Although there are no randomised trials directly comparing topical chemotherapeutic agents mitomycin-C, 5-fluorouracil, and interferon-α2b, published studies indicate equal efficacy of these agents for treatment of non-invasive ocular surface squamous neoplasia (80%–88%). 5-Fluorouracil may be preferred, given low incidence of serious side effects and low cost to the patient.
- Ocular surface
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Ocular surface squamous neoplasia (OSSN) is a spectrum of malignant neoplasia of the conjunctiva, limbus and cornea that includes epithelial dysplasia, carcinoma-in situ and invasive squamous cell carcinoma (SCC). Numerous factors including genetic predisposition, UV light exposure, smoking, immunosuppression, and human papillomavirus infection have been identified as risk factors.1
The traditional treatment for OSSN has been complete surgical excision with visible clear margins combined with intraoperative cryotherapy to the conjunctival margins.1–5 Large resections of conjunctiva and limbal tissue, however, may lead to limbal stem cell deficiency, shallowing of fornices and restriction of ocular motility, and may leave a glaucomatous eye with limited conjunctival tissue for a filtering procedure. Although recurrence rates after surgical excision with cryotherapy have improved in recent years (about 5%), recurrence rates as high as 52% have been reported.4 6 7
Recent studies have reported the use of topical chemotherapeutic agents such as mitomycin-C (MMC), 5-fluorouracil (5-FU) and interferon-α2b (IFN-α2b) in the treatment of OSSN. The topical chemotherapeutic agents offer many advantages over the traditional surgical excision and cryotherapy. They are able to deliver treatment not only to the affected surface but also to the entire ocular surface, potentially eliminating subclinical OSSN. Topical chemotherapy also has a superior cost-effective profile, has a diminished the risk of inducing limbal stem cell deficiency and is associated with reduced patient morbidity.8–11
Topical chemotherapy is used in several clinical settings; preoperatively, intraoperatively and postoperatively. Preoperative (neoadjuvant chemotherapy) application is with the intent of decreasing tumour size prior to definitive surgery.1 11 Intraoperative application is used as a substitute for cryotherapy. Postoperative application may be for the positive surgical margins (adjuvant chemotherapy) with an intention of reducing the risk of recurrence or when recurrence is observed, in which case, the chemotherapy is used instead of repeat excision. However, topical chemotherapy may also be used instead of traditional excision and cryotherapy.11
Structure and mechanism of action
Mitomycin-C is an antibiotic, usually classified as an alkylating agent, isolated from Streptomyces caespitosus. It has a molecular weight of 334 daltons and is soluble in water and organic solvents. When applied topically, it mainly acts under aerobic conditions generating free radicals causing cytotoxicity, DNA, and protein damage via lipid peroxidation.12 13 MMC also inhibits cell migration and production of extracellular matrix.14 15
Studies in rabbit models have found that topical MMC clears quite rapidly from the ocular tissues including the anterior chamber (0.18–0.45 h).16 Mietz et al17 found aqueous concentrations of 0.02 μg/ml MMC after topical use at a concentration of 0.5 mg/ml. A potential bioactivating enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1, DT-diaphorase) for MMC has been detected in OSSN and in normal tissues from human donor eyes.18 MMC may be stored at room temperature (22°C) for up to 1 week and refrigerated (4°C) for up to 3 months, and still preserve 90% of its activity.19 20
The use of topical MMC for OSSN was first described by Frucht-Pery et al in 1994.21 Since then, several case series using different treatment concentrations and duration have been published.22 23 The most widely used protocol consists of 0.02% of topical MMC given four times a day to the affected eye for 2 weeks and repeated until the lesion regresses. Others have demonstrated that an even smaller concentration of 0.002% of MMC may be effective.22 Overall, excellent response rates ranging from 87.5% to 100% have been reported.
It is important to wait for complete healing after the biopsy prior to starting the topical chemotherapy so as to avoid the risk of corneo-scleral melt. Mitomycin C is usually well tolerated by patients when taken daily for 1–2 weeks with a recovery period of 1 week. The cellular toxicity is dose-dependent. Patients with MMC toxicity may present with signs of conjunctival hyperaemia, blepharospasm,13 corneal punctate erosions, punctal stenosis24 and limbal stem cell deficiency with higher doses.25 Some of these side effects may be managed by stopping the medication and adding a topical steroid drop three or four times daily. To prevent punctal stenosis, punctal plugs are placed in both the superior and inferior puncti. This also allows for the drug to permeate the affected tissue for a longer period of time and reduces the drug absorption by the nasal mucosa. MMC may also cause allergic blepharoconjunctivitis.
Structure and mechanism of action
5-Fluorouracil (5-FU) is a pyrimidine analogue, structurally similar to thymine and uracil.26 The main mechanism of action is by inhibiting the production and incorporation of thymidine into DNA during the S phase of the cell cycle. 5-FU also inhibits RNA synthesis, destroys actin cytoskeleton and promotes apoptosis of the Tenon capsule fibroblasts.26 27
The minimum concentration required to achieve a 50% inhibitory effect on human dermal fibroblasts is only 0.35 mg/ml.28 Fantes et al demonstrated in rabbit models that 5-FU achieved intraocular penetration when applied topically,29 with aqueous concentration levels reaching 0.9 μg/ml in 12 h after one drop containing 2.4 mg of 5-FU. This intraocular level is non-toxic to the optic nerve or retina.30
The use of topical 5-FU in the treatment of premalignant ocular surface lesions was first described by de Keizer et al in 1986.31 5-FU is prescribed as a 1% topical solution typically applied four times a day for 4 weeks continuously or in cycles of 4 days ‘on’ followed by 30 days ‘off’ until resolution of the lesion is achieved.8 9 32 Some authors have described effectiveness of 5-FU in cases refractory to topical MMC.33
The ocular side effects of topical 5-FU are similar to those with MMC. The most common side-effects described in the literature are conjunctival and corneal inflammation, corneal epithelial defects and eyelid skin erythema.8 Patient complaints can range from irritation and discomfort to frank pain. In an effort to decrease the toxicity of 5-FU to the ocular surface, cycling of the antimetabolite is suggested by applying it four times a day for 2–4 days and stopping it for 30–45 days, followed by a new cycle until resolution of the lesion is accomplished. The side effects of conjunctival irritation may be managed by either stopping the drug or adding a topical corticosteroid and non-preserved artificial tears.
Structure and mechanism of action
The glycoprotein IFN-α 2b is a type 1 interferon consisting of 165 amino acid residues with arginine in position 23. It is produced by recombinant DNA technology (Intron-A, Schering, Bloomfield, New Jersey) and it is used for the treatment of Hepatitis B and C, condyloma acuminata, hairy cell leukaemia and Kaposi sarcoma in AIDS.34 35 The mechanism of action of IFN- α 2b in the treatment of ocular tumours is only partially understood. Kim et al36 found that IL-10 was strongly expressed in basal cell and squamous cell carcinoma of the skin. IL-10 is a known potent immunosuppressive cytokine which may contribute to immune dysregulation and suppression of antitumour T cell responses and perhaps facilitating tumour growth.37 It has been observed that the intralesional injection of IFN-α2b suppresses the expression of IL-10 and stimulates the expression of IL-2 and IFN-γ mRNA, which are type 1 cytokines important in T cell immunity.36 38 This evidence suggests that the expression of IL-10 by tumour cells provides a mechanism to evade the local immune response.36
The exact ocular pharmacokinetics is not well understood. The intraocular levels reached after topical application is unknown as well as its minimum inhibitory levels required for ocular tumour suppression. When applied subconjunctivally, systemic side effects similar to systemic application may occur.10
Because of its success in the treatment of epidermal squamous tumours and cervical intraepithelial neoplasia related to human papilloma virus infection, it was first investigated by Maskin et al in 1994 for therapeutic value in OSSN.10 39–43 The typical dose of IFN- α 2b given topically is 1 million IU/ml. It may also be given as a subconjunctival injection of 3 million IU/ml.10 Schechter et al44 have evaluated the recurrence rate after treatment with IFN-α 2b and found it to be 3.7% in patients followed for more than a year, and a resolution rate of 96.4% in this same group of patients.
In this issue, Galor et al report a retrospective study of 33 eyes with non-invasive OSSN and two eyes with SCC, treated with topical IFN-α2b. Neither eye with SCC responded to interferon therapy.45 However, 85% of the patients with non-invasive OSSN responded with no significant differences between those treated with 1 million IU/ml (21 eyes) and those with 3 million IU/ml (12 eyes). After a median follow-up of 24 months, three recurrences were observed. Topical interferon therapy was well tolerated, with most common side effects being ocular discomfort and photophobia. There was a trend towards a greater frequency of side effects with a dose of 3 million IU/ml. The authors recommend using the 1 million IU/ml dose for the treatment of non-invasive OSSN.45
In another retrospective but comparative interventional case series of 29 consecutive patients with OSSN, 15 elected topical interferon (1–3 million IU/ml), and 14 chose surgical excision.46 Two patients in the interferon group subsequently underwent surgical excision for lack of response. No patient in either group developed a recurrence during the mean study period of almost 3 years. The authors concluded that both topical interferon α-2b and aggressive surgical excision offer comparable disease-free interval.46
Topical IFN-α 2b has fewer ocular side effects than the other topical chemotherapeutic agents used in OSSN. The side effects range from none to a mild and transient keratitis and follicular conjunctivitis.10 34 35 41 Unusual complications of corneal epithelial microcysts have also been observed with both topical47 and systemic use of interferon α-2b.48 Although rare, systemic side effects such as fevers, myalgias and fatigue may occur when the drug is injected subconjunctivally.10 Retinopathy and neuropathy after systemic use of IFN- α 2b have been reported.49 50
Upon review of the literature, it became apparent that inclusion criteria vary widely among studies. Based upon the published data and personal experience, relative indications for using topical chemotherapy in the setting of non-invasive OSSN are summarised (table 1).
Topical chemotherapeutic agents have demonstrated acceptable efficacy in inducing tumour regression when used as primary therapy in non-invasive OSSN. However, topical chemotherapy as sole treatment for invasive SCC is not recommended. Instead, topical chemotherapy may be used before surgery (neoadjuvant) or after surgery (adjuvant) in cases with incompletely excised SCC.51
Comparison of these three drugs for the treatment of non-invasive OSSN reveals that MMC is the most effective (88%), followed by 5-FU (87%) and IFN-α 2b (80%).35 IFN-α2b has shown favourable regression rates in published case series,5 41 but resolution of the lesion may take several months.7 Although MMC has the highest reported rate of side effects (76% of patients developing at least one side effect), this may be a skewed observation, as MMC is also the most frequently used topical chemotherapy agent.35 MMC is contraindicated in cases of severe dry eye and atopy.42 44 5-FU is generally well tolerated with fewer side effects than MMC, which include keratitis and conjunctival hyperaemia as the most common. IFN-α 2b is the least toxic. When a patient is intolerant to topical treatment with one agent, switching to a different agent is possible. When electing a drug, one must always consider the cost/benefit aspects as well. Although the costs vary widely, IFN-α2b is the costliest of three agents. As these drugs are not approved for treatment of OSSN by the Food and Drug Administration (USA), their use is considered ‘off-label,’ and so informed consent should be obtained from the patient. It is preferable to use these agents in a setting of an institutionally approved clinical trial. Although there are no randomised trials directly comparing one agent with the other, 1% 5-FU may be the preferred topical chemotherapeutic agent, given its low incidence of serious side effects, comparable effectiveness to the other agents and low cost to the patient.
Linked articles 153197.
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.