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Original article
Adjuvant 5-fluorouracil in the treatment of localised ocular surface squamous neoplasia
  1. Adam K Rudkin1,
  2. James S Muecke1,2
  1. 1South Australian Institute of Ophthalmology, Adelaide, South Australia, Australia
  2. 2Discipline of Ophthalmology & Visual Sciences, University of Adelaide, South Australia, Australia
  1. Correspondence to Dr Adam K Rudkin, South Australian Institute of Ophthalmology, c/o Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia; rudkin.adam{at}gmail.com

Abstract

Aim To report the outcome of treatment of localised non-invasive ocular surface squamous neoplasia (OSSN) where topical 5-fluorouracil (5-FU 1%) is used as an adjuvant to surgical excision.

Methods The study was a prospective non-comparative interventional case series. 55 cases of primary localised OSSN and 10 cases of recurrent localised OSSN were treated with excision, cryotherapy and adjuvant 5-FU 1%. In all cases, irrespective of the involvement of surgical margins, a single cycle of 5-FU 1% was administered, four times a day for 2 weeks continuously. The main outcome measures were (1) recurrence and (2) complications related to adjuvant topical chemotherapy. Individuals were reviewed for a minimum of 12 months.

Results There was a single case of recurrence (1.5%). 57% of patients had short-term complications secondary to 5-FU 1%, most frequently lid toxicity (49%), followed by superficial keratitis, epiphora and corneal epithelial defects. Four patients were unable to complete the course of 5-FU 1% because of local toxicity.

Conclusions The management of localised non-invasive OSSN with adjuvant 5-FU 1% was associated with a low rate of local recurrence. Although 5-FU 1% frequently results in short-term complications, most commonly lid toxicity, a full course is usually tolerated. Serious complications appear uncommon in the treatment of localised disease.

  • conjunctival neoplasms [C04.588.364.235]
  • neoplasms
  • squamous cell [C04.557.470.700]
  • antineoplastic agents [D27.505.954.248]
  • ocular surface squamous neoplasia (non-MeSH)
  • 5-fluorouracil (non-MeSH)
  • conjunctiva
  • cornea
  • neoplasia
  • treatment surgery
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Introduction

Ocular surface squamous neoplasia (OSSN) comprises a spectrum of disease of the cornea and conjunctiva that includes conjunctival–corneal intraepithelial neoplasia and squamous cell carcinoma (SCC). Traditionally the treatment of choice for localised OSSN has been surgical excision, with or without adjuvant cryotherapy. Recurrence rates following excision are high and reflect, in part, the difficulty in clinical and histopathological demarcation of the tumour margins.

A number of topical chemotherapeutic agents are used to treat localised and diffuse OSSN, including mitomycin-C,1–6 5-fluorouracil (5-FU),7–12 and topical and intralesional interferon alpha 2b.13–15 Used as an adjuvant to excision and cryotherapy, mitomycin-C in particular has had favourable results in the treatment of localised non-invasive OSSN.6 The use of 5-FU has been described in a number of case reports and small case series as a successful primary treatment in many cases of invasive or diffuse OSSN.7–12 The efficacy of 5-FU as an adjuvant to surgery and cryotherapy for non-invasive OSSN has not been reported.

In this paper, we examine localised non-invasive OSSN that has been managed according to a standard chemotherapeutic protocol using 5-FU 1%. Specifically it reports rates of recurrence and surgical and medication complications.

Methods

This study is a prospective, non-comparative interventional case series of 65 eyes with primary or recurrent non-invasive OSSN lesions. All cases were treated in a single ocular oncology centre from July 2005 to December 2009. The study was conducted in accordance with the declaration of Helsinki, and informed patient consent was obtained in each case.

The study included consecutive cases in which there was an isolated OSSN lesion located at the limbus. The study included but distinguished between lesions that were primary, and lesions that were recurrent. All of the recurrent lesions had undergone treatment at a separate centre before referral and inclusion within this study. No patient with recurrent disease had previously undergone treatment with 5-FU. Lesions with inoperable diffuse spread (defined as more than five clock hours in limbal extent) were excluded. Lesions in which there was severe dysplasia and invasion of the basement membrane were classified histologically as squamous cell carcinoma (invasive OSSN) and were excluded from the study.

Diagnosis

Lesions were diagnosed as non-invasive OSSN on the basis of histopathological examination from an excisional biopsy (surgical method defined below). The following definitions were used to grade lesions:

  • CIN grade I: mild dysplasia limited to the basal one-third of the corneal or conjunctival epithelium;

  • CIN grade II: moderate dysplasia confined to the basal two-thirds of the corneal or conjunctival epithelium;

  • CIN grade III, or SCC in situ: severe dysplasia that may involve the entire thickness of the corneal or conjunctival epithelium but does not invade the basement membrane.

Additionally, data were collected regarding the clearance of tumour from the surgical margins of the specimen.

Treatment

All patients underwent excision of the lesion by a single ocular oncologist (JM). This was performed by complete superficial dissection from the cornea and limbus (not lamellar dissection). The margins of the conjunctival excision included a 2 mm rim of normal-appearing epithelium. Following excision, double freeze–thaw cryotherapy was applied with a nitrous oxide cryoprobe to the limbal base and to the full thickness of the conjunctival edge. Care was taken to elevate the conjunctiva to avoid freezing the underlying scleral bed. Postoperatively, all patients were treated with chloramphenicol and prednisolone acetate eye-drops four times daily until wound healing was complete.

The adjuvant chemotherapeutic agent administered in this study was 5-FU 1%. 5-FU is a pyrimidine analogue with a chemical structure related to thymine and uracil. Its active metabolite, 5-fluorodeoxyuridine 5′-monophosphate, inhibits thymidylate synthetase and the incorporation of thymidine into DNA. This mechanism is cell-cycle-specific, affecting only those cells in the S (synthesis) stage. A uniform, single-cycle, chemotherapy protocol was instituted after complete epithelial healing (typically within 1 month of excision). All patients received adjuvant chemotherapy irrespective of tumour involvement of the surgical margins. The 5-FU 1% solution was prepared under cytotoxic laminar flow conditions, and diluted to 1% with NaCl (0.9%). The 5-FU 1% eye-drops were self-administered by the patient, four times a day, continuously for 2 weeks. Punctal plugs were not used.

Follow-up

Upon completion of 5-FU 1%, the planned follow-up was at 1, 3 and 6 months, then at 6-monthly intervals for 2 years and then yearly for 5 years. A minimum of 12 months' follow-up was required for inclusion in this study. Data collected during follow-up included complications related to surgery, completion of the chemotherapy course, short- and long-term complications associated with adjuvant chemotherapy, and recurrence of tumour.

Results

Sixty-five eyes from 64 individuals were included in the study. There was a preponderance of males (49, compared with 15 females). The mean age was 66.3±14.1 years. All individuals were Caucasian. The median follow-up was 23 months (range 12–59 months). There were 55 cases of primary localised OSSN and 10 cases of recurrent disease. The histopathological grade of the lesions and the rate of surgical margin involvement are described in table 1.

Table 1

Localised ocular surface squamous neoplasia—disease type, involvement of surgical margins, and rate of recurrence

Tumour recurrence

A single recurrence was observed in the localised OSSN cohort. This occurred in a case of primary grade III CIN where the surgical margins were not clear of disease, and treatment with 5-FU 1% was ceased prematurely (day 8) because of corneal toxicity.

Complications

An adverse effect of 5-FU 1% was observed in 56.9% of cases (37 eyes). The frequency of short-term complications associated with 5-FU 1% is detailed in table 2. Lid toxicity was the most common complication. In one instance, lid toxicity was associated with generalised contraction of the lower lid skin and resulted in an ectropion and epiphora. Following cessation of treatment, the skin changes improved, and epiphora resolved without the need for further treatment. There was one instance of a corneal epithelial defect, which resulted from an occult area of residual corneal OSSN which shed as a result of treatment with 5-FU 1%.

Table 2

Frequency of short-term complications associated with adjuvant treatment of localised ocular surface squamous neoplasia with 5-fluorouracil

Long-term complications included a single case of epiphora that settled following saline irrigation of the lacrimal drainage system. It is hypothesised that this was related to punctal or canalicular stenosis. An example of lid toxicity in a patient from this series is represented in figure 1.

Figure 1

Example of severe lid toxicity observed in the treatment of ocular surface squamous neoplasia with 5-fluorouracil 1%.

Four patients were unable to complete their course of topical 5-FU 1% because of adverse effects. One patient had developed an epithelial defect, two had developed painful superficial keratitis, and three had severe lid toxicity.

Discussion

Surgical excision has been the traditional method of treatment for OSSN, and the use of adjuvant cryotherapy is also well established.2 16 17 However, this approach is associated with high rates of tumour recurrence.18 Large retrospective studies estimate the rate of recurrence in non-invasive disease to be 24–39%.19–21 A smaller, single centre, study which utilised a standard surgical technique of excision with a 2–3 mm margin reported a 15% recurrence rate in primary non-invasive OSSN.22 The same study noted that when recurrent tumours were treated in the same way, the rate of second recurrence increased to 33%.

Incomplete excision of the tumour is a major risk factor for tumour recurrence.19 21 However, it is notable that in a proportion of cases, complete excision appears to be insufficient to prevent recurrence. In the series with the longest follow-up, recurrence despite surgical clearance occurred with concerning frequency—one in three patients.21 A high recurrence rate with traditional techniques and the observation that surgical excision alone is inadequate for some lesions have led to the use of adjuvant antineoplastic agents, including mitomycin-C,1–6, 5-FU,7–12 and topical and intralesional interferon alpha 2b.13–15 The observation of recurrence despite clearance of surgical margins is also the basis of our protocol which treats all lesions irrespective of the clearance of the surgical margin.

In the absence of clear evidence to support one method over another, a diversity of treatment protocols exist for these antineoplastic agents. Two basic principles of treatment were considered in the creation of our protocol. The first principle was to obtain an adequate histopathological diagnosis through excisional biopsy. The second principle was to treat the lowest possible tumour load with a high but tolerable dose of a topical chemotherapeutic agent. The protocol used in this series was adapted from the work of Midena and colleagues who used 5-FU 1%, four times a day, for 4 weeks as a primary treatment of OSSN.11 As 5-FU was used as an adjuvant treatment in our series, we reduced the total length of treatment to 2 weeks in an effort to minimise toxicity.

In our series, the use of excision, cryotherapy and adjuvant 5-FU 1% resulted in an overall rate of recurrence of 1.5% for localised non-invasive OSSN. This is the largest series to date examining the use of 5-FU 1% in OSSN, and is the first series examining its use as an adjuvant to surgical excision and cryotherapy. Our rate of recurrence with 5-FU 1% is similar to results in which adjuvant mitomycin-C 0.04% was used in combination with excision and cryotherapy: in 80 cases of localised disease, no recurrence was observed over a median follow-up time of 57 months.6 It is notable that recurrence in the current study was low despite the involvement of surgical margins in 30% of cases of primary localised non-invasive OSSN and 60% of cases of recurrent localised non-invasive OSSN. The high rate of involvement of the surgical margin is characteristic of OSSN and exemplifies the difficulty in achieving tumour clearance by surgical excision based on the clinical features alone (in this study, a 2 mm margin of normal appearing conjunctiva).

We acknowledge that this study is limited by the period of follow-up (minimum 1 year) and that the rate of late recurrence is not certain. Although we have not yet observed late recurrences in our cohort of localised lesions treated with mitomycin-C during the period from 1998 to 2009, the incidence of late recurrence in the 5-FU 1% cohort is yet to be determined.6

5-FU in treatment of OSSN

De Keizer and colleagues first reported the successful treatment of two patients with diffuse OSSN with topical 5-FU 1% as primary treatment in 1986.7 Since that time, there have been a limited number of further studies describing the use of 5-FU for OSSN, and these studies often include a heterogeneous cohort of invasive and non-invasive disease, and heterogeneous treatment protocols.

Yeatts and colleagues reported using 5-FU 1% drops to treat six patients with OSSN lesions.8 In this series, topical 5-FU 1% was used either as primary chemotherapy or following debulking of the tumour. At a minimum follow-up of 10 months, remission was observed in four cases. One case required repeat excision, and notably, in one case invasive disease necessitated evisceration of the eye.

Yeatts and colleagues studied a series of seven patients with localised or diffuse OSSN lesions who were treated with 5-FU 1% as the primary therapy.9 Incisional biopsies were used to obtain histopathological diagnosis, and pathology included cases of both invasive and non-invasive disease. A pulsed dosing of 5-FU 1% was used, with durations of 2–4 days for each cycle. The number of initial treatment cycles was two to six, with the time between cycles being 30–45 days. At a minimum of 7 months' follow-up, three patients had tumour recurrence; two patients were successfully treated with additional cycles of topical 5-FU 1%, and one patient required additional treatment with topical mitomycin-C for persistent disease.

After demonstrating its use in a single case of diffuse OSSN, Midena and colleagues carried out a prospective study of eight patients with invasive OSSN who were treated with a uniform chemotherapy protocol comprising 5-FU 1% administered four times daily for 4 weeks.11 12 Two patients had primary disease and had not undergone excision, three patients had undergone incomplete excision, and three patients had recurrent disease and had not undergone re-excision. At a minimum follow-up of 13 months, local recurrence was identified in one patient who was successfully retreated with a second 4-week course of topical 5-FU 1%.

Although these studies include cases of invasive OSSN that have been effectively treated with 5-FU, we specifically excluded cases of invasive disease from this study. In our practice, invasive OSSN without evidence of ocular or orbital invasion is typically managed with excision and cryotherapy, followed by adjuvant beta radiotherapy (strontium-90) following wound healing. Our concern is that topical 5-FU, while potent against the rapidly dividing squamous cells at the ocular surface, will have limited efficacy against poorly differentiated squamous neoplasia beneath the basement membrane. We note that in a number of published cases, orbital invasion has occurred despite topical chemotherapy for invasive SCC.9 23

Complications

5-FU is toxic to actively replicating cells, and at sufficient concentration, its effect on the corneal epithelium is pronounced.24 5-FU is commonly used as an adjunct to glaucoma surgery, and in this context its side-effect profile is well known. Manifestations include punctate keratopathy, filamentary keratopathy, epithelial defects and whorl-like keratopathy. The side effects are generally self-limiting once the 5-FU is withdrawn. Although uncommon, serious adverse effects from 5-FU have been reported following glaucoma surgery, and these include endophthalmitis, bacterial ulceration, corneal melting and perforation.25

In the context of treatment of ocular surface malignancies, side effects appear to be mild.24 Midena and colleagues used 5-FU 1% (one drop, four times per day) for 4 weeks to treat OSSN, and noted near universal occurrence of transient conjunctivitis and superficial keratitis.11 Toxicity was easily controlled with topical drugs (artificial tears and antibiotics) within 5–6 days following cessation of treatment. The same research group has recently published a prospective study on the effects of 5-FU 1% for OSSN and demonstrated that it had no long-term effects on endothelial cell count, pleomorphism and polymegatism, anterior stromal keratocyte density, subbasal nerve plexus fibre number, density, and beadings or central cornea epithelium thickness.26 In our series, side effects occurred commonly (57% of cases) but were generally transient and well tolerated. No serious side effects or long-term morbidity was observed.

Interferon alpha-2b and mitomycin-C are alternatives to the treatment of OSSN and offer differing side-effect profiles. Interferon alpha-2b is regarded as having fewer side effects than either 5-FU or mitomycin-C.27 However, interferon apha-2b typically takes several months to achieve tumour regression, is associated with higher rates of tumour recurrence when compared with either 5-FU or mitomcin-C, and is the most expensive of all three potential agents.26 Mitomycin-C has been used with success most commonly as either a 0.02% or 0.04% concentration, although there is a paucity of evidence as to whether the side-effect profile of 5-FU 1% is superior to that of mitomycin-C. In our own practice, we found that adjuvant mitomycin-C (0.04%, four times a day, for two to three 1-week cycles) was not associated with serious side effects and was generally well tolerated.6 However, the rate of post-treatment epiphora appears to be higher in cases treated with mitomycin-C 0.04% (15%, versus 8% for cases treated with 5-FU 1%). The underlying cause for epiphora following treatment with 5-FU is not certain. In some cases, it appears to be related to punctal or canalicular stenosis, and symptoms resolve following cessation of treatment, and punctal dilatation and syringing of the lacrimal drainage system. In one case, epiphora was associated with lid toxicity and contracture of the lower lid skin. Punctal or cannalicular stenosis may have been avoided with the universal use of punctal occlusion prior to chemotherapy, although the conceivable benefits of punctal occlusion need to be measured against the potential cost and inconvenience of these devices.

Conclusion

This study suggests that 5-FU 1% is an effective adjuvant to excision and cryotherapy in the management of localised non-invasive OSSN. Rates of recurrence in this study were comparatively low compared with studies examining the use of surgical excision alone or excision with adjuvant cryotherapy. Our results also suggest that 5-FU 1% may be an effective alternative to the use of mitomycin-C 0.04%. It is, however, unlikely that a head-to-head randomised trial could be established to compare the efficacy of 5-FU 1% and mitomycin-C, as the rate of recurrence is sufficiently low in both groups that an unworkably large population of cases of OSSN would be required to find a statistically significant difference.

The choice of adjuvant antineoplastic therapy might be guided by the side-effect profile of the agent. Both 5-FU 1% and mitomycin-C 0.04% are generally well tolerated by the patient in the treatment of localised OSSN; in our experience, the use of 5-FU 1% in the treatment of localised OSSN less commonly resulted in chronic epiphora. The role of 5-FU 1% in the management of non-localised or diffuse OSSN remains to be determined.

References

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Footnotes

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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