– – Visual changes have been attributed to a number of chemotherapeutic agents such as the antimetabolites, alkylating agents, taxanes, and platinum agents
– – In addition to the eye itself, structures of the skin, including the eyelids and eyebrows, may be affected by side effects of antineoplastic chemotherapy
– – An ophthalmologist should be part of a multidisciplinary team caring for patients undergoing systemic chemotherapy for baseline exams and ongoing assessment
For more than a decade, clinical literature has documented ocular changes that are believed to be related to the administration of certain chemotherapeutic drugs. An article by O’Dea and colleagues reported historical and current knowledge on the subject, components of a comprehensive visual assessment, and 4 case studies of patients who experienced visual changes while receiving therapy with oxaliplatin.1 Changes in visual fields and acuity have been attributed to a number of pharmaceutical agents, including allopurinol, cephalosporins, and narcotics, as well as to chemotherapeutic agents such as the antimetabolites, alkylating agents, taxanes, and platinum agents. Patients undergoing treatment for breast cancer often report changes in visual acuity and dry-eye syndrome. Agents targeting the epidermal growth factor receptor (EGFR) also are reported to cause ocular toxicity.2
Antineoplastic chemotherapy, especially carmustine, vinblastine, and vincristine, can cause damage to the optic nerve and the ocular motor nerves. Interferon may cause neuro-ophthalmic lesions. Ischemic optic neuropathy, which may be bilateral, presenting with optic disc edema and progressing to optic atrophy, has been reported with the use of interferon. Interferon a treatment may cause, or aggravate the risk of developing, anterior ischemic optic neuropathy, and vulnerable patients should be advised of this potential complication.
Reported adverse effects vary from mild changes, such as dry eyes and blurred vision, to more severe and sometimes permanent changes, such as retinal damage, glaucoma, and cataracts. Medications taken for comorbid conditions may also cause ocular changes; therefore, a full medication assessment should be undertaken when a patient reports visual changes. Comorbid conditions, such as diabetes mellitus, lupus, multiple sclerosis, and pheochromocytoma, may also cause visual changes. In certain types of cancer known to metastasize to the brain, persistent visual changes should prompt radiologic examination of the brain to rule out brain metastases.
Case reports of blepharitis related to long-term (> 15 wk) cetuximab monotherapy were reported by Dranko et al.2 A chemotherapy agent, specific to the care of patients with colorectal cancer (CRC), that may cause visual changes is oxaliplatin. Leonard and coworkers conducted a survey to evaluate neurotoxicity secondary to oxaliplatin therapy.3 Eighty-six patients with metastatic CRC being treated with oxaliplatin plus capecitabine were interviewed. The participants reported blurred vision, eye pain, and visual field cuts. The incidence rates were < 20%, and all changes were transient and resolved after discontinuing oxaliplatin therapy. The prescribing information for oxaliplatin reports low rates (< 20% for all grades) of visual disturbances, including tearing, conjunctivitis, and abnormal lacrimation.4
Fluorouracil (5-FU) and the oral 5-FU prodrug capecitabine, may cause dry eyes and/or excessive tearing.5 In a 2000 case report, Waikhom and colleagues6 reported severe ocular irritation associated with capecitabine therapy; the package insert for capecitabine reports a 5% to 15% incidence for all types of visual disturbance.7 Irritation to the anterior (corneal) surface leading to ocular surface lesions can result from the systemic administration of 5-FU. The calculated prevalence rates of ocular surface lesions with use of systemic 5-FU are ocular irritation, 5.8%; conjunctivitis, 3.8%; keratitis, 3.8%; tearing, 26.9%; and blurred vision, 11.5%.8
Ocular toxicity has been reported with EGFR inhibitors (eg, cetuximab, panitumumab) used in treatment of CRC and other solid tumors.2 Panitumumab administration resulted in ocular toxicities in 15% of patients, which included, but were not limited to, conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%).9 Cetuximab administration reports blepharitis (erythema of the eyelids), conjunctivitis, keratitis (inflammation of the cornea), cheilitis (inflammation of the lip), and hypertrichosis (abnormal hair growth) in patients receiving cetuximab therapy, although specific percentages are not reported in the prescribing information.10 Bevacizumab has not been reported to cause visual changes or abnormalities.11
Cataracts have been reported with use of tamoxifen, a selective estrogen receptor modulator (SERM) commonly used in treatment of breast cancer, and with high-dose corticosteroids, such as dexamethasone and prednisone, commonly used in treatment of hematologic malignancies or for symptom management of conditions such as cerebral edema secondary to brain metastases.12
Ocular toxicity induced by cancer chemotherapy includes a broad spectrum of disorders, reflecting the unique anatomic, physiologic, and biochemical features of the eye. Structures of the skin, including the face, eyelids, and eyebrows, may be affected by side effects of chemotherapy. Epiphora (watery eyes) resulting from permanent lacrimal gland stenosis has been reported in patients receiving combination chemotherapy of cyclophosphamide, methotrexate, 5-FU, and docetaxel.12 5-FU may produce lacrimal gland irritation in some patients leading to excessive lacrimation.12
The mechanism of visual toxicity induced by cisplatin is unknown, but it may result from central nervous system accumulation of drug after repeated doses, especially with high-dose platinum-containing regimens. Toxic neuropathies, including disc edema, retinal edema, and optic neuritis are rare, but have been described as occasional side effects of treatment with cisplatin. Tamoxifen has been reported to cause bilateral optic neuritis followed by optic atrophy and visual loss. This effect is dose related.12
Ocular changes may include areas just outside the eye itself, commonly called the ocular adnexa, which clinicians may consider part of the dermatologic system. Structures of the skin, including the eyelids and eyebrows, may be affected by side effects of antineoplastic chemotherapy, resulting in blepharitis (Figure 1), eyelid dermatitis, and excessive tearing. Excessive tearing that resolves on cessation of treatment is a reported side effect of 5-FU.12 A National Comprehensive Cancer Network (NCCN) multidisciplinary task force compiled a report that describes commonly used therapies for management of dermatologic and ophthalmologic toxicities associated with EGFRIs.13
Figure 1. Blepharitis
Photo courtesy of Susan Moore.
Grading Ocular Changes
Many visual changes, covering a wide range of symptoms and eye disorders, may occur as a side effect of cancer therapy. Readers are advised to consult the National Cancer Institute, Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events (CTCAE) v4.03 (pages 10-11) for definitions and specific criteria for each grade of ocular toxicity.14 Grade refers to the severity of the adverse event. The CTCAE displays grades 1 through 5 with unique clinical descriptions of severity for each adverse event based on this general guideline (Table 1). 14
Table 1. General Adverse Event Grading Criteria
1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated
2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL
3 Severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL
4 Life-threatening consequences; urgent intervention indicated
5 Death related to AE
ADL = activities of daily living; AE = adverse event.
Based on information from the National Cancer Institute.14
Management of Ocular Changes
It is easy to miss the association between chemotherapy and visual changes because the incidence is relatively uncommon and many other conditions can cause ocular changes, especially in older adults. Hazin et al15 and Schmid et al16 suggest that ophthalmologists should be part of a multidisciplinary team caring for patients undergoing systemic chemotherapy to provide the following:
Baseline examination to evaluate for preexisting eye disorders
Evaluate for dry-eye syndrome
Ongoing consultation for eye problems that present during systemic chemotherapy
Omoti and Omoti12 recommend a baseline exam and ongoing follow-up every 3 months thereafter during active therapy.12 Other than recommending over-the-counter eye lubricants, patients reporting visual changes should be referred to an ophthalmologist immediately to preserve vision. Ophthalmalogic intervention may include topical or systemic medication or, in the case of excessive tearing, the insertion of lacrimal stents.
Implications for Health Care Professionals
Ophthalmologic side effects are generally uncommon, but important to note because of the extreme debility produced by loss of vision. Although most chemotherapeutic agents seem to be relatively free of ocular toxicity, certain drugs carry a significant risk of visual changes. Long-term effects of chemotherapy are of increasing importance as survival of patients with cancer improves. The long-term ocular effects of most chemotherapeutic agents are unknown. Nurses caring for patients with cancer can assist them to protect their visual health by doing a thorough review of systems related to visual changes during therapy, and referring a patient to an ophthalmologist for a baseline exam and complete visual assessment when a patient reports these changes.
Assessment and Patient Care Management Tools
National Cancer Institute, Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events (CTCAE) v4.03 (pp 10-11). http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.
Health on the Net Foundation, Vision FAQ, section 5: disease of the eye (posterior eye disease)
Optometric clinical practice recommendations for monitoring ocular toxicity of selected medications can be viewed online at http://www.aoa.org/documents/Ocular-Toxicity.pdf.
O’Dea D, Handy C, Wexler A. Ocular changes with oxaliplatin. Clin J Oncol Nurs. 2006;10:227-229.
Dranko S, Kinney C, Ramanathan RK. Ocular toxicity related to cetuximab monotherapy in patients with colorectal cancer. Clin Colorectal Cancer. 2006;6:224-225.
Leonard G, Wright M, Quinn M. Survey of oxaliplatin-associated neurotoxicity using an interview-based questionnaire in patients with metastatic colorectal cancer. BMC Cancer. 2005;5:116-125.
Eloxatin (oxaliplatin for injection) prescribing information. http://products.sanofi-aventis.us/eloxatin/eloxatin.html.
Wilkes G, Barton-Burke M. 2006 Oncology Nursing Drug Handbook. Boston, MA: Jones & Bartlett Publishers; 2005.
Waikhom B, Fraunfelder F, Henner W. Severe ocular irritation and corneal deposits associated with capecitabine use. N Engl J Med. 2000;343:740-741.
Xeloda (capecitabine) tablets prescribing information; 2010. http://www.gene.com/gene/products/information/xeloda/.
Eiseman AS, Flanagan JC, Brooks AB, Mitchell EP, Pemberton CH. Ocular surface, ocular adnexial, and lacrimal complications associated with the use of systemic 5-fluorouracil. Ophthal Plast Reconstr Surg. 2003;19:216-224.
Amgen, Inc. Vectibix prescribing information; 2010. http://pi.amgen.com/united_states/vectibix/vectibix_pi.pdf.
Bristol-Myers Squibb, Inc. Erbitux prescribing information; 2010. http://packageinserts.bms.com/pi/pi_erbitux.pdf
Genentech, Inc. Avastin prescribing information; 2011. http://www.gene.com/gene/products/information/pdf/avastin-prescribing.pdf.
Omoti AE, Omoti CE. Ocular toxicity of systemic anticancer chemotherapy. Pharm Pract. 2006;4:55-59.
Burtness B, Anadkat M. Basti S, et al. NCCN Task Force Report: Management of Dermatologic and Other Toxicities Associated With EGFR Inhibition in Patients With Cancer. J Natl Compr Canc Netw. 2009;7(suppl 1):S5-S22.
National Cancer Institute, Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events (CTCAE) v4.03 (pp 10-11). http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf
Hazin R, Abuzetun JY, Daoud YJ, Abu-Khalaf MM. Ocular complications of cancer therapy: a primer for the ophthalmologist treating cancer patients. Curr Opin Ophthalmol. 2009;20:308-317.
Schmid KE, Kornek GV, Scheithauer W, Binder, S. Update on ocular complications of systemic cancer chemotherapy. Surv Ophthalmol. 2006;51:19-40.
abnormal lacrimation—abnormal or excessive production of tears as a result of exposure of the eyes to an irritant
acuity—keenness of sense perception
blepharitis— inflammation of the eyelids characterized by redness, swelling, and dried crusts
cataracts—a clouding of the lens of the eye or its surrounding transparent membrane that obstructs the passage of light
conjunctivitis—inflammation of the conjunctiva, the membrane that lines the inner surface of the eyelids, usually from an allergy, virus, or bacterium; often called “pink eye”
glaucoma—a disease of the eye marked by increased pressure within the eyeball that can result in damage to the optic disk and gradual loss of vision
lupus—any of several diseases (as lupus vulgaris or systemic lupus erythematosus) characterized by skin lesions
pheochromocytoma—a tumor that is derived from chromaffin cells and is usually associated with paroxysmal (recurrent, sudden attacks) or sustained hypertension
visual field cuts—alterations to the extent of area visible to an eye as it looks straight ahead; measured in degrees away from direct line of sight