Although they occur less frequently than other eyesight issues linked to anti-cancer drugs, ocular toxicities resulting from chemotherapy can impair quality of life and should be readily recognized by clinicians.

As with all medication-related toxicities, ocular toxicities should be carefully managed following diagnosis, possibly with the involvement of ophthalmologists along with oncologists.

 

Differential diagnosis

Because problems with eyesight due to anti-cancer drugs are encountered infrequently and are non-life threatening in most cases, they may be missed in a clinic visit. Consequently, the frequency of these complications can be underestimated, according to a retrospective study published by Investigational New Drugs.

Takamizawa S, Katsuya Y, Chen YN, et al. Ocular toxicity of investigational anti-cancer drugs in early phase clinical trials. Invest New Drugs. 2022;December 5 [online ahead of print].

 

Paraneoplastic syndromes tend to be rare, but they can include melanoma-associated retinopathy, paraneoplastic optic neuropathy (optic neuritis), and cancer-associated retinopathy, as per an UpToDate review.

Liu CY, Francis JH, Abramson DH. Ocular side effects of systemically administered chemotherapy. UpToDate. Updated January 5, 2023.

 

The most common metastasis to the eye is intraocular malignancy. This typically involves the uveal tract, which comprises the iris and ciliary body anteriorly and the choroid posteriorly.

Choroidal metastases usually manifest as raised amelanotic choroidal lesions, with the retinal pigment epithelium appearing along with a patchy disturbance. Overlying retinal detachment commonly occurs and is typically out of proportion to the lesion.

Other areas of metastases are the orbit and ocular nerve, which can lead to optic-disc swelling, as well as metastases to the retina. The latter often leads to retinal inflammation and intracranial hemorrhages. Metastases to the vitreous may yield accumulated leukocytes in the vitreous humor.

An ophthalmologist can determine which compartment of the eye is affected, such as the cornea, uvea (ie, choroid, ciliary body, and iris), periocular and orbital tissue, retina, or optic nerve.

The severity of ocular/visual adverse effects should be graded using the Common Terminology Criteria Adverse Events reporting system of the National Cancer Institute (NCI-CTCAE), which lists grading tables for the severity of various eye disorders.

Safety profiler. National Cancer Institute.

Examples cited in the UpToDate review include blurred vision, cataracts, corneal ulcer, eye pain, and dry eye.

 

 

Ocular toxicity examples

Molecularly targeted agents harbor mechanisms vastly different from cytotoxic chemotherapy and can interfere with cellular signaling and angiogenesis pathways, which are required for tumor growth. These agents have distinct profiles resulting in specific ocular toxicities.

A full evaluation of all of the causes of ocular drug toxicity is outside the scope of this article. Instead, it will discuss a couple of related examples of drug toxicity: watery eyes and corneal epithelial defects.

Watery eyes. This condition—also referred to as epiphora—can result from permanent lacrimal gland stenosis. It has been observed in patients taking the combination chemotherapy of cyclophosphamide, methotrexate, and 5-fluorouracil (although this regimen is not commonly used). In particular, 5-fluorouracil is linked to excessive tearing that usually stops once the chemotherapy is stopped, according to research published by Pharmacy Practice.

Omoti AE, Omoti CE. Ocular toxicity of systemic anticancer chemotherapy. Pharm Pract (Granada). 2006;4(2):55–59.

Rarely, epiphora may necessitate the interruption of chemotherapy.

 

No gold-standard test or consensus of criteria exists for the diagnosis of dry eye. A diagnosis is usually based on patient symptoms and supporting findings on physical exam (eg, conjunctival injection, excess tearing, and a decreased blink rate).

Common treatments for dry eye include artificial tears or a short course of corticosteroids/ophthalmic cyclosporine.

Another option for dry eye is the topical (ie, ophthalmic) solution lifitegrast. This drug belongs to a class of medications called lymphocyte function-associated antigen-1 (LFA-1) antagonists and decreases swelling of the eye tissue.

Lifitegrast ophthalmic. Medline Plus. Updated September 15, 2016.

 

Corneal epithelial defects. Patients taking epidermal growth factor receptor inhibitors can experience poor healing of the epithelial layer of the cornea, which can result in chronic corneal defects and erosions.

This presentation is similar to dry eye but is more severe. Examples may include blurriness of vision or burning/stinging pain. Nonhealing corneal epithelium can increase the risk of keratitis and other infections, as well as corneal ulcers, which could threaten vision and will require urgent care.

Because of the threat of superinfection, patients exhibiting corneal abrasions should receive topical antibiotics. Other ulcer-preventive measures include a bandage contact lens and temporary tarsorrhaphy (ie, temporary closure of the eyelids).

It should be noted that ulcers may not be readily observed without slit-lamp examination, so it’s a good idea to have an ophthalmologist or cornea specialist on board.

 

Looking forward

In the retrospective study published by Investigational New Drugs, researchers assessed the ocular toxicities of newer agents in early clinical trials, including first-in-class agents. They found the incidence of ocular toxicities was 7.6%, affecting 33 of 434 patients. In total, 37 cases of ocular toxicity occurred in 33 patients.

HSP90 inhibitors and FGFR inhibitors were drugs that resulted in high rates of ocular toxicities. The most frequent complication was retinopathy, with other conditions including conjunctivitis, dry eye, keratitis, keratopathy, and uveitis. The vast majority of toxicities affected both eyes, and 22 of 37 ocular toxicity cases required pauses in drug therapy.

Some ocular toxicities arose after a long period of time from the initial administration of the drug.

“Most patients developed ocular toxicities even though their dose was below the [maximum tolerated dose],” the authors continued. “Ocular toxicities were generally not severe and were reversible after a temporary hold of the drug. Bilateral ocular toxicity could be used as a trigger for diagnosis of drug-induced toxicities.”

A study published by the Journal of Ocular Pharmacology and Therapeutics found that a “diverse range” of ocular adverse effects (AEs) were associated with the administration of antibody-drug conjugates (ADCs) for the treatment of cancer in human clinical trials.

Eaton JS, Miller PE, Mannis MJ, et al. Ocular adverse events associated with antibody–drug conjugates in human clinical trials. J Ocul Pharmacol Ther. 2015;31(10):589–604.

Most of the ocular AEs were not severe and improved or resolved when the ADC treatments were stopped.