Topical Mitomycin C for the Treatment of Conjunctival and Corneal Epithelial Dysplasia and Neoplasia

doi:10.1016/S0002-9394(14)70822-0

American Journal of Ophthalmology

Volume 124, Issue 3, September 1997, Pages 303-311

https://doi.org/10.1016/S0002-9394(14)70822-0 Get rights and content

Purpose

To evaluate the efficacy of topical mitomycin C in treating conjunctival and corneal epithelial dysplasia and neoplasia.

Methods

Seven eyes of seven patients with conjunctival and corneal epithelial dysplasia and neoplasia were treated with one drop of topical mitomycin C 0.04% four times a day for 7 days in alternate weeks. The patients' charts were reviewed retrospectively. Patients with either multiple recurrences or extensive ocular surface involvement were treated. In all eyes, the diagnosis of epithelial dysplasia or neoplasia was confirmed by histopathology before the onset of therapy. Patients were examined at least every 14 days during treatment and examined at intervals after completion of treatment.

Results

With topical mitomycin C, six eyes of seven patients had complete clinical regression of their conjunctival and corneal epithelial dysplasia and neoplasia. One eye of one patient had partial clinical regression of conjunctival and corneal epithelial dysplasia. Follow-up after completion of topical mitomycin C therapy and excision of residual disease ranged from 2 to 16 months (mean, 9 months; SD, 4.3 months) and was without clinical sign of recurrence. Topical mitomycin C therapy was associated with transitory ocular discomfort, conjunctival injection, tearing, photophobia, and punctate epithelial keratopathy.

Conclusion

In this small series of eyes, topical mitomycin C was effective as a treatment for conjunctival and corneal epithelial dysplasia and neoplasia.

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One study by Russell et al. reported that long-term complications following topical MMC therapy occurred in 33% of cases [24]. The most common side effects are ocular irritation (30–100%) [15,18,19,22,23,25], allergic lid or conjunctival reaction (9.3–60%) [19–21,25–27], conjunctival hyperemia (8–100%) [15,19,21–23,28] and corneal epithelial erosions (1–50%) [15,19–23]. The most severe complication is cytotoxicity to limbal stem cells and corneal epithelial cells, leading to LSCD (0–12%) [15,18,24,26,29].
Local chemotherapy is increasingly used, either in combination with surgery or as monotherapy, for management of ocular tumors. Yet many of the local chemotherapeutic agents used for ocular tumors are cytotoxic drugs that are frequently associated with toxicities in normal ocular tissues. Understanding and managing these side effects are important because they affect treatment tolerability, outcome and quality of vision. Herein, we review local anticancer drugs administered for the treatment of ocular tumors, with an emphasis on their toxicities to the ocular surface, adnexa and lacrimal drainage system. We provide the underlying mechanisms and management strategies for the ocular side effects. Recent innovations in anticancer immunotherapy and ocular drug delivery systems also are discussed as new potential therapeutic modalities for alleviation of side effects.
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To compare the efficacy of topical 5-fluorouracil 1% (5FU) and interferon alfa-2b 1 MIU/mL (IFN) eye drops as primary treatment modalities for ocular surface squamous neoplasia (OSSN).
Retrospective, comparative, interventional case series.
Fifty-four patients who received 5FU and 48 patients who received IFN as primary therapy for OSSN were included. Primary outcome measures were the frequency of clinical resolution and time to OSSN recurrence by treatment modality. Secondary outcome was the frequency of side effects with each therapy.
The mean age of patients was 68 years. More Hispanics were treated with 5FU. In a univariable analysis, frequency of OSSN resolution was higher with 5FU (96.3%, n = 52) than with IFN (81.3%, n = 39), P = .01. In a multivariable analysis, treatment modality did not remain a significant predictor of resolution. In patients whose OSSN resolved, time to resolution was similar with both agents, (5FU mean 6.6 months, standard deviation (SD) 4.5 vs IFN mean 5.5 months, SD 2.9, P = .17). Of the 52 eyes whose OSSN resolved with 5FU, 11.5% of lesions (n = 6) recurred, whereas of the 39 eyes whose OSSN resolved with IFN, 5.1% of lesions (n = 2) recurred, P = .46. Kaplan-Meier survival curves of OSSN recurrence were similar between groups (log-rank = 0.16). One-year recurrence rates were 11.4% with 5FU and 4.5% with IFN. Eyelid edema (P = .04) and tearing (P = .02) were more significant with 5FU.
This is the first direct comparison study between 5FU and IFN eye drops as primary treatment modalities for OSSN. Both modalities resulted in a high frequency of tumor resolution and low recurrence rates and are effective treatment options for OSSN.
Topical 5-Fluorouracil 1% as Primary Treatment for Ocular Surface Squamous Neoplasia Presented Cornea Society/Fall Educational Symposium, November 2015, Las Vegas, Nevada.
2016, Ophthalmology
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In our study, representing the largest group of patients treated with 5-FU as primary therapy to date, we found that 82% of patients experienced complete resolution of OSSN. Our response frequency of 82% for 5-FU is similar to what has been reported in larger series of IFN- and MMC-treated patients.11,20–26,28–35 One issue in comparing treatment response between 5-FU studies is that varying regimens have been used to treat OSSN.
To determine the efficacy of topical 5-fluorouracil 1% (5-FU) as a primary treatment of ocular surface squamous neoplasia (OSSN).
Retrospective study.
Topical 5-FU was used as primary therapy in 44 patients with OSSN.
5-Fluorouracil 1% administered topically 4 times daily for 1 week followed by a drug holiday of 3 weeks. Patients were identified through a pharmacy database. Patients were excluded if 5-FU was used as adjuvant therapy, if they did not complete therapy, or if they were still actively receiving treatment for OSSN at the time of last follow-up.
The primary outcome measures were the frequency of complete resolution with topical 5-FU treatment and the rate of OSSN recurrence.
Of the 44 patients identified, 32 were men and 12 were women. The mean age was 68 years. Complete resolution of OSSN was noted in 82% of patients (36/44); 18% (8/44) were considered treatment nonresponders. Patients were treated with a median of 4 cycles (range, 2–9 cycles). Nasal location was the only risk factor identified for nonresponse to therapy (P = 0.04). The median follow-up after resolution was 10 months (range, 2–77 months). In the 36 patients who showed complete resolution, 4 experienced tumor recurrence. Recurrence rates at 1 and 2 years were 6% and 15%, respectively, using Kaplan-Meier survival analysis. At least 1 side effect from the medication was reported by 61% of patients (21/44), but only 1 patient discontinued the medication because of intolerance. The most common side effect was pain (n = 17; 39%), followed by tearing (n = 10; 23%), photophobia (n = 6; 14%), itching (n = 4; 9%), swelling (n = 2; 5%), and infection (n = 1; 2%). No long-term complications were reported.
5-Fluorouracil is effective and well tolerated as a primary treatment for OSSN, with 82% of tumors responding completely to therapy.
The corneal fibrosis response to epithelial-Stromal injury
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The corneal wound healing response, including the development of stromal opacity in some eyes, is a process that often leads to scarring that occurs after injury, surgery or infection to the cornea. Immediately after epithelial and stromal injury, a complex sequence of processes contributes to wound repair and regeneration of normal corneal structure and function. In some corneas, however, often depending on the type and extent of injury, the response may also lead to the development of mature vimentin+ α-smooth muscle actin+ desmin+ myofibroblasts. Myofibroblasts are specialized fibroblastic cells generated in the cornea from keratocyte-derived or bone marrow-derived precursor cells. The disorganized extracellular matrix components secreted by myofibroblasts, in addition to decreased expression of corneal crystallins in these cells, are central biological processes that result in corneal stromal fibrosis associated with opacity or “haze”. Several factors are associated with myofibroblast generation and haze development after PRK surgery in rabbits, a reproducible model of scarring, including the amount of tissue ablated, which may relate to the extent of keratocyte apoptosis in the early response to injury, irregularity of stromal surface after surgery, and changes in corneal stromal proteoglycans, but normal regeneration of the epithelial basement membrane (EBM) appears to be a critical factor determining whether a cornea heals with relative transparency or vision-limiting stromal opacity. Structural and functional abnormalities of the regenerated EBM facilitate prolonged entry of epithelium-derived growth factors such as transforming growth factor β (TGF-β) and platelet-derived growth factor (PDGF) into the stroma that both drive development of mature myofibroblasts from precursor cells and lead to persistence of the cells in the anterior stroma. A major discovery that has contributed to our understanding of haze development is that keratocytes and corneal fibroblasts produce critical EBM components, such as nidogen-1, nidogen-2 and perlecan, that are essential for complete regeneration of a normal EBM once laminin secreted by epithelial cells self-polymerizes into a nascent EBM. Mature myofibroblasts that become established in the anterior stroma are a barrier to keratocyte/corneal fibroblast contributions to the nascent EBM. These myofibroblasts, and the opacity they produce, often persist for months or years after the injury. Transparency is subsequently restored when the EBM is completely regenerated, myofibroblasts are deprived of TGFβ and undergo apoptosis, and the keratocytes re-occupy the anterior stroma and reabsorb disordered extracellular matrix. The aim of this review is to highlight factors involved in the generation of stromal haze and its subsequent removal.
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To review the published literature assessing the efficacy and safety of mitomycin-C (MMC) as an adjunctive treatment in corneal surface excimer laser ablation procedures.
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Topical Mitomycin C for the Treatment of Conjunctival and Corneal Epithelial Dysplasia and Neoplasia

Purpose

Methods

Results

Conclusion

Ophthalmology

Am J Ophthalmol

Am J Ophthalmol

Am J Ophthalmol

Ophthalmology

Am J Ophthalmol

Ophthalmology

Ophthalmology

Ophthalmology

Ophthalmology

Ophthalmology

Ophthalmology

Bowen's disease of the conjunctiva: a misnomer

Therapy of intraepithelial epitheliomas and squamous cell carcinoma of the limbus

Trans Am Ophthalmol Soc