Ocular Side Effects of Anticancer Drugs and Molecular Targeted Therapies

Key points of this disease

• Anticancer drugs, molecular targeted drugs, and immune checkpoint inhibitors (ICIs) can cause ocular adverse events through different mechanisms.
• Hydroxychloroquine (HCQ) retinopathy occurs in about 0.5% of patients after long-term use for more than 5 years and is an irreversible disorder that can progress even after discontinuation.
• Tamoxifen (for breast cancer) causes crystalline deposits around the macula and CME, with an incidence of visual abnormalities of about 0.2% in Japan.
• MEK inhibitors cause serous retinal detachment and retinal pigment epithelial detachment in about 10-25% of cases, while EGFR inhibitors cause trichomegaly and blepharitis.
• ICIs (nivolumab, pembrolizumab, etc.) cause uveitis, dry eye, and VKH-like syndrome as immune-related adverse events (irAEs) in about 1% of patients.
• For patients using HCQ, baseline ophthalmologic examination at the start of treatment and annual screening after 5 years are recommended.
• The decision to continue, reduce, or discontinue the drug based on the severity of ocular side effects should be made collaboratively by the oncology and ophthalmology departments.

1. What are ocular side effects of anticancer drugs and molecular targeted drugs?

Ocular side effects of anticancer drugs and molecular targeted drugs are a general term for conditions in which drugs used for cancer treatment and immune disease treatment cause adverse events in ocular tissues.

The categories of drugs involved are extensive.

• Cytotoxic chemotherapy (5-FU, cisplatin, taxanes, etc.): epiphora, corneal epithelial disorders, optic neuropathy, etc. ¹⁾
• Hormonal therapy (tamoxifen, etc.): crystalline macular deposits, CME, corneal vortex opacities
• Immunomodulatory drugs (chloroquine, hydroxychloroquine, interferon): retinopathy, fundus hemorrhage, cotton-wool spots
• Molecular targeted drugs (MEK inhibitors, EGFR inhibitors, BRAF inhibitors, ALK inhibitors, etc.): Each drug has specific ocular side effects²⁾
• Immune checkpoint inhibitors (ICIs) (nivolumab, pembrolizumab, etc.): Uveitis and Vogt-Koyanagi-Harada-like syndrome as irAE³⁾
• Antibody-drug conjugates (ADCs) (trastuzumab deruxtecan, etc.): Corneal damage¹⁰⁾

With advances in cancer treatment, survival has been prolonged, and the importance of managing ocular side effects during long-term therapy is increasing¹⁾. Ocular side effects range from mild discomfort to irreversible vision loss, and appropriate screening and early intervention directly affect visual prognosis.

Q What should I do if I notice eye abnormalities during cancer treatment?

A

If symptoms such as decreased vision, redness, eye pain, floaters, photopsia, or metamorphopsia (distorted vision) occur, promptly see an ophthalmologist. Even if symptoms are mild, neglecting them can lead to irreversible damage, so it is important to report to your primary oncologist and coordinate with an eye doctor.

2. Symptoms and clinical findings by drug category

Ocular side effects vary by drug category. The main drugs and their ocular symptoms are shown below.

Cytotoxic chemotherapy

5-FU: Tearing (lacrimal duct stenosis), conjunctivitis, corneal epithelial damage¹⁾

Cisplatin: Optic neuropathy, color vision disturbance (rare)¹⁾

Taxanes (docetaxel, paclitaxel): Tearing, cystoid macular edema⁴⁾

Hormone therapy and immunomodulators

Tamoxifen: Perifoveal crystalline deposits, corneal vortex keratopathy, CME. Incidence: 3–6% overseas, 0.2% in Japan.

HCQ/chloroquine: Bull’s eye maculopathy (annular atrophy), decreased vision, night blindness, color vision abnormalities. Approximately 0.5% after 5 years of use.

Interferon: Small hemorrhages and cotton-wool spots at the posterior pole of the fundus. Occur within 2–3 months after administration. Mostly asymptomatic and resolve spontaneously.

Molecular Targeted Drugs

MEK inhibitors (e.g., trametinib): Serous retinal detachment and PED. Incidence approximately 10–25%²⁾

EGFR inhibitors (e.g., gefitinib): Trichomegaly, blepharitis, corneal epithelial disorders⁵⁾

BRAF inhibitors (e.g., vemurafenib): Uveitis, serous retinal detachment⁶⁾

ALK inhibitors (e.g., crizotinib): Photopsia, blurred vision. Approximately 60% develop visual disturbances⁷⁾

Immune Checkpoint Inhibitors (ICIs)

Uveitis (anterior, posterior, panuveitis): Incidence approximately 1%³⁾

VKH-like syndrome: Severe form requiring high-dose steroids³⁾

Dry eye, conjunctivitis, orbital inflammatory disease, external ophthalmoplegia⁸⁾

ADC (e.g., T-DXd): Corneal disorders (punctate superficial keratitis, corneal stromal opacity)¹⁰⁾

Macular Edema Due to Fingolimod

Docetaxel (taxane)-induced lower punctum stenosis — slit-lamp microscopy findings and nasolacrimal duct irrigation

Esmaeli B, Valero V, Ahmadi MA, Booser D. Canalicular stenosis secondary to docetaxel (taxotere): a newly recognized side effect. BMC Res Notes. 2014;7:322. doi: 10.1186/1756-0500-7-322. Figure 1. PMCID: PMC4046091. License: CC BY 2.0.

Slit-lamp examination (A) shows severe stenosis of the lower punctum indicated by the arrow, demonstrating that tears are not drained into the lacrimal duct. (B) shows the procedure of nasolacrimal duct probing and irrigation. This corresponds to epiphora and punctum stenosis caused by taxanes (docetaxel, paclitaxel) discussed in the section “2. Symptoms and Clinical Findings by Drug Category”.

Fingolimod (Imusera/Gilenya), used to prevent relapse of multiple sclerosis, is known to cause macular edema. The incidence of macular edema is 0.2% with fingolimod 0.5 mg/day and 1.4% with 1.25 mg/day, and most cases occur within 3–4 months after starting treatment.

3. Causes and Risk Factors

Risk factors for ocular adverse effects differ by drug category.

Drug Category	Major Risk Factors
HCQ/Chloroquine	Treatment duration >5 years, CQ >3.0 mg/kg/day or HCQ >6.5 mg/kg/day, elderly, renal/hepatic impairment, concurrent retinal disease
Tamoxifen	High dose and long-term use (increased cumulative dose)
Interferon	High initial dose, elderly, diabetes, hypertension, anemia
MEK Inhibitors	Dose-dependent (higher frequency with higher doses) 2)
ICI	Ocular irAEs are more likely in patients with systemic irAEs (e.g., thyroiditis, colitis) 3)
ADC	Drug-specific corneal toxicity mechanism 10)

Specific risk factors for HCQ retinopathy include the following.

• Duration of use: Long-term use for 5 years or more (cumulative dose: CQ >460 g, HCQ >1,000 g)
• Daily dose: CQ >3.0 mg/kg/day, HCQ >6.5 mg/kg/day
• Systemic risks: Older age, reduced kidney function (delayed HCQ excretion), liver dysfunction
• Ocular local risks: Preexisting retinal disease or maculopathy

Interferon retinopathy is more frequent and severe in patients with systemic conditions such as diabetes, hypertension, and anemia, and is also more likely to occur in treatment-resistant or recurrent cases.

4. Diagnosis and Examination Methods

HCQ Screening Protocol

Based on the recommendations of the American Academy of Ophthalmology (AAO)⁹⁾, the following screening is performed.

• At initiation of treatment (baseline): Visual acuity, fundus examination, and SD-OCT
• After 5 years of treatment: If no high-risk factors, begin annual screening
• With risk factors: Start screening early, before 5 years, and shorten intervals
• Recommended maximum dose: 5 mg/kg/day or less based on actual body weight⁹⁾

Useful tests include Humphrey 10-2 central visual field testing, SD-OCT, fundus autofluorescence, multifocal ERG, and full-field ERG. Bull’s eye maculopathy (annular atrophy) is a characteristic fundus finding in advanced HCQ retinopathy.

Screening Recommendations by Drug

Drug	Screening timing and tests
HCQ/Chloroquine	Baseline at start of treatment + annually from year 5 onward (SD-OCT, 10-2 visual field, FAF) 9)
Tamoxifen	At symptom onset and periodic fundus examination, SD-OCT
Interferon	Fundus examination 2–3 months after starting treatment. Prompt ophthalmology consultation if symptoms occur.
MEK inhibitors	OCT to confirm serous retinal detachment when decreased vision or metamorphopsia occurs 2)
ICI	Prompt ophthalmology consultation when decreased vision, redness, or eye pain occurs 3)
Fingolimod	Baseline fundus examination before treatment + follow-up 3–4 months after starting

In patients using ICI who develop decreased vision, redness, or eye pain, evaluate for anterior chamber inflammatory cells, vitreous opacities, and choroidal lesions, and consider the possibility of uveitis or VKH-like syndrome as an irAE ³⁾.

Q What eye examinations are necessary during hydroxychloroquine use?

A

At the start of treatment, it is recommended to undergo an eye examination including visual acuity, fundus examination, and SD-OCT as a baseline. Thereafter, if there are no risk factors (treatment duration ≥5 years, high dose, advanced age, renal dysfunction, etc.), annual screening should begin after 5 years. If risk factors are present, earlier and more frequent examinations are needed. SD-OCT, Humphrey 10-2 visual field test, and fundus autofluorescence are the main tests.

5. Standard Treatment

HCQ/Chloroquine Retinopathy

Discontinuation of the drug is the only treatment. Because elimination from the body is slow, the condition may progress or worsen even after stopping the medication. Therefore, early detection is extremely important, and the decision to discontinue the drug before irreversible damage occurs determines the visual prognosis.

Tamoxifen Ocular Side Effects

• Basic: Discontinue the drug if possible. Discontinuation halts progression and sometimes leads to improvement.
• CME: If CME does not resolve, anti-VEGF agents are effective.
• Crystalline deposits: Often persist after discontinuation; complete resolution is unlikely.
• Corneal vortex keratopathy: Observe in mild cases. Consider discontinuation in severe cases.

Interferon Retinopathy

Most cases have a good prognosis; if asymptomatic, the basic approach is to wait until the end of IFN therapy. In severe cases or those with vision loss, consider reducing or discontinuing IFN. Early intervention is needed in patients with diabetes or hypertension.

Serous Retinal Detachment Due to MEK Inhibitors

Bilateral serous retinal detachment due to MEK inhibitor (selumetinib) — SD-OCT findings

Hazar L, Acar U, Acar DE. New features in MEK retinopathy. BMC Ophthalmol. 2018;18:229. doi: 10.1186/s12886-018-0861-7. Figure 3. PMCID: PMC6157024. License: CC BY 4.0.

Comparison of infrared fundus images (left column) and high-resolution SD-OCT B-scans (right column) for the right eye (top row) and left eye (bottom row). Both eyes show thickening of the ellipsoid zone and accumulation of subretinal and intraretinal fluid, findings 5 days after discontinuation of the MEK inhibitor. This corresponds to serous retinal detachment due to MEK inhibitors discussed in section “6. Pathophysiology and Detailed Mechanism.”

• For moderate to severe serous retinal detachment, discontinue or reduce the drug ²⁾
• For mild cases, it is possible to continue administration while monitoring, and most cases resolve spontaneously ²⁾
• Confirm resolution of subretinal fluid after discontinuation or dose reduction

Ocular adverse effects of EGFR inhibitors

• Trichiasis: Remove deformed eyelashes ⁵⁾
• Blepharitis: Apply steroid or antibiotic ointment topically ⁵⁾
• Corneal epithelial disorder: Preservative-free artificial tears and corneal protective eye drops

ICI-related uveitis

Manage according to CTCAE grade ³⁾.

• Grade 1 (mild): Manage with steroid eye drops. ICI can be continued
• Grade 2 (moderate): Systemic steroids (prednisolone). Consider temporary ICI discontinuation
• Grade 3–4 (severe): High-dose systemic steroids. Consider ICI discontinuation or permanent cessation
• VKH-like syndrome: Methylprednisolone 1 g/day × 3 days pulse therapy, followed by oral steroid taper ⁸⁾

Collaboration between cancer treatment and ophthalmology

When ocular adverse effects occur due to anticancer drugs or molecular targeted agents, the decision to continue cancer treatment depends on the type of drug and the severity of the ocular adverse effects. In mild cases, it may be possible to continue treatment while providing symptomatic therapy, so do not discontinue treatment on your own; it is important for the oncology attending physician and ophthalmologist to collaborate.

Fingolimod Macular Edema

In many cases, improvement occurs upon discontinuation of administration. If necessary, NSAIDs eye drops or steroid eye drops are used concomitantly.

Q If ocular side effects of anticancer drugs occur, must cancer treatment be discontinued?

A

Discontinuation is not always necessary. The management differs depending on the severity of ocular side effects (CTCAE grade) and the type of drug. While discontinuation is the basic approach for conditions such as HCQ retinopathy and tamoxifen retinopathy, in cases of mild serous retinal detachment due to MEK inhibitors or trichomegaly due to EGFR inhibitors, continuation of administration while performing symptomatic treatment may be chosen. It is important for the oncologist and ophthalmologist to collaborate and make decisions based on the individual situation.

6. Pathophysiology and Detailed Mechanisms

The mechanisms of damage to ocular tissues differ by drug category.

Retinal Toxicity of Chloroquine and HCQ

CQ and HCQ have high affinity for melanin and bind to melanin granules in retinal pigment epithelium (RPE) cells, accumulating intracellularly. Accumulated CQ/HCQ is taken up into lysosomes, causing an increase in lysosomal pH and impairing lysosomal enzyme activity. When the metabolic function of RPE enzymes is impaired, the degradation and renewal of photoreceptor outer segments are disrupted, leading to photoreceptor degeneration. Due to the large amount accumulated in the body, damage may progress even after discontinuation.

Mechanism of Tamoxifen Retinopathy

Spherical lesions (degeneration of nerve fibers and axonal swelling) form in the nerve fiber layer and inner plexiform layer. Crystalline deposits are thought to be degenerative products containing calcium and complex carbohydrates deposited within nerve fibers. Cystoid macular edema (CME) occurs due to Müller cell dysfunction and fluid accumulation.

Mechanism of Interferon Retinopathy

IFN induces vasospasm, leukocyte infiltration, and vascular endothelial damage, and immune complexes deposit in capillaries, causing capillary occlusion. Cotton-wool spots (nerve fiber layer infarcts) occur anterior to the occluded capillaries (on the arterial side), and hemorrhages from occluded areas are observed as small hemorrhages. Most are transient and resolve after IFN discontinuation.

Serous Retinal Detachment Due to MEK Inhibitors

MEK inhibitors block the MAPK/ERK pathway (cell proliferation and survival signals). Since RPE maintains active transport (ions and water) via ERK signaling, ERK inhibition impairs RPE ion transport and pump function. This leads to subretinal fluid accumulation, manifesting as serous retinal detachment and retinal pigment epithelial detachment (PED)²⁾.

Ocular irAE of Immune Checkpoint Inhibitors (ICIs)

VKH-like uveitis after nivolumab administration — fundus photograph, OCT, and retinal nerve fiber layer thickness map

Takahashi T, Inoue T, Sakamoto M, Tanaka M. Vogt–Koyanagi–Harada disease-like uveitis following nivolumab administration treated with steroid pulse therapy: a case report. BMC Ophthalmol. 2020;20:264. doi: 10.1186/s12886-020-01519-3. Figure 1. PMCID: PMC7313170. License: CC BY 4.0.

Wide-angle fundus photographs (a: right eye, b: left eye) show optic disc swelling and multiple serous retinal detachments. OCT (c: right eye, d: left eye) reveals subretinal fluid accumulation (arrows) and retinal pigment epithelium folds. The retinal nerve fiber layer thickness map (e) shows marked thickening of 138 µm in the right eye and 178 µm in the left eye. This corresponds to ocular irAE from immune checkpoint inhibitors (ICIs) discussed in Section 6, Pathophysiology and Detailed Mechanisms.

ICIs (PD-1/PD-L1 inhibitors, CTLA-4 inhibitors) release T-cell immune checkpoints and enhance antitumor immunity. However, this mechanism also releases autoimmune suppression, triggering autoimmune reactions in ocular tissues (uvea, sclera, orbit, lacrimal gland). In VKH-like syndrome, self-reactive T cells against melanocytes (choroid, ciliary body, iris) are activated, leading to panuveitis, serous retinal detachment, and depigmented lesions ³⁾.

7. Latest Research and Future Perspectives

For patients: Please read this

The following content is based on research-stage or investigational reports and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Large-scale registry studies of ICI-related ocular irAE

To understand the overall picture of ICI-related ocular irAE, international multicenter registry studies are underway ³⁾. By clarifying the spectrum, frequency, and outcomes of various ocular irAEs such as uveitis, VKH-like syndrome, and extraocular myositis, risk stratification and protocol establishment are expected.

Corneal toxicity of antibody-drug conjugates (ADCs)

ADCs such as trastuzumab deruxtecan (T-DXd) are becoming widespread as next-generation anticancer therapies, but corneal toxicity (punctate keratitis, corneal stromal opacity) is recognized as an adverse event ¹⁰⁾. Case accumulation through pharmacovigilance studies and establishment of corneal protection strategies are challenges.

Ultra-early detection of HCQ retinopathy

Adaptive optics OCT and multispectral fundus imaging are being used to visualize early RPE structural changes that cannot be detected by conventional methods ¹¹⁾. In addition, development of automated screening using artificial intelligence (AI) analysis of OCT images is progressing, which is expected to reduce the risk of missed detection ¹¹⁾.

Establishment of ophthalmology-oncology collaboration protocols

With the widespread use of ICIs and molecular targeted drugs, standardized collaboration protocols between ophthalmology and oncology are needed ⁸⁾. Guidelines for ocular adverse event management algorithms based on CTCAE grading are being developed.

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3. Dalvin LA, Shields CL, Orloff M, et al. Checkpoint inhibitor immune therapy: systemic indications and ophthalmic side effects. Retina. 2018;38(6):1063-1078.

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7. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012;13(10):1011-1019.

8. Sun MM, Levinson RD, Filipowicz A, et al. Uveitis in patients treated with CTLA-4 and PD-1 checkpoint blockade inhibition. Ocul Immunol Inflamm. 2020;28(7):1036-1040.

9. Marmor MF, Kellner U, Lai TY, et al. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology. 2016;123(6):1386-1394.

10. Matsuoka H, Tanaka H, Nagai Y, et al. Corneal adverse events associated with trastuzumab deruxtecan: a pharmacovigilance study. Target Oncol. 2023;18(1):77-85.

11. Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmol. 2014;132(12):1453-1460.