Side effects of chemotherapeutic oculo-toxic agents: a review

ELS EVI E R

Clinical Eye and Vision Care 12 (2000) 113-117

www.elsevier.com/locate/clineyeviscare

Clinical review

Side effects of chemotherapeutic oculo-toxic agents: a review Dominick M. Maino", Saly Tran, Faresh Mehta Pediatric / Binocular !&ion Service, Illinois Eye Institute /Illinois College of Optometry, 3241 S. Michigan Ave., Chicago, I L 60616, USA Accepted 1 September 2000

Abstract

Patients with cancer are often prescribed chemotherapeutic substances that can be extremely oculo-visual-toxic in nature. Over the past several years, advances in cancer treatment have resulted in increased survival rates and patient longevity. Unfortunately, greater survival rates and longevity mean increased exposure to potentially harmful oculo-toxic substances and a higher incidence of oculo-visual side effects. Patients receiving chemotherapy may complain of symptoms that can imitate functional disorders such as blurred vision and photophobia (i.e. disorders of accommodation) and also include dry eyes or other symptomology commonly associated with disorders of the primary eye care system. These deleterious side effects affect the patient's quality of life and warrant our attention. It is essential that eye and vision care professionals appropriately diagnose and manage these induced disorders. This review presents the oculo-visual side effects of commonly used chemotherapeutic agents, the available treatment options when these unwanted side effects occur, and when known, the mechanism by which these agents cause oculo-visual toxicity. 0 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Chemotherapeutic agents; Cancer; Oculo-visual toxicity

1. Introduction

Individuals with cancer are frequently prescribed chemotherapeutic substances that can be extremely bio-toxic in nature. For several decades, advances in cancer treatment have resulted in an overall increase in the survival rate and longevity of patients with life-threatening tumors and other malignancies. Unfortunately, higher survival rates and greater longevity also mean increased exposure to potentially harmful oculo-toxic substances and a higher incidence of oculo-visual side effects due to these therapeutic

* Corresponding author. Tel.: + 1-312-949-7280. E-mail address: [email protected] (D. Maino).

agents. Patients receiving chemotherapy may complain of symptoms that can imitate functional disorders such as blurred vision and photophobia 6.e. disorders of accommodation) and include dry eyes or other symptomology commonly associated with disorders of the primary eye care system. All of these affect the patient's quality of life and deserve our attention. While severe side effects are rare, it is essential that they be recognized by the eye and vision care professional and that appropriate diagnosis and management be initiated. This review presents the oculo-visual side effects (Table 1) of commonly used chemotherapeutic agents, the available treatment options when these unwanted side effects occur, and when known, the mechanism by which these agents cause oculo-visual toxicity.

0953-4431/00/$ - see front matter 0 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 9 5 3 - 4 4 3 1( 0 0 ) 0 0 0 5 3 - 9

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2. Chemotherapeutic agents

The chemotherapeutic drug, busulfan, is an orally administered agent used in the treatment of chronic myelocytic leukemia, polycythemia and myelofibrosis with myeloid metaplasia [l]. It is an alkylating agent that causes the disruption of DNA synthesis. Cautious use of this drug is essential for patients with bone marrow depression and seizures. Serious systemic side effects include pulmonary, endocardia1 and pericardial fibrosis. Other systemic effects can include nausea and vomiting. The development of a posterior subcapsular cataract is the main ocular complication. It is believed that busulfan causes cataracts by interrupting DNA synthesis in the lens epithelium [2,3]. The severity and incidence of these cataracts were found to be dependent upon the total dose and length of treatment [l]. A less common complication is keratoconjunctivitis sicca associated with a non-specific decrease in visual acuity [4]. It is known that the progression of prostate cancer is dependent on an excess of or an increased sensitivity to androgens. The two classes of antiandrogen chemotherapeutic agents include both steroidal and non-steroidal agents 151. These two classes of antiandrogens possess agonistic and antagonistic activity with androgen receptors. Anandron is a non-steroidal antiandrogen successfully used in the treatment of prostate cancer. It is purely antagonistic in nature and works by inhibiting the binding of androgens to the androgen receptor 161. In one study, 65% of patients complained of a decrease in visual recovery after exposure to bright illumination. Harnois et al. used the photostress recovery test (PRT) and noted a delay in regeneration of visual photopigments. While Harnois et al. found no change in the anatomic fundus, the cause of the delay in regeneration could be due to alterations in the retinal pigment epithelium, choriocapillaris or choroid. These symptoms reversed with cessation of therapy [7]. Suramin sodium is another agent used in the treatment of metastatic prostate cancer and adrenocortical carcinoma. It inhibits various autocrine growth factors [8]. Ocular toxicities to this agent include photophobia, chemosis, edema of lids, iritis, optic atrophy and vortex keratopathy [9,10]. A study by Hemady et al. found that 16.6% of patients on suramin sodium treatment developed ocular symptoms and 11.4% developed bilateral corneal whorl-like deposits with associated foreign body sensations and increased lacrimation. These symptoms were relieved with the use of topical lubricants. A hyperopic shift in refractive error was also noted in 6.2% of patients [ll]. Carmustine (BCNU) is used in the treatment of colorectal cancer and malignant gliomas. Carmustine works by inhibiting glutathione reductase within cells.

Glutathione reductase inhibition leads to the formation of vacuoles in the anterior portion of the lens between the lens epithelium and the lens fibers. A study by Ikebe et al. found that the crystalline lenses of rabbits treated with carmustine exhibited swollen epithelial cells. Other side effects reported include non-specific blurring of vision [12], orbital vasodilation with glaucoma secondary to orbital congestion or rubeosis [13,14], severe orbital pain and conjunctival hyperemia. In one case, a patient developed a fixed unreactive pupil on the same side as the carmustine infusion. Additional complications include visual loss ranging from 20/60 to light perception, cotton wool spots and visual field changes characterized by central scotomas. Acute cavernous sinus syndrome with partial third nerve and sixth nerve paralysis with pupillary involvement has been documented as well [14]. Greenberg et al. noted disc edema and nerve fiber layer hemorrhages and infarcts [15]. Other noteworthy complications include cilioretinal artery occlusions [16], choroidal thrombi [17], papillitis [13], optic neuroretinitis [18] and unilateral optic neuritis [19]. Cruciani et al. found that carmustine altered the tear film composition leading to mild corneal de-epithilialization and conjunctival epithelial changes with symptoms of foreign body sensation and burning 1201. Kupersmith et al. reported no visual loss, however, 100% of the patients developed rod photoreceptor dysfunction and 67% had cone dysfunction [21]. These ocular toxicities were mainly seen with ipsilateral intracarotid infusion and are rarely encountered with intravenous therapy [13,15,16,181. The agent 5-flourouracil(5-FU) is used in the treatment of breast cancer, gastrointestinal and genitourinary tract cancers, actinic keratosis and carcinoma. It is also used extensively in glaucoma filtering surgery to decrease scarring post-operatively [ 11. The human DNA p53 gene is thought to regulate cell cycle progression and cellular response to DNA damage. Overexpression of this p53 gene occurs in more than 50% of colorectal tumors [22]. 5-FU functions by inducing DNA damage (including damage to the p53 gene) which explains its success in treating cancers. 5-FU has been known to cause blurred vision, circumorbital edema, ocular pain, photophobia, excessive lacrimation, conjunctivitis, blepharitis, keratitis [23], cicatrical ectropion [24], ankyloblepharon [25] and rarely punctal and canalicular stenosis [26]. In one study, 50% of patients using 5-FU developed corneal epithelial defects that resolved after several weeks 127,281. Interferon is a chemotherapeutic agent used in the treatment of chronic myelogenous leukemia, multiple myeloma, malignant melanoma, non-Hodgkin’s lymphoma and renal cell carcinoma [l]. It is also widely used as a treatment for chronic hepatitis. Retinal

D.M. Main0 et al. /Clinical Eye and !&ion Cave 12 (2000)113-117 Table 1 Summary of ocular side effects Agent

Use

Ocular side effects

Anandron

Prostate cancer

Decreased visual function after exposure to bright light

Busulfan

Mylocytic leukemia Polycythemia myelofibrosis

Posterior subcapsular cataracts Keratoconjunctivitis Decreased vision

Carmustine

Colorectal cancer Malignant gliomas

Non-specific decreased vision Cornea/conjunctival epithelial changes Orbital vasodilation Orbital pain Glaucoma Cotton wool spot Artery occlusions Choroidal thrombi Papilitis Optic neuroretinitis/neuritis

5-Flurouracil

Breast cancer Gastrointestinal cancer Genitourinary cancer Actinic keratosis Basal cell carcinoma Glaucoma filtering surgery

Blurred vision/photophobia Blepharitis Circumlimbal edema Conjunctivitis Ocular pain Keratitis/epithelial defects

Interferon

Myelogenous leukemia multiple Myeloma malignant melenoma Non-Hodgkins Lymphoma Renal-cell carcinoma Chronic hepatitis

Vitiligo Cotton wool spots Splinter hemes Retinal hemorrhages Mild disc edema

Methotrexate

Leukemia Solid tumors Rheumatoid arthritis

Periorbital edema Photophobia Ocular pain Burning blepharitis Conjunctivitis Decreased tear production

Mitomycin C

Small tumors Colorectal cancer Glaucoma filtering Surgery

Alteration in tear film Corneal inflammation Stromal necrosis Endothelial loss

Suramin Sodium

Prostate cancer Adrenocortical Carcinoma

Hyperopic shift photophobia Chemosis of lid Vortex keratopathy Iritis Optic atrophy

Tamoxifen

Breast Cancer

Refractile retinal opacities Posterior subcapsular cats Cuticular drusen Ophthalmic vein thrombosis Acute angle closure glaucoma with choroidal detachme

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complications with cotton wool spots and splinter hemes were noted in 42% of patients taking interferon [29]. Previous studies have found retinal hemorrhages in 24% of patients with 66% of these patients also having cotton wool spots [30]. These retinal findings resolved gradually with treatment. Mild disc edema was also seen. The unwanted side effects reversed with cessation of therapy [31]. One case reported a patient with vitiligo during the eighth week of treatment of active chronic hepatitis C with interferon alpha 2a [32]. Systemically, mitomycin C is used in a variety of small tumors. This agent inhibits carbonic anhydrase and ATPase in cells [33]. As eye care professionals, we see its used most commonly in glaucoma filtering surgery to minimize post-operative scarring. Cruciani et al. administered mitomycin C to patients with advanced non-pigmented colorectal cancer. Their study revealed an alteration of the quality and quantity of the tear film resulting in damage to the corneal epithelium [20]. Topically, mitomycin C causes serious ocular complications. It has been shown in rabbits to cause corneal inflammation, stromal necrosis and endothelial loss. Hemorrhagic iris necrosis was also seen 1341. Improper dosage of mitomycin C on cultured corneal keratocytes and endothelial cells can result in severe damage 1351. Tamoxifen is an estrogen antagonist mainly used in the treatment of breast cancer. It functions by interfering with the binding of estradiol by competitive inhibition [36].Tamoxifen is also a high affinity blocker of specific chloride channels, unrelated to estrogen receptors. In the lens, chloride channels are responsible for maintaining normal lens hydration. Blockage of chloride channels causes an imbalance in lens hydration and subsequent formation of cataract within the lens 1371. Other studies have shown tamoxifen to cause an associated retinopathy consisting of intraretinal crystals or refractile retinal opacities [38-41]. Other ocular findings include decreased vision and corneal opacities [41]. Sekhar et al. documented cases of superior ophthalmic vein thrombosis, painful proptosis and angle closure glaucoma with choroidal detachment. These conditions resolved with discontinuation of tamoxifen treatment [42]. Methotrexate is commonly used in the treatment of various leukemias and solid tumors [43]. As an immunosuppressive agent, it is successful in the treatment of chronic uveitis and rheumatoid arthritis. More specifically, methotrexate is a folic acid antagonist. It is a potent inhibitor of dihydrofolate reducatase, which is needed for nucleotide synthesis in rapidly dividing cells. It is postulated that methotrexate’s mechanism of action is inhibition of macrophage invasion during early angiogenesis and endothelial cell proliferation [44]. Its side effects include burning, pruritus and dry

eye. Patients exhibiting these symptoms were found to have a decrease in reflex tear production 145,461.

3. Discussion

It is important that all health care professionals working with patients who have been diagnosed with cancer recognize the potential oculo-visual toxic side effects associated with frequently utilized chemotherapeutic agents. The correct diagnosis and management of these side effects may be as straightforward as prescribing spectacles for various refractive shifts to relieving symptoms of dry eyes with topical lubricants. Severe toxicities, such as optic neuropathy or retinal hemorrhages can require discontinuation of the chemotherapy. It is important, however, that a careful analysis of the risk of toxicity vs. the benefit of chemotherapy be considered. Additional investigations are required to determine why so many of these oculo-visual side effects occur. The studies reported here have noted various ocular toxicities because of these chemotherapeutic agents but often, do not address the bio-physiologic mechanisms that cause these side effects. Distinguishing between ocular disease and the ocular toxicity caused by these agents can prove to be quite challenging. It is important to obtain a thorough medical history for each patient and then to appropriately differentiate any induced oculo-visual toxicities vs. non-induced abnormal ocular findings. The prompt detection and proper management of these side effects with the assistance of the patient’s oncologist may help to determine adequate dosing when attempting to minimize ocular toxicity while maintaining the efficacy of the anticancer agent. References 111 Imperia P, Hillard L, Lass J. Ocular complications of sys121 131 141 151

161 171

temic cancer chemotherapy. Surv Ophthalmol 1989;34 (3):209-230. Grimes P, Von Sallman L, Frichette A. Influence of myleran on cell proliferation in lens epithelium. Invest Ophthalmol Vis Sci 1964;3:566-576. Dahlgren S, Holm G, Svawborg N et al. Clinical and morphological side effects of busulfan (Myleran) treatment. Acta Med Scand 1972;192:129-135. Sidi Y, Douer D, Pinkhas J. Sicca syndrome in a patient with toxic reaction to bulsulfan. J Am Med Assoc 1977;238:1951. Miglaiari R, Muscas G, Murru M, Verdacchi T, De Benedetto G, De Angelis M. Antiandrogens: a summary review of pharmachodynamic properties and tolerability in prostate cancer therapy. Arch Ital Urol Androl 1999;71(5):293-302. Singh SM, Gauthier S, Labrie F. Androgen receptor antagonists (antiandrogens): structure activity relationships. Curr Med Chem 2000;7(2):211-247. Harnois C, Malefant M, Du Pont A, Labrie F. Ocular toxicity

D.M. Main0 et al. /Clinical Eye and !&ion Cave 12 (2000)113-117 of anandron in patients treated for prosthetic cancer. Br J Ophthalmol 1986;170:471-473. Stein CA, La Rocca RV, Thomas R, Mcatec N, Myers CE. Suramin an anticancer drug with a unique mechanism of action. J Clin Oncol 1987;14:499-508. Teich SA, Handwerger S, Mathur-Wagh U, Yancovitz S, Dosnick RJ, Mildvan D. Toxic keratopathy associated with suramin therapy. N Engl J Med 1986;314:1455-1456. Holland EJ, Stein CA, Palestine AG, La Rocca RV, Chan CC, Kuwabara T et al. Suramin keratopathy. Am J Ophthalmol 1988;106:216-220. Hemady R, Sinibald V, Eisenberger M. Ocular symptoms and signs of associated suramin sodium treatment for metastatic cancer of the prostate. Am J Ophthalmol 1996;121:291-296. Okich J, Skarin A, Frei E. Methyl CCNU and adriamycin combination therapy. Cancer 1974;34:1593-1597. Grimson BS, Maheley Jr MS, Dubey HID et al. Ophthalmic and central nervous system complications following intracarotid BCNU(carmustine). Clin Neurol Ophthalmol 1981;1:261-264. Miller DF, Bay JW,Lederman RJ et al. Ocular and orbital toxicity following intracarotid injection of BCNU (carmustine) and cisplatinum for malignant gliomas. Ophthalmology 1981;92:102-140. Greenberg HS, Ensminger WD, Chandler WF et al. Intraarterial BCNU chemotherapy for treatment of malignant gliomas of the central nervous system. J Neurosurg 1984;61:423-429. Shingleton BJ, Bienfang DC, Albert DN et al. Ocular toxicity associated with high dose of carmustine. Arch Ophthalmol 1982;100:1766-1772. Vizel M, Oster MW. Ocular side effects of cancer chemotherapy. Cancer 1982;49:1999-2002. McLennan R, Taylor HR. Optic neuroretinitis in association with BCNU and procarbazine therapy. Med Pediatr Oncol 1978;4:43-48. Louis AC, Tuwisi AT, Muggla FM, Bono Jr VH. Visual abnormalities following nitrosurea treatment. Med Pediatr Oncol 1978;5:245-247. Cruciani F, Tamanti N, Adolrahimzedeh S, Franchi F, Gabrieli CB. Ocular toxicity of systemic chemotherapy with megadoses of carmustine and mitomycin. Ann Ophthamol 1994;26:97-100. Kupersmth MJ, Frohman LP, Choi IS et al. Visual system toxicity following intra-arterial chemotherapy. Neurology 1988;38:284-289. Brett MC, Pickard M, Green B, Howel-Evans A, Smith D, Kinsella A. Poston G: p53 protein overexpression and response to biomodulated 5-fluorouracil chemotherapy in patients with advanced colorectal cancer. Eur J Surg Oncol 1996;22(2):182-185. Hamersley J, Luce JK, Florent TR et al. Excessive lacrimation from flurouracil treatment. J Am Med Assoc 1973;225:747-748. Strauss IDJ, Mansolf FA, Ellerby RA et al. Cicatrical ectropion secondary to 5-flurouracil therapy. Med Pediatr Oncol 1977;3:15-19. Insler MS, Helm CJ. Ankyloblepharon associated with systemic 5-flurouracil treatment. Ann Ophthalmol 1987;19: 374-375. Lee V, Bentley C, Olver J. Sclerosing canaliculitis after 5-flurouracil breast cancer chemotherapy. Eye 1998;12 343-349.

117

Knapp A, Heuer DK, Stern GA et al. Serious corneal complications of glaucoma filtering surgery with postoperative 5flurouracil. Am J Ophthalmol 1987;103:183-187. Lee DA, Hersh DK, Kersater D et al. Complications of subconjunctival 5-flurouracil following glaucoma filtering surgery. Ophthalmic Surg 1987;18:187-190. Kadayifcilar S, Boyacioglus S, Kart H, Gursoy M, Aydin P. Ocular complications with high dose interferon alpha in chronic hepatitis. Eye 1999;13(2):241-246. Sugano S, Suzuki T, Watanabe M, Ohe K, Ishii K, Okajima T. Retinal complications and plasma C5a levels during interferon alpha therapy for chronic hepatitis C. Am J Gastroenterol 1998;93(12):2441-2444. Frakkilia M, Livanainen M, Roine R et al. Neurotoxic and other side effects of high dose interferon in amyotrophic lateral sclerosis. Acta Neurol Scand 1984;70:42-46. Nouri K, Busso M, Machler BC. Vetiligo associated with alpha interferon in a patient with chrons active hepatitis C. Cutis 1997;60(6):289-290. Xia X, Huang P, Jiang Y, Zhou J, Wang C, Wu Z. The effect of mitomycin C on activities of carbonic anhydrase and ATPase of the ciliary body epithelium in rabbit. Yen KO Hsueh Pao 1996;12(2):74-78. Morrow GL, Stein RM, Heathcate JG, Ikeda-Douglas JV, Feldman F. Ocular toxicity of mitomycin in rabbit. Can J Ophthal 1994;29(6):268-273. Wu KY, Hong ST, Huang HT, Lin CP, Chen CW. Toxic effects of mitomyicin C on cultured corneal keratocytes and endothelial cells. J Oculo Pharmacol Ther 1999;15(5): 401-411. Clark JH, Peck EJ, Anderson JN. Oestrogon receptors and antagonism of steroid h o r m o n e action. N a t ur e 1974;251:446-448. Zhahng JJ, Jacob TJ, Valverde MA et al. Tamoxifen blocks chloride channels: a possible mechanism for cataract formation. J Clin Invest 1994;94(4):1690-1697. Lazzaroni F, Scorolli L, Pizzolco CF et al. Tamoxifen retinopathy: does it really exist? Graefes Arch Clin Exp Ophthalmol 1998;236(9):669-673. Gorin MB, Day R, Costantino JP et al. Long-term tamoxifen citrate use and potential ocular toxicity. J Ophthalmol 1998;125(4):493-501. Ah-song R, Sasco A.J. Tamoxifen and ocular toxicity. Cancer Defect Preview 1997;21(6):522-531. Pavlidis NA, Petris E, Briassoulis E et al. Clear evidence that long term, low dose tamoxifen treatment can induce ocular toxicity: a prospective study of 63 patients with cancer. Cancer 1992;69:2961-2964. Sekhar GC, Nagarajan R. Ocular toxicity of tamoxifen. Indian J Ophthalmol 1992;43(1):23-26. Frei E, Joffe N, Tattersall MHN et al. New approaches to cancer chemotherapy with methotrexate. N Engl J Med 1975;292846-851. Joussen AM, &use FE, Volcker HE, Kirchhof B. Topical application of methotrexate for inhibition of corneal angiogenesis. Graefes Arch Clin Exp Ophthalmol 1999; 237(11):920-927. Doroshow JH, Locker GY, Gaasterland DE, Hubbard SP, Young RC, Myers CE. Ocular irritation from high dose methotrexate therapy: pharmacokinetics of drug in the tear film. Cancer 1981;15(10):2158-2162. Epocrates. wwwepocrates.com 06/2000.