy and/or topical MMC. The importance of 570
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
OCTOBER 2006
and suspected as an etiologic agent in OSSN. Interferons also demonstrate antitumor activity by way of inhibition of cell growth and/or induction of tumor cell apoptosis. The antiviral effects of IFN-␣2b may also explain why IFN-␣2b may be less effective as a primary treatment in lesions not linked to HPV infection. Thus, IFN-␣2b’s recommended role in the management of OSSN is for recurrent or recalcitrant lesions that have failed to respond to MMC treatment. Our approach to noninvasive OSSN is a course of topical MMC (for example, MMC 0.04% four times a day for seven days, then three weeks off, repeating for up to four cycles), and if this fails to resolve the lesion, subsequent topical IFN-␣2b therapy. If there is no sign of treatment response after two months, then surgical excision is indicated. Other antiviral agents, such as cidofovir ((S)-1-[3-hydroxy-2-(phosphonomethoxy-propyl]cytosine), have been shown to enhance the antiviral effects of interferon on HPV-infected keratinocytes in vitro and may be useful as adjunctive therapy.13,14 Topical IFN-␣2b is a beneficial treatment modality for recalcitrant noninvasive OSSN that may be effective where surgical excision and MMC have failed. It is well tolerated and does not markedly damage the limbal stem cells. Further investigation is required to determine why certain lesions respond to topical MMC alone, whereas others require IFN-␣2b in combination with MMC, and how this may relate to concurrent ocular HPV infection. For invasive OSSN, topical therapy alone is contraindicated and necessitates surgical excision.
REFERENCES 1. Maskin SL. Regression of limbal epithelial dysplasia with topical interferon. Arch Ophthalmol 1994;112:1145–1146. 2. Schechter BA. Conjunctival intraepithelial neoplasia. Ophthalmology 1999;106:1642–1643.
VOL. 142, NO. 4
TOPICAL IFN-␣2B
FOR
3. Karp CL, Moore JK, Rosa RH Jr. Treatment of conjunctival and corneal intraepithelial neoplasia with topical interferon alpha-2b. Ophthalmology 2001;108:1093–1098. 4. Schechter BA, Schrier A, Nagler RS, Smith EF, Velasquez GE. Regression of presumed primary conjunctival and corneal intraepithelial neoplasia with topical interferon alpha2b. Cornea 2002;21:6 –11. 5. Schechter BA, Nagler RS. Successful treatment with 5-FU. Ophthalmology 2003;110:1262–1263. 6. Vann RR, Karp CL. Perilesional and topical interferon alfa-2b for conjunctival and corneal neoplasia. Ophthalmology 1999;106:91–97. 7. Hu FR, Wu MJ, Kuo SH. Interferon treatment for corneolimbal squamous dysplasia. Am J Ophthalmol 1998;125: 118 –119. 8. Kobayashi A, Yoshita T, Uchiyama K, et al. Successful management of conjunctival intraepithelial neoplasia by interferon alpha-2b. Jpn J Ophthalmol 2002;46:215–217. 9. Boehm MD, Huang AJ. Treatment of recurrent corneal and conjunctival intraepithelial neoplasia with topical interferon alfa 2b. Ophthalmology 2004;111:1755–1761. 10. Yeatts RP, Engelbrecht NE, Curry CD, Ford JG, Walter KA. 5-Fluorouracil for the treatment of intraepithelial neoplasia of the conjunctiva and cornea. Ophthalmology 2000;107: 2190 –2195. 11. Wilson MW, Hungerford JL, George SM, Madreperla SA. Topical mitomycin C for the treatment of conjunctival and corneal epithelial dysplasia and neoplasia. Am J Ophthalmol 1997;124:303–311. 12. Frucht-Pery J, Rozenman Y. Mitomycin C therapy for corneal intraepithelial neoplasia. Am J Ophthalmol 1994;117: 164 –168. 13. Johnson JA, Gangemi JD. Alpha interferon augments cidofovir’s antiviral and antiproliferative activities. Antimicrob Agents Chemother 2003;47:2022–2026. 14. Sherman MD, Feldman KA, Farahmand SM, Margolis TP. Treatment of conjunctival squamous cell carcinoma with topical cidofovir. Am J Ophthalmol 2002;134:432– 433.
TREATMENT
OF
NEOPLASIA
571
Biosketch David J. Holcombe, BSc, has a Bachelor of Science degree and is currently undertaking a combined Bachelor of Medicine and Surgery with a Doctorate of Philosophy at the University of Queensland, Australia. Dr Holcombe’s current PhD thesis involves investigating disturbances in neurotransmitter homeostasis in ocular disease. Dr Holcombe is expected to complete his studies in 2007 and pursue his long-term goal of a career in Ophthalmology.
571.e1
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OF
OPHTHALMOLOGY
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Biosketch Graham A. Lee, MD, FRANZCO, is an Associate Professor and completed his MBBS in 1991 at the University of Queensland (UQ), Brisbane, Australia, a MMedSc (Oph) in 1994 and FRANZCO in 2000. Dr Lee returned from the United Kingdom in 2001 completing a Glaucoma Fellowship at Birmingham and Midlands Eye Centre and a Cataract, Cornea and Refractive Fellowship at Moorfields Eye Hospital in London. In 2005, Dr Lee was awarded an MD (UQ) for his published works on anterior segment disease.
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FIGURE 6. Regression of dysplasia of the limbus, two months following a further course of topical mitomycin C (MMC) after failure of topical INF-␣2b.
FIGURE 5. Recurrent dysplasia of the limbus recalcitrant to previous excision, topical mitomycin C (MMC) and two months of topical INF-␣2b.
571.e3
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● PURPOSE: To evaluate topical interferon alfa-2b (IFN␣2b) for the treatment of recalcitrant ocular surface squamous neoplasia (OSSN). ● DESIGN: Prospective, noncomparative, interventional consecutive case series. ● METHODS: Ten patients with recalcitrant OSSN were treated with topical IFN-␣2b (1 million IU/ml) four times a day until clinical resolution of the lesion or until the lesion appeared nonresponsive—that is, treatment failure. Progress was assessed by clinical examination and photographic records, with a minimum follow-up of six months. ● RESULTS: Eight of 10 patients achieved clinical resolution from topical IFN-␣2b treatment. One patient developed invasive squamous cell carcinoma and underwent exenteration. The other patient required further mitomycin C therapy to achieve clinical resolution. The mean duration to clinical resolution for the eight patients treated with IFN-␣2b was 21.9 weeks (range six to 59 weeks). There have been no recurrences for any of the nine patients during follow-up (mean 55.0 weeks; range 26 to 84 weeks). ● CONCLUSIONS: Topical IFN-␣2b is an important treatment modality for recalcitrant OSSN; it avoids the risks of further limbal stem cell destruction from other agents and surgical excision. If invasive disease is diagnosed at any stage, topical therapy is contraindicated, necessitating surgical excision. (Am J Ophthalmol 2006;142:568 –571. © 2006 by Elsevier Inc. All rights reserved.)
T
HE TREATMENT OF RECURRENT OCULAR SURFACE
over the whole ocular surface while relatively conserving the limbal stem cell population. Interferon alfa-2b (IFN␣2b) as a topical preparation has recently been used successfully in the treatment of primary OSSN.1– 8 The efficacy of topical IFN-␣2b as a treatment for recalcitrant OSSN—that is, recurrent OSSN after previously unsuccessful standard treatment—is not as well established, and thus the aim of this study was to further investigate its role as a treatment modality.
METHODS TEN CONSECUTIVE PATIENTS WITH RECALCITRANT BIOPSY-
proven OSSN, who presented between 2002 and 2005 at the Royal Brisbane Hospital, Queensland, Australia, were treated with topical IFN-␣2b (Table). All patients provided informed consent. The topical IFN-␣2b was prepared by diluting 18 mol/l IU/1.2 ml injectable recombinant IFN-␣2b (Intron A; Schering Plough, Kenilworth, New Jersey, USA) with a balanced salt solution. Approval for the use of topical IFN-␣2b in the treatment of OSSN was obtained from the Royal Brisbane Hospital Drug and Ethics Committee. Patients were supplied with one month’s course divided into three bottles (one bottle/10 days). Treatment consisted of one drop (1 million IU/ml) four times a day until clinical resolution of the lesion or until lesion regression appeared to be unresponsive—that is, treatment failure. Progress was assessed by clinical examination and photographic records. Minimum follow-up was six months.
squamous neoplasia (OSSN) is associated with high rates of failure as a result of insufficient eradication of neoplastic cells. Topical therapy has an advantage over surgical excision in that it potentially treats abnormal cells
Supplemental Material available at AJO.com. Accepted for publication May 22, 2006. From the University of Queensland (D.J.H., G.A.L.) and Royal Brisbane Hospital (G.A.L.), Brisbane, Queensland, Australia. Inquiries to Graham A. Lee, MD, FRANZCO, City Eye Centre, 135 Wickham Tce, Brisbane Q 4000, Australia; e-mail: [email protected]
568
©
2006 BY
RESULTS TEN EYES OF 10 PATIENTS (SEVEN MEN AND THREE WOMEN)
were enrolled onto this study. The mean age of patients was 73.4 years (range 60 to 84 years). Six patients had at least one attempted excision before interferon therapy, and all had previously been treated with mitomycin C (MMC).
ELSEVIER INC. ALL
RIGHTS RESERVED.
0002-9394/06/$32.00 doi:10.1016/j.ajo.2006.05.058
TABLE. Recalcitrant Ocular Surface Squamous Neoplasia Treated With Topical INF-␣2b Patient
Age (years)
Gender
Previous Excision
Previous MMC Courses
INF-␣2b Treatment (weeks)
Clinical Resolution (weeks)
Follow-up (weeks)
1 2 3* 4 5 6† 7 8 9 10 Mean
72 69 84 80 61 60 73 81 79 75 73.4
F M F M M M F M M M 7M:3F
0 6 0 4 2 1 0 2 0 1 1.6
3 11 2 2 2 1 2 6 6 2 3.7
20 23 43 19 28 8 6 18 28 51 24.4
20 15 — 19 19 14 6 9 28 59 21.0
71 35 NA 26 58 68 84 42 72 39 55.0
MMC ⫽ mitomycin C. *Patient progressed to invasive squamous cell carcinoma with eye and orbital contents exenterated. † Patient discontinued interferon alfa 2b (INF-␣2b) therapy and commenced topical MMC 0.04% to achieve clinical resolution.
After IFN-␣2b therapy, eight of the 10 patients obtained clinical resolution after a mean duration of 21.9 weeks (range six to 59 weeks) (Table). In these patients, there have been no recurrences of OSSN after a mean follow-up of 53.4 weeks (range 26 to 84 weeks). The topical IFN-␣2b was well tolerated, with only one patient reporting minor irritation; this irritation resolved after cessation of the treatment. Patient 2: an 69-year-old man who presented with a 12-month history of right eye epiphora and foreign body sensation. At his nasal limbus was a raised lesion measuring 6.5 ⫻ 6.5 mm. Impression cytology diagnosed carcinoma in situ, and the lesion was excised with additional cryotherapy to the base and wound edges. Recurrences occurred over the next five years, with the patient undergoing five further excisions with cryotherapy and 11 courses of topical MMC (Figure 1). Therapy with topical IFN-␣2b four times a day was commenced. Fourteen weeks later, the lesion had resolved, and after a further two weeks, IFN-␣2b treatment was stopped (Figure 2). The patient has been observed without recurrence for two years since the topical IFN-␣2b was ceased. Patient 3: an 84-year-old woman who presented complaining of a red eye. Excision biopsy was performed and severe dysplasia diagnosed. After recurrence, she was treated with topical MMC 0.04% for three weeks. Residual dysplasia was present one month later, and an additional three week course of topical MMC 0.04% was given. The lesion did not resolve, and four months later, she initiated therapy with topical IFN-␣2b four times a day (Figure 3). At follow-up three months later, there was no resolution, and the dose was increased to six times a day. After a further four months, including 3 ⫻ 0.8-ml intralesional injections of IFN-␣2b, the lesion showed progression (Figure 4). Analysis of a biopsy sample of the lesion showed invasive squamous cell carcinoma. Although the VOL. 142, NO. 4
TOPICAL IFN-␣2B
FOR
FIGURE 1. Recurrent carcinoma in situ of limbus recalcitrant to previous excision and topical mitomycin C (MMC).
patient was reluctant to undergo surgery, extensive excision, including removal of the underlying scleral wall, was undertaken, but surgery failed to fully remove the OSSN. The eye and orbital contents were subsequently exenterated. Patient 6: an 60-year-old male presented with a recurrent OSSN of his left medial limbus. He had undergone previous excisions with cryotherapy as well as a previous course of topical MMC 0.04%. He was commenced on topical IFN-␣2b qid and two months later, the area of dysplastic epithelium had enlarged to involve both the superior and inferior cornea (Supplementary Figure 5 at AJO.com). The topical IFN-␣2b was ceased, and topical MMC 0.04% qid for seven days was repeated. Two months later, the lesion showed improvement (Supplementary Figure 6 at AJO.com), and a second course of MMC for seven days was administered with full resolution after one TREATMENT
OF
NEOPLASIA
569
FIGURE 2. Resolution of recurrent carcinoma in situ of limbus after 16 weeks of topical interferon alfa-2b (IFN-␣2b).
FIGURE 4. Progression of dysplasia to invasive squamous cell carcinoma of conjunctiva after failure of four months of topical and intralesional interferon alfa-2b (IFN-␣2b).
impression cytology and/or biopsy confirmation of the grade of the OSSN is highlighted by patient 3 of our series. Invasive squamous cell carcinoma cannot be managed by topical treatment alone, with persistence of topical therapy delaying definitive surgical treatment. For lesions that are extensive, involve the visual axis, or are residual, recurrent, multifocal or diffuse, surgery is not the ideal treatment. Topical preparations have advantages in the treatment of such lesions. There is no requirement to ensure clear tissue margins because the medication contacts the entire ocular surface, thus enabling treatment of multifocal or diffuse lesions with targeting of tumor cells.4,10 Furthermore, the increased cost, stress, pain, and trauma associated with a surgical procedure are avoided.4,10 Topical MMC, and to a lesser degree 5-fluorouracil, can resolve lesions when used alone and can reduce recurrence rates when used as an adjunct to surgical excision; however, their use can be associated with marked ocular surface toxicity with side effects including corneal edema, punctate epithelial keratoplasty, transient conjunctival injection, tearing, photophobia, ocular pain, and, potentially, limbal stem cell failure.11,12 In contrast, topical IFN-␣2b appears to be associated with few or no side effects. Schechter and associates4 reported local conjunctival injection and follicular conjunctivitis in four (57.1%) of seven patients. It was proposed, however, that the folliculitis was likely to be due to the vehicle that contained benzyl alcohol 0.09%, glycerin, and human albumin, and not the IFN-␣2b itself. Subconjunctival injections of IFN-␣2b have been associated with transient fevers and myalgias.6,8 The efficacy of IFN-␣2b in treating OSSN may be explained by its dual antiviral and antitumor effects. The onocogenic link between human papilloma virus (HPV) and squamous neoplasia of the uterine cervix is well established
FIGURE 3. Recurrent dysplasia of limbus and conjunctiva recalcitrant to previous excision and topical mitomycin C (MMC).
month. The patient has been observed for 68 weeks without recurrence.
DISCUSSION IFN-␣2B HAS BEEN REPORTED IN THE LITERATURE TO BE
effective as a primary treatment for OSSN, but its use as a chemotherapeutic agent for recalcitrant OSSN is not as well established.1,6 – 8 Boehm and Huang9 reported six cases of recurrent OSSN that were treated successfully with topical IFN-␣2b with a mean duration to resolution of 16.4 weeks (range five to 28 weeks). The cases in our report were specifically recalcitrant, having failed previous standard treatments, including surgical excision with or without cryotherapy and/or topical MMC. The importance of 570
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
OCTOBER 2006
and suspected as an etiologic agent in OSSN. Interferons also demonstrate antitumor activity by way of inhibition of cell growth and/or induction of tumor cell apoptosis. The antiviral effects of IFN-␣2b may also explain why IFN-␣2b may be less effective as a primary treatment in lesions not linked to HPV infection. Thus, IFN-␣2b’s recommended role in the management of OSSN is for recurrent or recalcitrant lesions that have failed to respond to MMC treatment. Our approach to noninvasive OSSN is a course of topical MMC (for example, MMC 0.04% four times a day for seven days, then three weeks off, repeating for up to four cycles), and if this fails to resolve the lesion, subsequent topical IFN-␣2b therapy. If there is no sign of treatment response after two months, then surgical excision is indicated. Other antiviral agents, such as cidofovir ((S)-1-[3-hydroxy-2-(phosphonomethoxy-propyl]cytosine), have been shown to enhance the antiviral effects of interferon on HPV-infected keratinocytes in vitro and may be useful as adjunctive therapy.13,14 Topical IFN-␣2b is a beneficial treatment modality for recalcitrant noninvasive OSSN that may be effective where surgical excision and MMC have failed. It is well tolerated and does not markedly damage the limbal stem cells. Further investigation is required to determine why certain lesions respond to topical MMC alone, whereas others require IFN-␣2b in combination with MMC, and how this may relate to concurrent ocular HPV infection. For invasive OSSN, topical therapy alone is contraindicated and necessitates surgical excision.
REFERENCES 1. Maskin SL. Regression of limbal epithelial dysplasia with topical interferon. Arch Ophthalmol 1994;112:1145–1146. 2. Schechter BA. Conjunctival intraepithelial neoplasia. Ophthalmology 1999;106:1642–1643.
VOL. 142, NO. 4
TOPICAL IFN-␣2B
FOR
3. Karp CL, Moore JK, Rosa RH Jr. Treatment of conjunctival and corneal intraepithelial neoplasia with topical interferon alpha-2b. Ophthalmology 2001;108:1093–1098. 4. Schechter BA, Schrier A, Nagler RS, Smith EF, Velasquez GE. Regression of presumed primary conjunctival and corneal intraepithelial neoplasia with topical interferon alpha2b. Cornea 2002;21:6 –11. 5. Schechter BA, Nagler RS. Successful treatment with 5-FU. Ophthalmology 2003;110:1262–1263. 6. Vann RR, Karp CL. Perilesional and topical interferon alfa-2b for conjunctival and corneal neoplasia. Ophthalmology 1999;106:91–97. 7. Hu FR, Wu MJ, Kuo SH. Interferon treatment for corneolimbal squamous dysplasia. Am J Ophthalmol 1998;125: 118 –119. 8. Kobayashi A, Yoshita T, Uchiyama K, et al. Successful management of conjunctival intraepithelial neoplasia by interferon alpha-2b. Jpn J Ophthalmol 2002;46:215–217. 9. Boehm MD, Huang AJ. Treatment of recurrent corneal and conjunctival intraepithelial neoplasia with topical interferon alfa 2b. Ophthalmology 2004;111:1755–1761. 10. Yeatts RP, Engelbrecht NE, Curry CD, Ford JG, Walter KA. 5-Fluorouracil for the treatment of intraepithelial neoplasia of the conjunctiva and cornea. Ophthalmology 2000;107: 2190 –2195. 11. Wilson MW, Hungerford JL, George SM, Madreperla SA. Topical mitomycin C for the treatment of conjunctival and corneal epithelial dysplasia and neoplasia. Am J Ophthalmol 1997;124:303–311. 12. Frucht-Pery J, Rozenman Y. Mitomycin C therapy for corneal intraepithelial neoplasia. Am J Ophthalmol 1994;117: 164 –168. 13. Johnson JA, Gangemi JD. Alpha interferon augments cidofovir’s antiviral and antiproliferative activities. Antimicrob Agents Chemother 2003;47:2022–2026. 14. Sherman MD, Feldman KA, Farahmand SM, Margolis TP. Treatment of conjunctival squamous cell carcinoma with topical cidofovir. Am J Ophthalmol 2002;134:432– 433.
TREATMENT
OF
NEOPLASIA
571
Biosketch David J. Holcombe, BSc, has a Bachelor of Science degree and is currently undertaking a combined Bachelor of Medicine and Surgery with a Doctorate of Philosophy at the University of Queensland, Australia. Dr Holcombe’s current PhD thesis involves investigating disturbances in neurotransmitter homeostasis in ocular disease. Dr Holcombe is expected to complete his studies in 2007 and pursue his long-term goal of a career in Ophthalmology.
571.e1
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
OCTOBER 2006
Biosketch Graham A. Lee, MD, FRANZCO, is an Associate Professor and completed his MBBS in 1991 at the University of Queensland (UQ), Brisbane, Australia, a MMedSc (Oph) in 1994 and FRANZCO in 2000. Dr Lee returned from the United Kingdom in 2001 completing a Glaucoma Fellowship at Birmingham and Midlands Eye Centre and a Cataract, Cornea and Refractive Fellowship at Moorfields Eye Hospital in London. In 2005, Dr Lee was awarded an MD (UQ) for his published works on anterior segment disease.
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NEOPLASIA
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FIGURE 6. Regression of dysplasia of the limbus, two months following a further course of topical mitomycin C (MMC) after failure of topical INF-␣2b.
FIGURE 5. Recurrent dysplasia of the limbus recalcitrant to previous excision, topical mitomycin C (MMC) and two months of topical INF-␣2b.
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AMERICAN JOURNAL
OF
OPHTHALMOLOGY
OCTOBER 2006