Molecular targeted anticancer drugs have improved survival rates for various cancers. However, they also inhibit signaling pathways in normal tissues in addition to tumor cells, which can cause various ocular side effects. The range of toxicity varies from mild dry eye to severe complications that pose an immediate threat to vision.
In recent years, the number of patients using anticancer drugs who visit general ophthalmology clinics has increased. Patients themselves are often unaware of the ocular side effects of systemically administered drugs, and when differentiating unexplained corneal epithelial disorders or vision loss, it is essential to check the history of anticancer drug use.
Chemotherapeutic agents can induce macular edema and serous retinal detachment through disruption of the blood-retinal barrier (BRB) 1). Furthermore, malignant tumors themselves can cause uveitis, making it often difficult to differentiate between drug-induced and tumor-related causes 1).
It varies greatly depending on the drug class. With the ALK inhibitor crizotinib, visual disturbances occur in 65% of patients, while for many drugs, side effects are limited to mild CTCAE grade 1-2. The recommended frequency of regular ophthalmic examinations also differs for each drug.
Ocular subjective symptoms associated with systemic chemotherapy vary depending on the drug class.
Clinical findings of ocular toxicity range widely from the anterior segment to the posterior segment.
Anterior Segment Findings
Corneal epithelial disorder: Representative is “tyrosine kinase keratitis” caused by EGFR inhibitors.
Conjunctivitis: Frequently observed with EGFR inhibitors and HER2 inhibitors.
Anterior uveitis: The most common ocular TRAE with BRAF inhibitor monotherapy. Also seen with immune checkpoint inhibitors.
Chalazion and blepharitis: Prevalence 6.8% with the proteasome inhibitor bortezomib.
Posterior segment findings
Serous retinal detachment: Occurs dose-dependently with MEK inhibitors. Multifocal.
Macular edema: Reported with paclitaxel, BRAF inhibitors, and MEK inhibitors.
Retinal vein occlusion: Reported with MEK inhibitors and BCR-ABL inhibitors (ponatinib).
Panuveitis: There is a Vogt-Koyanagi-Harada disease-like condition caused by immune checkpoint inhibitors1).
Ocular toxicity occurs because the signaling pathways targeted by drugs are also expressed in normal ocular tissues. The main drug classes and their associated ocular toxicities are shown below.
| Drug Class | Main Ocular Toxicity | Associated Disease |
|---|---|---|
| MEK inhibitors | Serous retinopathy | Metastatic melanoma |
| BRAF inhibitors | Uveitis | Melanoma |
| EGFR inhibitors | Corneal epithelial disorders | Non-small cell lung cancer |
| Immune checkpoint inhibitors | Uveitis | Various solid tumors |
| FGFR inhibitors | Serous retinopathy | Cholangiocarcinoma |
BRAF V600E mutation is associated with melanoma, as well as Hodgkin lymphoma, hairy cell leukemia, lung adenocarcinoma, and colorectal cancer. MEK inhibition suppresses IGF-1-induced VEGF production and affects vascular permeability.
Known risk factors for ocular toxicity include advanced age and hepatic/renal dysfunction (leading to prolonged or severe symptoms). The onset timing varies, ranging from a few days to several months after treatment initiation.
Many ocular toxicities are difficult to prevent, but for FGFR inhibitors, prophylactic use of artificial tears is recommended. Early detection is most important, and for FGFR inhibitors, regular eye examinations are required for 4 to 6 months after starting treatment.
The diagnosis of drug-induced ocular toxicity is based on understanding the medication used and the temporal relationship with ophthalmic findings.
The treatment of drug-induced ocular toxicity is based on discontinuation or dose reduction of the causative drug, but collaboration with the primary physician is essential considering the treatment of the underlying disease (cancer).
Uveitis caused by immune checkpoint inhibitors is often mild, and treatment may be continued in some cases. Consultation with the primary physician is necessary depending on severity. Since checkpoint inhibition activates T cells and induces autoimmune responses, it can cause Vogt-Koyanagi-Harada (VKH)-like panuveitis 1).
Many ocular toxicities improve after discontinuing the causative drug. MEK inhibitor-associated serous retinopathy is self-limiting and may resolve regardless of drug discontinuation. However, some conditions, such as cetuximab-induced corneal ulcers and certain retinopathies, may leave irreversible changes.
The mechanisms of ocular toxicity from systemic chemotherapy vary by drug class.
BRAF inhibitors inhibit BRAF kinase, enhancing T-cell infiltration and activity in tumors. MEK inhibition activates antitumor immune responses and affects retinal vascular permeability by suppressing IGF-1-induced VEGF production.
Serous retinopathy caused by MEK inhibitors is thought to involve dysfunction of the retinal pigment epithelium pump due to inhibition of the MEK signaling pathway. Since the FGFR pathway shares downstream components with the MEK pathway, similar serous retinopathy can occur with FGFR inhibitors.
EGFR is expressed in the epithelium of the cornea, limbus, and conjunctiva, regulating cell proliferation, regeneration, and differentiation. Blockade of these pathways reduces corneal epithelial regenerative capacity, leading to keratopathy, conjunctivitis, and dry eye. Since EGFR is also involved in eyelash growth, eyelash hypertrophy occurs frequently.
Immune checkpoint inhibitors, as monoclonal antibodies, block inhibitory receptors of the immune system, enhancing tumor surveillance mechanisms 1). As a result of checkpoint inhibition, the incidence of autoimmune diseases increases. In patients undergoing melanoma treatment, Vogt-Koyanagi-Harada-like reactions have been reported due to antigen sharing between tumor cells and normal melanocytes 1). T-cell activation and subsequent immune responses damage retinal vascular tight junctions, leading to breakdown of the blood-retinal barrier 1).
Taxane anticancer drugs inhibit microtubule reassembly and cause cytotoxicity. The mechanism of macular edema is speculated to involve disruption of the blood-retinal barrier at a molecular weight lower than fluorescein and an association with fluid retention tendency. It is characteristic that no fluorescein leakage is observed on FA.
Decreased estrogen levels affect the ocular surface and are thought to induce meibomian gland dysfunction (MGD). In some cases, anastrozole and letrozole have been suggested to trigger de novo Sjögren’s syndrome.
The FGFR pathway shares downstream signaling with the MEK pathway. Therefore, FGFR inhibitors can also cause serous retinopathy similar to MEK inhibitors. In both cases, the main cause is thought to be an effect on retinal pigment epithelial function.
ERK inhibitors are downstream targets of the MAPK pathway and may cause more cystoid macular edema and intraretinal fluid in addition to retinopathy similar to MEK inhibitors.
A case series of 20 patients showed that ERK inhibitor-associated retinopathy was reversible and did not cause serious eye damage.
Tomkins-Netzer et al. (2024) examined the pathophysiology of blood-retinal barrier (BRB) breakdown caused by chemotherapeutic agents (such as cytarabine, immune checkpoint inhibitors, BRAF inhibitors, and EGFR inhibitors) 1). It has been noted that because malignant tumors themselves can also cause uveitis, it is clinically difficult to identify the cause of BRB breakdown. They concluded that understanding the mechanisms of BRB injury will contribute to the development of future treatment strategies.
Epacadostat, currently in clinical trials, has been reported in case reports to induce uveitis. Further accumulation of safety data is awaited.
