Ocular Toxicity of Oncology Treatments: Keeping An Eye Out

Cancer is the second leading cause of death in the United States, with rates increasing to 442.4 cases per 100,000.^1,2 While these statistics are staggering, many advances have been made in cancer prevention, detection, and treatment. Overall rates of cancer-related deaths in the US peaked in 1991 and steadily declined.³

With the increase in life expectancy of cancer patients, the likelihood of encountering these patients, for acute complaints or routine ophthalmic exams, becomes more probable. Both cancer and systemic medications can impact the ophthalmic system. Given these facts, it is vital to understand patients’ diagnoses and treatment regimens. This article will explore some of the various types of treatment for cancer and their possible ocular adverse effects.

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Ocular toxicity

When patients present with ocular complaints, it is essential to consider any form of treatment or systemic medications that they may be taking. It has been well established that ocular complications can occur from different therapeutics. By staying up to date on the medicines that could potentially harm the eyes, practitioners can assess patients. More specifically, practitioners will recognize signs of early toxicity, provide potential relief and even help guide treatment where possible.

Oncologic treatments and their ocular adverse effects

Cytotoxic chemotherapy

Cytotoxic chemotherapeutics, sometimes referred to as traditional chemotherapeutics, function by disrupting the mitotic process of cells. Various drugs have been developed and disrupt cell replication via direct or indirect inhibition mechanisms.

Examples of these drugs include:

Alkylating agents (i.e., cisplatin, carboplatin)
Antimetabolites (i.e., methotrexate, 5-fluorouracil, 6-mercaptopurine)
Topoisomerase inhibitors (i.e., topotecan, etoposide)

Adverse ocular effects have been reported using cytotoxic drugs ranging from adnexal changes to optic neuropathies. For instance, bortezomib, a proteasome inhibitor, has been reported to cause meibomian gland disease, specifically the development of significant recurrent chalazion with its use.⁴ The use of taxanes and fluoropyrimidines has been shown to cause stenosis of the canalicular system leading to excess tearing.

Similarly, administration of methotrexate and anthracyclines have been shown to cause dry eye-like symptoms and conjunctivitis.⁴ The cornea can also become affected as well.

One study revealed patients being treated with cytarabine developed corneal deposits, irritating and causing a decrease in vision in up to 85% of patients.⁴

The posterior segment is not spared with cytotoxic chemotherapeutics and should be monitored as well. It has been well documented that interferon-alfa 2b has many ocular side effects. Both severe panuveitis and retinal ischemia have been seen with their use.⁵. Its impact is potentially vision-threatening and should be considered in patients undergoing these treatments who develop symptoms.

Platinum analogs, such as cisplatin, can cause ischemic retinopathy. In contrast, agents such as vincristine have been shown to cause toxic neuropathies, possibly involving the optic nerve or even nerves of oculomotor function.⁴

Checkpoint inhibitors

Immune checkpoint inhibitors are immunomodulatory antibodies that aid the body’s immune system against the dampening effects of cancerous cells. This class of drugs includes Programmed Cell Death 1 inhibitors (PCD-1), Programmed Cell Death Ligand inhibitors (PD-L1), and Cytotoxic T-Lymphocyte Associated Antigen-4 inhibitors (CTLA4). With the increased activity of the immune system, these drugs have been linked to autoinflammatory reactions of the ophthalmic system.

PCD-1 (Pembrolizumab, Nivolumab) and PDL1 (Atezolizumab, Avelumab, Durvalumab) inhibitors have been associated with anterior and posterior uveitis. Cases of episcleritis and iritis have been reported.⁴ Interestingly, there have been reports of white-dot syndromes, such as birdshot-like retinopathy, after the administration of these agents.⁷

CTLA4 inhibitors (Ipilimumab, Tremelimumab) have been reported to cause similar occurrences of uveitis. They have also been linked to unique occurrences of orbital inflammation described as a “Graves-like” ophthalmopathy in both euthyroid and thyroglobulin positive patients.⁸ A rare report of ipilimumab-induced VKH syndrome with bilateral panuveitis, serous retinal detachments and dermatologic manifestations has been reported.⁹

MEK inhibitors

Mitogen-activated protein kinase inhibitors (Trametinib and cobimetinib), or MEK inhibitors, are used to treat malignant melanoma with BRAF mutations. These medications have associations with adverse effects on the posterior segment postulated to be caused by RPE dysfunction leading to characteristic bilateral multifocal serous retinal detachments.¹² These changes are referred to as MEK-Inhibitor associated retinopathy. Studies have reported these findings in up to 75% of cases and within one week of therapy induction.⁵

Radiation

Radiation is known to cause adverse effects when used to treat intraocular neoplasms or when the eyes are exposed during treatment of tumors in their vicinity. Any tissues exposed to radiation can have a disruption in normal physiologic function. Anteriorly, radiation has been shown to most frequently damage the meibomian glands, lacrimal system, and ocular surface, leading to dry eye symptoms.^7,8

Cataract formation can also occur. In the posterior segment, radiation retinopathy can develop. This well-documented entity is thought to be the result of the loss of vascular endothelial cells. It is most commonly seen 6 months to 3 years from exposure and results in characteristic fundoscopic findings including retinal microaneurysms, hemorrhages, cotton wool spots, neovascularization, or tractional retinal detachment.^7,8

Range of antineoplastic agents

Aromatase inhibitors, such as tamoxifen, are selective estrogen receptor inhibitors used to treat breast cancer. Their use has been linked to some unique ophthalmic adverse effects. In the anterior segment, patients have developed corneal opacities described as whorl-like subepithelial deposits as well as posterior subcapsular cataracts.⁶ In the posterior segment, this drug has been shown to cause deposition of refractile bodies in the macula with association to microcystic changes in the macula seen on OCT.⁶

Molecularly targeted drugs

Cetuximab and panitumumab are classified as epithelial growth factor inhibitors. This class of medications is associated with the highest frequency of ocular adverse effects.⁴ The use of these medications has been associated with dysregulation of hair cycle growth leading to trichomegaly. Aberrant eyelashes in these cases have led to recurrent corneal injury including ulceration.⁴ Even without hair growth abnormalities, many of these drugs have been linked to corneal epithelial compromise causing keratitis, recurrent erosions, corneal thinning, and even perforation.⁴

Tyrosine kinase inhibitors are a class of medications used to treat leukemias and gastrointestinal tumors. These drugs, particularly imatinib, have been associated with significant systemic edema, with periorbital edema being the most reported adverse effect.⁴ In some cases, the degree of periorbital edema has been reported to be severe enough to cause visual obstruction requiring steroid treatment or surgical debulking.⁶

BRAF inhibitors are currently used for the treatment of malignant melanoma. This class of medication includes vemurafenib, dabrafenib, and encorafenib. Reports of dry eye symptoms and uveitis have been reported with their use. More notably, the use of vemurafenib has been linked to frequent cutaneous side effects, including changes in the eyelids.⁴ The development of eyelid squamous cell carcinoma and verruca vulgaris lesions has been reported.⁴

Management and monitoring

Given the vast number of medications now being used to treat cancer with varying side effect profiles, there are no specific guidelines regarding ocular adverse effects. However, this does not mean eyecare providers cannot play a pivotal role in caring for patients diagnosed with cancer. When encountering cancer patients with any ocular complaint, obtaining a list of medications and treatments like all other patients remains essential. After diagnosing any ocular pathology, clinicians should consider complications secondary to medication-use in their differential.

In clinical practice, eye care providers can benefit immensely from resources such as Drug-Induced Ocular Side Effects: Clinical Ocular Toxicology by Frederick T. Fraunfelder, MD, and Frederick W. Fraunfelder, Jr. MD, MBA. Now on its 8th edition, this guide provides clinicians with information regarding drugs and their reported ocular adverse effects in an organized fashion. They have also established the National Registry of Drug-Induced Ocular Side Effects, which serves as a database that collects reports of adverse ophthalmic drug reactions from clinicians worldwide.

Conclusion

Ophthalmologists can play a vital role in caring for patients who have cancer. Even when their primary diagnosis is unrelated to the visual system, side effects from their treatment can involve the eyes. Prompt recognition and management of these ocular adverse effects can help alleviate discomfort and disruption in quality of life.

By utilizing resources such as the National Registry of Drug-Induced Ocular Side Effects, clinicians can aid in excelling in the field of ocular toxicology.

As we learn more, ophthalmologists can work in conjunction with oncologists to recognize ocular adverse effects early, monitor symptoms, and assist in considering the use of alternative agents if available. Ultimately, this would allow for improvement in the care of cancer patients and aid in the preservation of their vision.

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References

Centers for Disease Control and Prevention. (2022, January 13). FASTSTATS - deaths and mortality. Centers for Disease Control and Prevention. Retrieved January 25, 2022, from https://www.cdc.gov/nchs/fastats/deaths.htm
Cancer statistics. National Cancer Institute. (n.d.). Retrieved January 25, 2022, from https://www.cancer.gov/about-cancer/understanding/statistics
Cancer facts & figures 2019. (n.d.). Retrieved January 25, 2022, from https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2019/cancer-facts-and-figures-2019.pdf
Liu CY. Ocular Side Effects of Systemically Administered Chemotherapy. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. Retrieved January 26, 2022.
Wes A, Hong ES, Oetting TA. Interferon-AssociatedRetinopathy: Communicating with Internal Medicine. EyeRounds.org. July 26, 2010; Retrieved January 26, 2022, from http://www.EyeRounds.org/cases/116EInterferonERetinopathy.htm.
Fraunfelder, F. T., & Fraunfelder, F. W. (2020). Drug-induced ocular side effects: Clinical ocular toxicology (8th ed.). Elsevier - Health Sciences Division=
Birdshot-like Chorioretinopathy Associated With Pembrolizumab Treatment. Acaba-Berrocal LA, Lucio-Alvarez JA, Mashayekhi A, Ho AC, Dunn JP, Shields CL. JAMA Ophthalmol. 2018;136(10):1205.
Thyroid-like ophthalmopathy in a euthyroid patient receiving Ipilimumab. McElnea E, NíMhéalóid A, Moran S, Kelly R, Fulcher T Orbit. 2014;33(6):424. Epub 2014 Sep 10.
Bilateral drug (ipilimumab)-induced vitritis, choroiditis, and serous retinal detachments suggestive of vogt-koyanagi-harada syndrome. Wong RK, Lee JK, Huang JJ. Retin Cases Brief Rep. 2012;6(4):423.
Nuzzi, R., Trossarello, M., Bartoncini, S., Marolo, P., Franco, P., Mantovani, C., & Ricardi, U. (2020). Ocular Complications After Radiation Therapy: An Observational Study. Clinical ophthalmology (Auckland, N.Z.), 14, 3153–3166. https://doi.org/10.2147/OPTH.S263291
Wen, J. C. (2021, April 3). Radiation retinopathy. EyeWiki. Retrieved January 27, 2022, from https://eyewiki.aao.org/Radiation_Retinopathy
Chhablani, J. (2021, September 5). Drug induced maculopathy. EyeWiki. Retrieved February 5, 2022, from https://eyewiki.aao.org/Drug_induced_maculopathy