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Lacrimal canalicular stenosisassociated with systemic5-fluorouracil therapySomdutt Prasad, Girish G. Kamath and Russell P. Phillips

Department of Ophthalmology, Arrowe Park Hospital, Upton, Wirral, UnitedKingdom

ABSTRACT.Purpose: Ocular side effects of systemic 5-fluorouracil therapy include excess-ive lacrimation which often resolves on cessation of therapy. Permanent stenosisof lacrimal puncta and canaliculi is rare. This report highlights this uncommoncomplication of 5-fluorouracil therapy.Methods: Report of two cases and review of literature.Results: Severe stenosis of puncta and canaliculi may be associated with pro-longed systemic 5-fluorouracil therapy.Conclusion: It is important for both the oncologist and ophthalmologist to beaware of the potential ocular toxicity of 5-fluorouracil. Surgical managementto relieve the epiphora is often challenging, and early intervention may be bene-ficial.

Key words: 5-fluorouracil (5-FU) – drug side effects – ocular toxicity – epiphora – canalicularstenosis – cancer chemotherapy.

Acta Ophthalmol. Scand. 2000: 78: 110–113Copyright c Acta Ophthalmol Scand 2000. ISSN 1395-3907

Cancer chemotherapy is being effec-tively used to enhance survival in

patients suffering from a variety of malig-nancies. 5-Fluorouracil (5FU) is a pyrim-idine analog and potent inhibitor of thym-idylate synthetase. It is used either as theprincipal chemotherapeutic agent or aspart of a combination with other antineo-plastic drugs in the treatment of carci-nomas of the gastrointestinal tract, breast,ovaries and skin. Systemic use of 5FU hasbeen associated with numerous ocular sideeffects manifesting as a variety of ocularsurface and/or neuro-ophthalmologicproblems. Neuro-ophthalmologic prob-lems that have been reported are blepharo-spasm, oculomotor disturbances, nystag-mus and optic neuropathy. Ocular surfaceeffects include blurred vision, ocular pain,photophobia, excessive lacrimation, con-junctivitis, blepharitis and keratitis (Im-peria et al. 1989). Increased lacrimationwhich resolves after therapy ceases is com-mon and widely documented in the litera-ture (Fraunfelder & Meyer 1983;

Hamersley et al. 1973). Stenosis of thepunctum and canaliculus is an uncommonand less well known side effect of systemic5FU therapy. An extensive search un-covered only 18 cases reported in theworld literature. We present two new casesof canalicular stenosis associated with sys-temic 5FU therapy. There is no consensusabout the management of this condition.Recommendations are varied, rangingfrom simple measures such as wiping theeyelid in an upward direction (Hassan etal. 1998) and topical antibiotics and ster-oids (Brink & Beex, 1995) to prophylacticintubation of the tear passages with silicontubes (Caravella et al. 1981). We have,therefore, reviewed the literature and dis-cussed the treatment options.

MaterialWe present two patients who developedstenosis of lacrimal passages followingsystemic 5FU therapy. We have already

reported these to The Committee onSafety of Medicines, Medicines ControlAgency of the United Kingdom.

Case 1A 65-year-old woman was referred to uswith an 11-month history of epiphora inJune 1998. Her eyes were very watery,more so when outdoors, and a source ofconstant discomfort and embarrassmentto her. Examination revealed all fourpuncta to be severely stenosed. Thesecould not be dilated in clinic and syring-ing of the nasolacrimal passages couldnot be accomplished. There was no his-tory of facial trauma, allergy, conjuncti-vitis, ocular herpetic infection, or use oftopical ocular medications. In July 1996,she had undergone a left hemicolectomyfor a carcinoma of the descending colon.Following this, she received chemo-therapy consisting of 5FU, folinic acidand levamisole between October 1996and July 1997. Shortly after completionof chemotherapy, she developed epipho-ra, which got progressively worse, leadingto the referral for ophthalmic opinionand management.

Punctal dilatation and probing of na-solacrimal passages under microscopicvisualisation was planned. At surgery, al-though the puncta could be identifiedand dilated, all the canaliculi were foundto be extensively stenosed and could notbe negotiated. It was not possible to enterthe nasolacrimal sac on either side. Aconjunctivo-dacryocystorhinostomy wasdiscussed with the patient, but the de-cision about this was deferred.

Case 2A 56-year-old man was referred for oph-thalmic opinion and management in No-vember 1994, having recently developed

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troublesome epiphora. Examinationshowed all four puncta to be stenosed. Hehad had a carcinoma of the bowel re-sected in February 1994, following whichhe received 30 doses of 750 mg intra-venous 5FU, together with folinic acidand metoclopromide over a one-yearperiod. Ocular history included primaryopen angle glaucoma for which he hadbeen using a topical beta-blocker (levobu-nolol 0.5%) for five years. This was welltolerated with no history of allergy orconjunctivitis. There was no other sig-nificant ocular history or systemic his-tory.

At surgery, both the lower punctacould be dilated and the lower canaliculiwere marsupialised. The rest of the naso-lacrimal passages were patent and couldbe freely syringed. His symptoms re-solved following this.

DiscussionThe overall incidence of cancer is increas-ing worldwide with breast cancer aloneshowing a 33% increase in 10 years (Boyle1997). Improved therapeutic regimes areprolonging survival of affected patients.Because of these facts it is becomingmore important for both oncologists andophthalmologists to be aware of the ocu-lar toxicity of drugs used in cancerchemotherapy. 5FU is commonly used inthe treatment of breast and gastrointesti-nal malignancies and in palliative treat-ment for metastatic disease. Epiphoramay not seem to be an important issue inthe management of life threatening ma-lignancies, and given the magnitude ofmany of the side effects of the anti-neo-plastic drugs in use in these situations, itmay seem to be an insignificant problemto the treating physician. However,chronic epiphora can significantly impairthe quality of life of these patients, oftenpreventing them from participating in theactivities they enjoy most, besides beingan embarrassment for them.

Excessive lacrimation that resolvesshortly after the discontinuation of 5FUtherapy is well known and does not leadto permanent sequelae. Canalicular fi-brosis leading to permanent, intractableepiphora may, however, develop in somepatients on prolonged high doses of 5FU.Eighteen such cases have been previouslyreported in the literature (Brink & Beex1995; Caravella et al. 1981; Haidak et al.1978; Hassan et al. 1998; Lee et al. 1998;

Seiff et al. 1985; Straus et al. 1977). It isdifficult to categorically prove that 5FUwas the actual cause of the stenosis of thepuncta and canaliculi in our two cases orthe cases previously reported in the litera-ture, but evidence points towards 5FU asthe causative agent. Our patients did nothave any predisposing factors to lacrimalsystem obstruction and were not receiv-ing other medications known to causepunctal-canalicular stenosis. In both ourpatients epiphora commenced while thepatient was receiving 5FU. A review ofthe previously reported cases (Table 1)shows these to be a common theme. Theevidence does not conclusively prove that5FU was the causative agent in these pa-tients, but the temporal course of eventsand a plausible pathophysiology arguesstrongly to incriminate 5FU as the re-sponsible agent. Patients with epiphoraare referred to an ophthalmologist in anarbitrary manner, with some patientsbeing referred with minor symptoms andothers with major symptoms not seeingan ophthalmologist. The presented datatherefore cannot be used to estimate theincidence of canalicular stenosis in pa-tients treated with systemic 5FU.

The pathophysiology of stenosis of lac-rimal passages is multifactorial. 5FU hasbeen demonstrated in the tears of pa-tients with epiphora, but not in patientsreceiving 5FU who did not have eyesymptoms (Christophidis et al. 1979).5FU is known to cause mucosal inflam-mation, as evidenced by confirmed oralmucosal inflammations, conjunctivitisand GI tract inflammations. Inhibition ofDNA synthesis in rapidly proliferatingtear duct cells also plays a role. Systemic5FU may cause hypersecretion from thelacrimal gland, thus gaining access to theocular surface causing further ocular sur-face toxicity and reflex tearing. The inci-dence and severity of lacrimation corre-lates with the concentration of 5FU intears but is not directly related to theplasma concentration (Christophidis etal. 1979). The development of cicatricialectropion further exacerbates the situ-ation. Although our cases and those pre-viously reported in the literature, did nothave a history suggesting previous ocularherpetic viral infection, the possibilitythat the stenoses were due to viral infec-tion or reactivation in an immunocom-promised patient cannot be entirely ex-cluded.

Previously reported cases of anatomi-cal obstruction of the nasolacrimal pas-sages ascribed to 5FU therapy (Table

1), together with our two cases demon-strate a wide spectrum ranging fromminor membranous blockages, whichcould be easily relieved by probing, tosevere canalicular fibrosis necessitatingconjunctivo-dacryocystorhinostomy. Thedevelopment of extensive permanent ste-nosis, as seen in our first case, probablyrepresents the end stage of a cicatricialprocess, which may have been arrestedif recognised and treated in the earlystages.

The wide variation in the extent of ste-nosis makes it difficult to adopt a com-mon approach to these patients. Gener-ally, treatment with 5FU cannot bestopped on account of the patient devel-oping epiphora, but it is important forthe oncologist to be aware that this is atreatable situation and that early referralto the ophthalmologist is beneficial.Simple measures, such as wiping thelower lids with an upward motion andtopical steroids applied to the lid skinmay relieve symptoms and prevent devel-opment of cicatricial ectropion. In pa-tients who develop stenosis, prophylacticintubation of the lacrimal system shouldbe considered if 5FU therapy is to becontinued for systemic reasons. This willrelieve symptoms and may prevent exten-sive stenosis from developing. Patientswho are seen when extensive stenosis ofcanaliculi has already set in can be offer-ed conjunctivo-dacryocystorhinostomy torelieve symptoms.

ConclusionThe increasing incidence of various ma-lignancies together with improved sur-vival has led to the need for both oncolo-gist and ophthalmologist to be aware ofthe ocular side effects of cytotoxicchemotherapy. 5FU is widely used in thechemotherapy of common malignancies,such as breast, gastrointestinal and meta-static disease. This agent can cause ste-nosis of nasolacrimal passages leading tochronic tearing. Intractable epiphora canseriously affect quality of life and causedebility. Oncologists need to be awarethat this is a treatable condition. Earlyophthalmic evaluation and treatmentmay alleviate symptoms and maintainpatency of the nasolacrimal passages,avoiding later fibrotic sequelae, althoughmanagement of cases with extensive ste-nosis due to pericanalicular fibrosis maybe difficult.

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Table 1. Summary of features of previously reported cases of nasolacrimal passage stenosis ascribed to 5FU.

Age OnsetAuthor (yr)/Sex Tumour Regimen (months) Type of lacrimal block Treatment

Straus et al. (1977) 61/M Pancreas 5 FU (5-day loading 1 Bilateral cicatricial ectropion Ectropion correctedπweekly and blocked nasolacrimal surgically, symptoms notmaintenance) ducts. resolved

Haidak et al. (1978) Not Not specified 5 FU (i.v, long term – Obstructed canaliculi with Surgical correction – detailspecified ±6 months) thickening and scarring of not specified

lacrimal sac – dacryostenosis.Biopsy confirmed fibrosis ofpunctum and adjacent tissue.

Caravella et al. (1981) 54/F Recto- 5FU (600 mg i.v. for 4 Stenosed puncta with Free drainage on syringingsigmoid colon 5 days then 500–800 mucosal membrane, slight

mg weekly) stenosis of lower leftcanaliculus.

58/M Colon 5FU (800 mg i.v. for 2.5 Inferior right puncta totally Bilateral free irrigation5 days then 500–1000 occluded by membrane andmg weekly) other three puncta stenosed.

Left lower canaliculus showeduniform stenosis throughout.

38/F Small bowel 5FU (500 mg i.v. for 4 All puncta severely stenosed, Probed patent, silastic5 days then 500–750 severe uniform stenoses of all tubes inserted; recurredmg weekly) canaliculi. when removed tubes

43/F Breast CMF (5FU – 500 mg ’Shortly’ Stenosed right lower Free drainage on syringingi.v on days 1 and 8 of punctum.monthly cycle)

Seiff et al. (1985) 69/F Pancreas 5FU (12.5 mg/kg 26 Impossible to cannulate due Bilateral conjunctivoloading dose for 5 to complete punctal and DCRs (successful indays then 500 mg i.v. canalicular obstruction. relieving symptoms)weekly)

Brink and Beex 61/F Breast 5FU, tamoxifen Im- Complete occlusion of all Membrane excised, topical(1995) mediate puncta by membrane steroids and antibiotics;

conjunctivo DCR declined62/F Breast CMF Im- All puncta stenosed, partial Repeated probing, topical

mediate stenosis of both lower steroids; symptoms resolvedcanaliculi. Complete on stopping 5FUobstruction of right lowercanaliculus developed later

49/F Breast 5FU, tamoxifen 1 Severe stenosis of all puncta Topical steroids; symptomsresolved on stopping 5FU

70/F Breast 5FU, tamoxifen 1 Stenosis of all puncta, Probed through occlusivebilateral lower canalicular membrane, artificial tears,obstruction with occlusive resolution of symptomsmembrane,

70/F Breast 5FU, tamoxifen 2 Severe lower right punctal Right conjunctivo – DCR –stenosis with complete good resultcanalicular obstruction.Complete stenosis of lowerleft punctum.

Hassan et al. (1998) 63/M Colon 5 FU 5 Scarring of both upper Declined surgerycanaliculi and right lowercanaliculus

56/F Stomach 5 FU 1 Scarring of all canaliculi with Declined surgerybilateral cicatricial ectropion

68/F Oesophagus 5 FU 2 Scarring of all canaliculi Declined surgeryLee et al. (1998) 53/F Breast CMF (monthly 3 Right distal lower canalicular Probed patent during

cycles, 5FU i.v on block dacryocystogramdays 1 and 8 of eachcycle for 6 months)

48/F Breast CMF (monthly cycles 3 Bilateral proximal upper and Failed bilateralfor 5 months) lower canalicular block canaliculo –

DCRπsilicone tubes;conjunctivo DCRπpyrextubes planned

68/F Breast CMF (weekly 1 Right sided proximal Declined treatmenti.v.treatment for 5 common canalicular block;weeks) left sided mid upper and

lower canalicular block.

5FUΩ5 Fluorouracil; CMFΩCyclophosphamide, Methotrexate and 5 Fluorouracil; DCRΩDacryocystorhinostomy.

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Received on September 2nd, 1999.Accepted on August 9th, 1999.

Corresponding author:

Somdutt PrasadClinical Lecturer in OphthalmologyThe University of SheffieldFloor ‘O’ ; Royal Hallamshire HospitalGlossop RoadSheffield S10 2JFUnited Kingdome-mail: somprasad/bigfoot.comS.Prasad/Sheffield.ac.ukTel: π44 114 2712107Fax: π44 114 2766381