effects side ocular induced-Drug •Pa7 rt

Fig. 7.11f  Corneal cyst from systemic cytarabine. Photo courtesy of Krachmer JH, Palay DA. Cornea Atlas. 2nd edn, Mosby Elsevier, London, 2006.

3. Subconjunctival or retinal hemorrhage secondary to druginduced anemia

4. Eyelids or conjunctiva – toxic epidermal necrolysis

Local ophthalmic use or exposure

Certain

1. Ocular pain

2. Iritis

3. Corneal opacities

4. Corneal ulceration

5. Delayed corneal wound healing

6. Decreased resistance to infection

Clinical significance

Ocular toxicity from systemic cytarabine is the most frequent side effect of the drug. The frequency of the ocular toxicity is both time and dose dependent. The most common ocular side effects are blurred vision and keratoconjunctivitis. The keratitis may occur in 100% of patients on high dosages, regardless of the method of administration. Barletta et al (1992) reported corneal and conjunctival changes even on low-dose systemic cytosine arabinoside. Cytarabine-induced ocular toxicity usually occurs after 5–7 days of therapy and is associated with pain, lacrimation, foreign body sensation and blurred vision. Clinically, one sees central punctate corneal opacities, subepithelial granular deposits, refractile microcysts, superficial punctate keratitis and, rarely, mild corneal edema with stria in Descemet’s membrane. Symptoms improve after a few days off the drug, vision improves in 1–2 weeks and the corneal opacities within 4 weeks. The cause of these adverse effects may primarily be due to the non-selective inhibition of DNA synthesis by this drug. This explains the 5- to 7-day delay in onset of corneal changes (i.e. the length of time it takes the basal cells of the corneal epithelium to reach the surface). Cytarabine can be found in the tears from systemic administration, which can account for

immediate ocular and periocular symptoms. Weak topical ocular steroids and frequent preservative-free artificial tears often improve these ocular symptoms. Anterior uveitis has been reported by Planer et al (2004) and there are a few cases in the National Registry but a clear-cut association has not been established.

Adverse effects associated with high-dose intravenous regimens may also include cerebral or cerebellar dysfunction, which is usually reversible. Ocular manifestations of this CNS toxicity may include lateral gaze nystagmus, diplopia and lateral rectus palsy. Neurotoxicity following intrathecal injection and intravenous cytarabine have been associated with optic atrophy and blindness (Hoffman et al 1993; Schwartz et al 2000). Wiznia et al (1994) and Lopez et al (1991) pointed to an additive effect of cytarabine and low-dosage radiation on occlusive microvascular retinopathy in patients with leukemia.

Topical cytarabine causes significant corneal toxicity, and therefore has been replaced by equally effective and less toxic antiviral agents.

References And Further Reading

Barletta JP, Fanous MM, Margo CE. Corneal and conjunctival toxicity with low-dose cytosine arabinoside [letter]. Am J Ophthalmol 113(5): 587–588, 1992.

Friedland S, Loya N, Shapiro A. Handling punctate keratitis resulting from systemic cytarabine. Ann Ophthalmol 25: 290–291, 1993.

Gressel MG, Tomsak RL. Keratitis from high dose intravenous cytarabine. Lancet 2: 273, 982.

Hoffman DL, Howard JR, Sarma R, Riggs JE. Encephalopathy, myelopathy, optic neuropathy, and anosmia associated with intravenous cytosine arabinoside. Clin Neuropharmacol 16(3): 258–262, 1993.

Hopen G, Mondino BJ, Johnson BL, et al. Corneal toxicity with systemic cytarabine. Am J Ophthalmol 91: 500–504, 1981.

Hwang TL, et al. Central nervous system toxicity with high-dose Ara-C. Neurology 35: 1475, 1985.

Imperia PS, Lazarus HM, Lass JH. Ocular complications of systemic cancer chemotherapy. Surv Ophthalmol 34(3): 209–230, 1989.

Lass JH, et al. Topical corticosteroid therapy for corneal toxicity from systemically administered cytarabine. Am J Ophthalmol 94: 617, 1982.

Lazarus HM, et al. Comparison of the prophylactic effects of 2-deoxycy- tidine and prednisolone or high-dose intravenous cytarabine-induced keratitis. Am J Ophthalmol 104: 476, 1987.

Lochhead J, Salmon JF, Bron AJ. Cytarabine-induced corneal toxicity. Eye 17: 677–678, 2003.

Lopez JA, Agarwal RP. Acute cerebellar toxicity after high-dose cytarabine associated with CNS accumulation of its metabolite, uracil arabinoside. Cancer Treat Rep 68: 1309, 1984.

Lopez PF, Sternberg P, Dabbs CK, et al. Bone marrow transplant retinopathy. Am J Ophthalmol 112(6): 635–646, 1991.

Matteucci P, Carlo-Stella C, di Nicola M, et al. Topical prophylaxis of conjunctivitis induced by high-dose cytosine arabinoside. Hematologica 91: 255–257, 2006.

Planer D, Cukirman T, Liebster D, et al. Anterior uveitis as a complication of treatment with high dose cytosine-arabinoside. Am H Hematol 76: 304–306, 2004.

Ritch PS, Hansen RM, Heuer DK. Ocular toxicity from high-dose cytosine arabinoside. Cancer 51: 430, 1983.

Schwartz J, Alster Y, Ben-Tal O, et al. Visual loss following high-dose cytosine arabinoside (ara-c). Eur J Hematol 64: 208–209, 2000.

Wiznia RT, Rose A, Levy AL. Occlusive microvascular retinopathy with optic disc and retinal neovascularization in acute lymphocytic leukemia. Retina 14(3): 253–255, 1994.

Generic name: Denileukin diftitox.

Proprietary name: Ontak.

Primary use

A recombinant DNA-derived cytotoxic agent used in persistent or recurrent cutaneous T-cell lymphoma as well as some systemic cancers. These are monoclonal antibodies that recognize a specific antigen.

agents Oncolytic • 11 Section

effects side ocular induced-Drug •Pa7 rt

3. Diplopia

4. Blepharospasm

5. May aggravate herpes infections

Possible 

1. Decreased accommodation

2. Subconjunctival or retinal hemorrhages secondary to druginduced anemia

3. Optic neuritis

Local ophthalmic use or exposure – (fluorouracil) ­subconjunctival

Certain

1.Irritation

a.Lacrimation

b.Ocular pain

c.Edema

d.Burning sensation

2.Conjunctiva

a.Edema

b.Hyperpigmentation

c.Keratinization

d.Cicatricial changes

e.Delayed wound healing

3.Periorbital edema

4.Cornea

a.Superficial punctate keratitis

b.Ulceration

c.Scarring – stromal

d.Keratinized plaques

e.Delayed wound healing

f.Striate melanokeratosis

g.Endothelial damage

h.Limbal stem cell deficiency

i.Crystalline keratopathy

j.Pannus

5. Filtering blebs

a.Delayed leaks

b.Giant blebs

c.Thin walled

d.Infections

e.Cystic blebs

f.Ectasia

6. Anterior uveitis

7. Hypotonous maculopathy

Injection into the eyelid (fluorouracil)

Certain

1.Eyelid

a.Edema

b.Erythema

c.Cicatricial reaction

d.Ectropion

e.Lid necrosis if followed by cryotherapy

f.Hyperpigmentation

g.Allergic or toxic reaction

2. Conjunctival

a.Chemosis

b.Erythema

c.Cicatrical reaction

Possible

1. Loss of eyelashes

2. Crystalline keratopathy

Clinical significance

Fluorouracil (5FU) is one of the more commonly used cytotoxic drugs in the palliative treatment of solid tumors. Since its therapeutic dose is often close to its toxic level, 25–35% of patients on systemic therapy have some ocular side effects. One of the more complete reviews of anterior segment 5FU complications is by Eiseman et al (2003). They point out that adverse effects can be divided into those occurring in the first 3 months (early) of therapy and those occurring with chronic therapy. The most common early adverse ocular effects, besides blurred vision, are low-grade blepharitis and conjunctival irritation with symptoms well out of proportion to the clinical findings. These reactions usually peak in the second and third weeks of therapy and, in rare instances, are severe enough to cause discontinuation of treatment. The reason for discomfort is multifactorial, including 5FU or its antimetabolite secreted in the tears, decrease in basal cell secretion and excessive lacrimation. Eiseman et al (2003) found epiphoria to be the most common adverse ocular event with the highest incidence among African Americans. With long-term therapy, up to one-third of patients may have a cicatricial reaction occurring in the conjunctiva, punctum, canaliculi or lacrimal sac. If recognized early, this may be reversed, but if unrecognized, the scarring is irreversible with resulting ­epiphora (Hassan et al 1998). There are a number of reports (Brink and Beex 1995; Prasad et al 2000; Stevens and Spooner 2001) of irreversible punctual, canalicular or lacrimal sac stenosis as well as cicatricial changes in the fornices. Agarwal et al (2002) reported severe squamous metaplasia in the lacrimal canalicui. A toxic effect to the cornea can occur for the same reasons as above. Fortunately, other than corneal sloughs, this uniformly resolves within a few weeks of the drug being discontinued. Corneal opacities can occur. Neurotoxicity, which possibly affects the brain stem and causes oculomotor disturbance, has been reported. This may include various ocular motor defects, including blepharospasm, nystagmus (Prasad et al 2000) and diplopia. Delval and Klastersky (2002) reported a case of bilateral anterior optic neuropathy in a patient with dihydropyrimidine dehydrogenase deficiency. Bixenman et al (1968) reported diplopia heralding the onset of further cerebral dysfunction. Sato et al (1988) reported that injections of 5FU in the superficial temporal artery caused complete bilateral visual loss. There are several cases of possible optic nerve toxicity secondary to fluorouracil in the literature and in the National Registry.

Direct injection of fluorouracil into the eyelids for the treatment of basal cell carcinoma can cause cicatricial ectropion and hyperpigmentation. This drug should be used with caution in patients with pre-existent corneal pathology, and in diabetics. Lid necrosis has been reported in one patient receiving cryo­ therapy for trichiasis when the patient was also on 5FU.

Fluorouracil has gained increasing popularity in the management of difficult glaucoma patients requiring filtration surgery. Initially, significant ocular side effects occurred but with the method of application and the ideal concentration of the drug being determined, this has decreased. 5FU is most commonly given as a subconjunctival injection, which enhances bleb formation. However, adverse ocular effects, most reversible, occur in up to 50% of cases. The most common is superficial keratitis, which may rarely become ulcerated. Hayashi et al (1994) reported a permanent corneal opacity requiring a lamellar keratoplasty when this agent was used after a trabeculectomy. Patitsas et al (1991) reported an infectious and Rothman et al (1999) a noninfectious reversible crystalline keratopathy secondary to subconjunctival 5FU injections in post-operative filtering surgery. Libre (2003) reported a profound transient cataract secondary to

­subconjunctival 5FU in after filtering surgery. Pires et al (2000) reported a late complication of limbal stem cell deficiency in two patients after 5FU subconjunctival injections. These required stem cell transplantation to correct. Other defects include conjunctival wound leaks, excessive filtration with shallow to flat anterior chambers and conjunctival or corneal keratnization. Ticho et al (1993) reviewed long-term complications and incidences with 8.6% mild iridocyclitis, 3.8% endophthalmitis, 2.9% hypotony and 1.9% transient leaking blebs. Stamper et al (1992) reported on hypotonous maculopathy, while Oppenhein and Ortiz (1993) suggested that some of these may be due to drug-induced ciliary body shutdown. Hickey-Dwyer and Wishart (1993) felt that 5FU subconjunctival injections should be used with great care in diabetic patients due to potential corneal complications and may be contraindicated in corneas with band keratopathy.

Topical 5FU has had some popularity in the management of conjunctival and corneal neoplasia (Yeatts et al 2000). Ocular irritation and other side effects are directly related to concentration, dose and length of treatment. All the signs of severe ocular toxicity of the anterior segment may be seen, including corneal erosions, opacities (permanent), pannus and scleral melts.

Recommendations

1. Ocular symptoms may be decreased by preservative-free topical ocular artificial tears or mild steroids during peak serum levels of 5FU.

2. If patients are given the drug intravenously or intra-arterially, ocular ice packs should be applied for 30 minutes in total, starting 5 minutes prior to injection. This significantly decreases ocular symptoms (Loprinzi et al 1994).

3. If chronic therapy is necessary, a prophylactic silastic intubation of the lacrimal system is advised (Imperia et al 1989; Agrawal et al 2002).

4. If topic ocular 5FU is used, consider using punctual plugs. 5. Pires et al (2000) found amniotic membrane transplants or conjunctival limbal autografts to be of value for limbal cell

deficiency induced by 5FU post glaucoma surgeries. 6. Use with caution in diabetic patients.

References And Further Reading

Adams JW, et al. Recurrent acute toxic optic neuropathy secondary to 5-FU. Cancer Treat Rep 68: 565, 1984.

Agarwal MR, Esmaeli B, Burnstine MA. Squamous metaplasia of the canaliculi associated with 5-fluorouracil: a clinicopathologic case report. Ophthalmology 109: 2359–2361, 2002.

Alward WLM, Farrell T, Hayreh S, et al. Fluorouracil filtering surgery study one-year follow-up. Am J Ophthalmol 108(6): 625–635, 1989.

Baldassare RD, Brunette I, Desjardine DC, et al. Corneal extasia secondary to excessive ocular massage following trabeculectomy with 5-fluoro­ uracil. Can J Ophthalmol 31(5): 252–254, 1996.

Bixenman WW, Nicholls JVV, Warwick OH. Oculomotor disturbances associated with 5-fluorouracil chemotherapy. Am J Ophthalmol 83: 604–608, 1968.

Brink HM, Beex LV. Punctal canalicular stenosis associated with systemic fluorouracil therapy. Doc Ophthalmol 90: 1–6, 1995.

Caravella LP Jr, Burns JA, Zangmeister M. Punctal-canalicular stenosis related to systemic fluorouracil therapy. Arch Ophthalmol 99: 284, 1981.

Delval L, Klastersky J. Optic neuropathy in cancer patients. Report of a case possibly related to 5-fluorouracil toxicity and review of the literature.

J Neurooncol 60: 165–169, 2002.

Eiseman AS, Flanagan JC, Brooks AB, et al. Ocular surface, ocular adnexal, and lacrimal complications associated with the use of systemic 5-fluorouracil. Ophthal Plast Reconstr Surg 19: 216–224, 2003.

Esmaeli B, Golio D, Lubecki L, et al. Canalicular and nasolacrimal duct blockage: an ocular side effect associated with the antineoplastic drug s-1. Am J Ophthalmol 140: 325–327, 2005.

Forbes JE, Brazier DJ, Spittle M. 5-Fluorouracil and ocular toxicity. Letters to the editor. Br J Ophthalmol 77(7): 465–466, 1993.

Galentine P, et al. Bilateral cicatricial ectropion following topical administration of 5-fluorouracil. Ann Ophthalmol 13: 575, 1981.

Hassan A, Hurwitz JJ, Burkes RL. Epiphora in patients receiving systemic 5-fluorouracil therapy. Can J Ophthalmol 33: 14–19, 1998.

Hayashi M, Ibaraki N, Tsuru T. Lamellar keratoplasty after trabeculectomy with 5-fluorouracil. Am J Ophthalmol 117(2): 268–269, 1994.

Hickey-Dwyer M, Wishart PK. Serious corneal complication of 5-fluoro­ uracil. Br J Ophthalmol 77: 250–251, 1993.

Hurwitz BS. Cicatricial ectropion: a complication of systemic fluorouracil. Arch Ophthalmol 111: 1608–1609, 1993.

Imperia PS, Lazarus HM, Lass JH. Ocular complications of systemic cancer chemotherapy. Surv Ophthalmol 34: 209–230, 1989.

Knapp A, et al. Serious corneal complications of glaucoma filtering surgery with postoperative 5-fluorouracil. Am J Ophthalmol 103: 183, 1987.

Lemp MA. Striate melanokeratosis. Arch Ophthalmol 109(7): 917, 1991. Libre PE. Transient, profound cataract associated with intracameral 5-fluoro­

uracil. Am J Ophthalmol 135: 101–102, 2003.

Loprinzi CL, Wender DB, Veeder MH, et al. Inhibition of 5-fluorouracil- induced­ ocular irritation by ocular ice packs. Cancer 74: 945–948, 1994.

Mannis MJ, Sweet EH, Lewis RA. The effect of fluorouracil on the corneal endothelium. Arch Ophthalmol 106: 816–817, 1988.

Ophir A, Ticho U. Subconjunctival 5-fluorouracil and herpes simplex keratitis. Ophthalmic Surg 22(2): 109–110, 1991.

Oppenheim B, Ortiz JM. Hypotonous maculopathy after trabeculectomy with subconjunctival 5-fluorouracil. Am J Ophthalmol 115(4): 546–547, 1993.

Patitsas C, Rockwood EJ, Meisler DM, et al. Infectious crystalline keratopathy occurring in an eye subsequent to glaucoma filtering surgery with postoperative subconjunctival 5-fluorouracil. Ophthalmic Surg 22(7): 412–413, 1991.

Pires RTF, Chokshi A, Tseng SCG. Amniotic membrane transplantation or conjunctival limbal autograft for limbal stem cell deficiency induced by 5-fluorouracil in glaucoma sugeries. Cornea 19: 284–287, 2000.

Prasad S, Kamath GG, Phillips RP. Lacrimal canalicular stenosis associated with systemic 5-fluorouracil therapy. Acta Ophthalmol 78: 110–113, 2000.

Rothman RF, Liebmann JM, Ritch R. Noninfectious crystalline keratopathy after postoperative subconjunctival 5-fluorouracil. Am J Ophthalmol 128(2): 236–237, 1999.

Sato K, Watanabe J, Nakayama T, Seki R. Clinical investigation of corneal damage induced by 5-fluorouracil. Folia Ophthalmol 39(1): 1754–1760, 1988.

Schmid KE, Kornek GV, Scheithauer W, et al. Update on ocular complications of systemic cancer chemotherapy. Surv Ophthalmol 51: 19–40, 2006.

Solomon LM. Plastic eyeglass frames and topical fluorouracil therapy. JAMA 253: 3166, 1985.

Stamper RL, McMenemy MG, Lieberman MF. Hypotonous maculopathy after trabeculectomy with subconjunctival 5-fluorouracil. Am J ­Ophthalmol 114(5): 544–553, 1992.

Stank TM, Krupin T, Feitl ME. Subconjunctival 5-fluorouracil-induced transient striate melanokeratosis. Arch Ophthalmol 108: 1210, 1990.

Stevens A, Spooner D. Lacrimal duct stenosis and other ocular toxicity ­associated with adjuvant cyclophosphamide, methotrexate and 5-fluoro­ uracil combination chemotherapy for early stage breast cancer. Clin Oncol 13: 438–440, 2001.

Ticho U, Ophir A. Late complications after glaucoma filtering surgery with adjunctive 5-fluorouracil. Am J Ophthalmol 115: 506–510, 1993.

Yeatts RP, Engelbrecht NE, Curry CD, et al. 5-fluorouracil for the treatment of intraepithelial neoplasia of the conjunctiva and cornea. Ophthalmology 107: 2190–2195, 2000.

Generic name: Imatinib mesilate.

Proprietary name: Gleevec.

Primary use

This selective inhibition of the bcr-abl and platelet-derived growth factor receptor (PDGFR) tyrosine kinase is a new form of targeted therapy for the management of myelogenous leukemia and gastrointestinal stromal tumors.

agents Oncolytic • 11 Section