INTRODUCTION — Molecularly targeted agents have emerged as an important component of systemic therapy for a wide range of cancer types. Most of these agents work through mechanisms that are markedly different from conventional cytotoxic chemotherapy, interfering with cellular signaling and angiogenesis pathways that are needed for tumor growth. Many of these agents are associated with distinct adverse effect profiles, several of which affect the eye. Although relatively uncommon, ocular side effects from targeted agents can be severe, disabling, and irreversible. While some ocular side effects can be managed symptomatically while chemotherapy is continued, others can be vision threatening and warrant immediate discontinuation of the drug.
The ocular side effects of intra-arterial chemotherapy administration (including chemotherapy administered into the ophthalmic artery for retinoblastoma) are beyond the scope of this topic review. (See "Retinoblastoma: Treatment and outcome", section on 'Local chemotherapy'.)
OVERVIEW OF THE APPROACH TO THE PATIENT WITH OCULAR SYMPTOMS — When a patient receiving chemotherapy presents with a specific ocular sign or symptom, it is important to delineate whether the complaint is due to the malignancy itself, an associated effect (eg, a paraneoplastic syndrome), or the anticancer treatment.
In general, paraneoplastic visual syndromes are rare; they include cancer-associated retinopathy, melanoma-associated retinopathy, and paraneoplastic optic neuropathy (optic neuritis). (See "Paraneoplastic visual syndromes".)
Differentiating metastasis from drug toxicity — The most common intraocular malignancy is metastatic disease, which most commonly involves the uveal tract. The uvea consists of the iris and ciliary body anteriorly, and the choroid posteriorly (figure 1).
Choroidal metastases typically appear as elevated amelanotic choroidal lesions with an overlying patchy disturbance of the retinal pigment epithelium (picture 1). They are often accompanied by an overlying serous retinal detachment that appears out of proportion to the lesion itself. Symptoms can depend on the location of the metastasis: a peripherally located tumor with minimal serous fluid can be asymptomatic, while lesions or subretinal fluid involving the macula can result in symptoms that include photopsia (a subjective sensation of flashing lights, sparks, or colors), metamorphopsia (a condition where objects appear distorted), floaters, blurry vision, difficulty focusing, and dyschromatopsia (abnormality in the ability to perceive colors). While some of these symptoms can be shared with the effects of drug toxicity, a dilated fundus examination, often supplemented with ocular ultrasound and optical coherence tomography, will usually distinguish choroidal metastases from drug-induced retinopathy.
There can also be metastases to the orbit or optic nerve, which can cause optic disc swelling. Disc swelling can also be seen secondary to metastases to the brain causing papilledema. Cross-sectional imaging of the head can help with diagnosis in these cases. (See "Overview and differential diagnosis of papilledema".)
Metastases to the retina can cause retinal inflammation and intraretinal hemorrhages, while metastases to the vitreous accumulate leucocytes in the vitreous humor. This can appear as vitritis (inflammation in the vitreous (figure 1)). A dilated fundus examination and possible biopsy of the vitreous can help with differentiation between true vitritis and metastases. (See 'Uveitis and ocular inflammation' below.)
Localizing the compartment affected by ocular toxicity — Different compartments of the eye (figure 1) are preferentially affected by different agents. Presenting signs and symptoms can help localize which compartment of the eye (ie, the cornea, uvea [choroid, ciliary body, and iris], periocular and orbital tissue, retina, and/or optic nerve) is affected:
●Cornea and anterior segment – Cornea damage from dry eye triggers reflexive tearing; burning; gritty, sandy, or foreign body sensation; sensitivity to light; and blurred vision. The conjunctiva may be injected (diffusely red). Drug-induced conjunctivitis may present with a pinkish hue, chemosis (a collection of serous fluid within the conjunctiva that reflects conjunctival irritation), and a discharge from the eyes. Blepharitis is characterized by inflammation of the base of the eyelashes (anterior blepharitis (picture 2)) or the inner portion of the eyelid at the level of the meibomian glands (posterior blepharitis (picture 3)). Most of these patients can be managed symptomatically while chemotherapy is continued. (See 'Cornea and anterior segment' below.)
●Uvea (choroid, ciliary body, and iris) – Symptoms of inflammation of the uveal structures (uveitis) include blurred vision; dark, floating spots in the vision (floaters); eye pain; redness in the eye; sensitivity to light (photophobia); and vision loss. Inflammation of the uveal tract can present as anterior uveitis (involving the anterior ocular compartment (figure 1)), intermediate uveitis, posterior uveitis, or panuveitis (involving all ocular compartments).
Patients suspected of having drug-induced uveitis need urgent referral to ophthalmology for examination. (See 'Uveitis and ocular inflammation' below.)
●Periocular and orbital tissue – Periocular tissue changes may include abnormalities of the eyelashes, scarring and outward turning of the lower lid (ectropion (picture 4)), chalazia (large, painful, inflamed, erythematous and nodular lesions that appear over days on the upper or lower lids due to a lipogranulomatous reaction (picture 5)), excess tearing with or without nasolacrimal duct obstruction, and periorbital edema. These conditions are generally treated symptomatically with continued drug treatment, but sometimes ophthalmologic referral and drug discontinuation are indicated. (See 'Orbit and periorbital tissue' below.)
By contrast, orbital inflammation is associated with pain with eye movement, orbital congestion (conjunctival injection and chemosis), proptosis of the eye, exposure keratopathy, ophthalmoplegia and diplopia, potential optic neuropathy, and blindness. This is an emergency, and immediate drug discontinuation and prompt evaluation with a specialist are recommended. (See 'Orbital inflammation' below.)
●Retina and/or optic nerve – The development of visual loss with or without ocular pain should always raise the possibility of damage to the retina and/or optic nerve. These patients warrant withholding of the suspected drug and urgent referral to an ophthalmologist. (See 'Retina' below.)
Grading the severity of ocular/visual side effects — The Common Terminology Criteria Adverse Events reporting system of the National Cancer Institute (NCI-CTCAE) includes grading tables for the severity of several eye disorders, including blurred vision, cataract, conjunctivitis, corneal ulcer, dry eye, extraocular muscle paresis, eye pain, eyelid function disorder, flashing lights, floaters, glaucoma, keratitis, night blindness, optic nerve disorder, papilledema, photophobia, retinal detachment, retinal tear, retinal vascular disorder, retinopathy, scleral disorder, uveitis, vitreous hemorrhage, watery eyes, and other toxicities .
CLINICAL MANIFESTATIONS OF DRUG TOXICITY AND OVERVIEW OF MANAGEMENT
Cornea and anterior segment — Several chemotherapy agents can affect the cornea, causing dry eye, meibomian gland dysfunction and blepharitis, nonhealing epithelium and corneal melt, corneal deposits, conjunctivitis, conjunctival hemorrhage, and cataracts.
Dry eyes — Corneal defects associated with dry eye trigger reflexive tearing; burning; gritty, sandy, or foreign body sensation; and sensitivity to light. The blurred vision associated with dry eyes tends to be variable, but blurriness often improves with blink.
There is no single definitive test or consensus of criteria to diagnose dry eye . Given the lack of clinically measurable signs and available diagnostic testing, dry eye is diagnosed primarily on the basis of patient symptoms and supporting findings on the physical examination (which may include conjunctival injection, the paradoxical finding of excess tearing, and a reduced blink rate). (See "Dry eye disease", section on 'Diagnosis'.)
Lubrication with artificial tears can help symptoms. Artificial tears generally include cellulose to maintain viscosity, a spreading agent, such as polyethylene glycol or polyvinyl alcohol, to prevent evaporation, and a preservative to prevent contamination. Available without a prescription, artificial tears come in liquid, gel, and ointment form. (See "Dry eye disease", section on 'Artificial tears'.)
Severe cases can sometimes be improved with a short trial of topical corticosteroids or with topical (ophthalmic) cyclosporine. (See "Dry eye disease", section on 'Topical cyclosporine'.)
Lifitegrast is an alternative agent that can be used as well. (See "Dry eye disease", section on 'Topical lifitegrast'.)
For patients with excess tearing caused by dry eye, punctal occlusion using temporary or permanent punctal plugs can help diminish tear outflow. These can be placed by a general ophthalmologist or a cornea specialist. (See "Treatment of moderate to severe dry eye in Sjögren's syndrome", section on 'Punctal occlusion'.)
Topical vitamin A (retinyl palmitate) can also help, especially in cases of vitamin A deficiency [3-5]. For severe cases, referral to a cornea specialist can be beneficial. Although dry eye symptoms can be quite uncomfortable, it is generally not vision threatening.
Blepharitis and meibomian gland dysfunction — Blepharitis is a chronic eye condition characterized by inflammation of the eyelids. Anterior blepharitis is characterized by inflammation at the base of the eyelashes (picture 2). Posterior blepharitis is characterized by inflammation of the inner portion of the eyelid at the level of the meibomian glands (picture 3) (eg, meibomian gland dysfunction) . Meibomian glands are modified sebaceous glands located within the tarsal plates of the eyelids. These glands are responsible for secretion of the oily layer of the tear film. This oily layer is critical for normal lubrication of the eye; it prevents tear evaporation, reduces the surface tension of the tear layer, and facilitates the spread of tears over the eye . (See "Blepharitis".)
Meibomian gland dysfunction and blepharitis can cause pruritus, transient blurry vision improved with blinking, a foreign body sensation, and dry eye symptoms. Examination can show crusting of eyelids and eyelid margin inflammation; oily white plugs may be visible at the meibomian gland openings (picture 3). The two classes of agents most commonly associated with blepharitis are the epidermal growth factor receptor (EGFR) inhibitors and the proteasome inhibitor bortezomib. (See 'Epidermal growth factor receptor (EGFR) inhibitor' below and 'Bortezomib and eyelid disorders' below.)
Mild cases can be managed conservatively with daily lid scrubs using baby shampoo and warm water, and warm compresses. Antibiotic or combination antibiotic and steroid ointment can be used as a scrub along the lash line as well. Systemic omega-3 fatty acids can also help . Significant eyelid margin inflammation can sometimes improve with systemic doxycycline. Referral to a cornea specialist can help with severe cases. This condition can predispose to formation of a chalazion, a chronic inflammatory lesion that develops when a meibomian tear gland of the eyelid becomes obstructed (picture 5 and picture 6). (See 'Chalazia and other eyelid masses' below and "Blepharitis" and "Eyelid lesions".)
Corneal epithelial defects — Poor healing of the epithelial layer of the cornea (figure 2) has been reported frequently with EGFR inhibitors. Poor healing may lead to persistent corneal epithelial defects and erosions. (See 'Epidermal growth factor receptor (EGFR) inhibitor' below.)
The symptoms associated with nonhealing corneal epithelium are similar to those of dry eye but are more severe, especially the blurriness of vision, and burning and stinging pain . In addition, nonhealing corneal epithelium can potentially increase the risks of infectious (especially bacterial) keratitis (inflammation of the cornea of the eye). Nonhealing corneal epithelium can also increase the risk of corneal ulcers (picture 7 and picture 8), which are vision threatening and need immediate attention. (See "The red eye: Evaluation and management", section on 'Infectious keratitis' and "Corneal abrasions and corneal foreign bodies: Clinical manifestations and diagnosis".)
Given the problem with poor healing, symptoms may not be relieved with lubrication alone (artificial tears). We suggest that patients with corneal abrasions receive topical antibiotics to prevent superinfection, rather than no treatment. Coverage with antibiotic eye drops or ointment, a bandage contact lens, and temporary tarsorrhaphy can help to prevent ulcer formation. (See "Corneal abrasions and corneal foreign bodies: Management".)
Corneal thinning and melt are other types of epithelial defects that have been reported with EGFR inhibitors; although rare, they are potentially vision threatening, as they may lead to corneal perforation requiring corneal transplant . (See 'Epidermal growth factor receptor (EGFR) inhibitor' below.)
Eye pain, change in vision, increased tearing, and light sensitivity are all possible symptoms. Sometimes a white/tan-colored round lesion can be seen on the cornea on gross observation, which can represent an ulcer. Without a slit lamp, it may be difficult to diagnose corneal thinning or melt. It generally does not have an infiltrate, as seen with corneal ulcers. On the other hand, ulcers may not be readily apparent without a slit lamp examination either if they are small. Both conditions are potentially vision threatening and should be referred if suspected. Aggressive lubrication with preservative-free artificial tears or ointments can be started in the interim.
Corneal deposits — Corneal deposits, including verticillata, can be associated with a variety of chemotherapy agents, including cytarabine, capecitabine, the multikinase inhibitor vandetanib, and tamoxifen. They may cause mild blurry vision and glare . Symptomatic treatments with lubricants (artificial tears) and topical corticosteroids may control symptoms . (See 'Tyrosine kinase inhibitors' below and 'Cytarabine and fludarabine' below and 'Tamoxifen and toremifene' below.)
Conjunctivitis — Drug-induced conjunctivitis typically causes a pinkish hue to the conjunctiva, chemosis (a collection of serous fluid within the substance of the conjunctiva, which is a nonspecific sign of conjunctival irritation (picture 9)) increased tearing, and a ropey discharge. Although the eye appears injected, it is not associated with eye pain, and the vision is not affected. The drugs most commonly implicated are the BRAF inhibitor vemurafenib, pemetrexed, and anthracyclines and related agents. (See 'BRAF inhibitors' below and 'Anthracyclines and anthracenediones' below and 'Cytarabine and fludarabine' below.)
Conjunctivitis can be caused by infectious and allergic etiologies as well. Patient history is important (ie, recent contact with someone with infectious conjunctivitis versus associated symptoms of seasonal allergies). If the diagnosis is unclear, referral to an ophthalmologist can be beneficial since a careful slit lamp examination can help to differentiate. (See "Conjunctivitis".)
Some cases of drug-induced conjunctivitis (eg, doxorubicin-associated) resolve quickly on their own. In other cases, a short course of topical corticosteroids can be considered. (See 'Anthracyclines and anthracenediones' below.)
Conjunctival hemorrhage — Conjunctival/subconjunctival hemorrhage, as has been rarely reported with imatinib, can appear dramatic, with a blood-red-colored eye (picture 10), but it is also painless, non-vision threatening, and usually resolves without need for treatment. (See 'Imatinib' below.)
Cataracts — A cataract is an opacity of the lens of the eye that is most often age related. Uncommonly, cataracts may be a long-term side effect of antiestrogenic drugs, such as tamoxifen and toremifene, as well as the alkylating agent busulfan. (See "Cataract in adults" and 'Tamoxifen and toremifene' below.)
Cataracts are painless, and they present with slow progressive vision loss. Patients can complain of glare or halos around lights at nighttime. If visually significant and affecting activities of daily living, cataract extraction with intraocular lens placement can be considered. (See "Cataract in adults", section on 'Surgical treatment'.)
Uveitis and ocular inflammation — Uveitis refers to inflammation of the uvea; the anterior portion of the uvea includes the iris and ciliary body, and the posterior portion of the uvea is known as the choroid (figure 1). (See "Uveitis: Etiology, clinical manifestations, and diagnosis", section on 'Definitions'.)
Ocular inflammation associated with chemotherapy (cytarabine, immune checkpoint inhibitors, BRAF inhibitors, the small-molecule EGFR inhibitor erlotinib, the bispecific anti-EGFR and MET receptor inhibitor amivantamab, the Bruton tyrosine kinase inhibitor ibrutinib) can present as anterior uveitis, intermediate uveitis, posterior uveitis (retinitis or choroiditis), or panuveitis (entire eye), including Vogt-Koyanagi-Harada syndrome (VKH). (See "Uveitis: Etiology, clinical manifestations, and diagnosis", section on 'Symptoms and findings' and "Uveitis: Etiology, clinical manifestations, and diagnosis", section on 'Systemic inflammatory diseases' and 'BRAF inhibitors' below and 'Epidermal growth factor receptor (EGFR) inhibitor' below and 'Immune checkpoint inhibitors' below and 'Cytarabine and fludarabine' below and 'Bruton tyrosine kinase inhibitors' below.)
The symptoms of uveitis, which are all nonspecific, depend upon the portion of the uveal tract that is involved; visual loss may occur with anterior, intermediate, or posterior involvement (see "Uveitis: Etiology, clinical manifestations, and diagnosis", section on 'Differential diagnosis'):
●Anterior uveitis – Inflammation of the anterior uveal tract, characterized by the presence of leukocytes in the anterior chamber of the eye, is called anterior uveitis and is synonymous with iritis. When the adjacent ciliary body is also inflamed, the process is known as iridocyclitis . Anterior uveitis may produce pain and redness, although these symptoms are minimal if inflammation begins insidiously. In anterior uveitis (iritis), the redness, if present, is primarily noted at the limbus (the junction between the cornea and the sclera (figure 3)); such patients often have photophobia and pain. The degree of visual loss associated with anterior uveitis is variable.
The presence of leukocytes in the anterior chamber of the eye on slit lamp examination is characteristic of anterior uveitis but is nonspecific. (See "Uveitis: Etiology, clinical manifestations, and diagnosis", section on 'Differential diagnosis'.)
Leukocytes are not normally found in the aqueous humor that fills the space between the cornea and the lens. A haze, described by ophthalmologists as a "flare," may also be appreciated by slit lamp examination and reflects protein accumulation in the aqueous humor secondary to disruption of the blood-aqueous barrier.
●Posterior and intermediate uveitis – The presence of leukocytes in the vitreous humor and evidence of active chorioretinal inflammation are diagnostic of intermediate uveitis and posterior uveitis, respectively. In contrast to anterior uveitis, posterior or intermediate uveitis is more likely to be painless but may result in nonspecific visual changes, such as floaters and/or reduced visual acuity. Redness of the eye is not a prominent feature of posterior inflammation unless there is an accompanying anterior uveitis.
In posterior or intermediate uveitis, direct visualization of active chorioretinal inflammation and/or leukocytes in the vitreous humor can be detected on ophthalmic examination. Complete examination of the eye posterior to the lens usually includes a technique called scleral depression. This maneuver allows the examiner to look for an inflammatory exudate over the pars plana, the portion of the eye just between the retina and the ciliary body.
Terms used to describe forms of uveitis posterior to the lens include vitritis, intermediate uveitis, pars planitis, choroiditis, retinitis, chorioretinitis, and retinochoroiditis .
●Panuveitis – Panuveitis is defined as simultaneous inflammation in the anterior chamber, vitreous humor, and retina or choroid. It causes severe eye pain, photophobia, conjunctival injection, vision loss, and the presence of floaters. In patients with panuveitis, inflammation is detected simultaneously in all three areas, either by use of a slit lamp in conjunction with special lenses to focus the beam posterior to the lens or by use of an indirect ophthalmoscope and a handheld lens.
An important step in the initial evaluation of suspected uveitis is to rule out infection (eg, endophthalmitis) or other disorders that can mimic uveitis (table 1). (See "Uveitis: Etiology, clinical manifestations, and diagnosis", section on 'Differential diagnosis'.)
Patients with suspected uveitis should be referred promptly to an ophthalmologist for diagnosis and treatment. Prompt treatment is recommended to control inflammation and prevent further vision loss. Treatment includes frequent topical corticosteroid drops to reduce inflammation and topical cycloplegic agents to prevent iris synechiae and decrease ciliary body spasms to help with pain. Periocular or intraocular steroid injections and systemic (oral) corticosteroids are sometimes needed, especially for posterior and panuveitis. Corticosteroid use can lead to elevated intraocular pressures, cataracts, and potential blindness, so close follow-up is recommended. (See "Uveitis: Treatment".)
Patients usually complain of the abrupt onset of redness, irritation, and watering of the eye; pain is typically minimal, and vision is preserved. Physical examination reveals bright-red episcleral discoloration caused by vasodilatation of the superficial episcleral vessels and edema of the episclera (picture 11) without edema or thinning of the sclera. (See 'Immune checkpoint inhibitors' below and "Episcleritis".)
Other disorders that may cause a red eye and other features that can resemble elements of episcleritis include scleritis, conjunctivitis, subconjunctival hemorrhage, blepharitis, keratitis, acute anterior uveitis, and acute angle-closure glaucoma. These conditions can generally be distinguished from episcleritis based upon the history and examination of the eye. (See "The red eye: Evaluation and management".)
Symptomatic relief is the goal of therapy and can be accomplished with topical lubricants (artificial tears), oral nonsteroidal anti-inflammatory drugs (NSAIDs), or topical glucocorticoids.
Orbit and periorbital tissue — The eyelids, nasolacrimal drainage system, and periorbital soft tissues can all be affected by chemotherapy.
Trichiasis and trichomegaly — Trichiasis (misdirection of eyelashes (picture 12)) and trichomegaly (abnormal eyelash length and texture), both complications of epidermal growth factor pathway inhibitors, can lead to corneal abrasions and a foreign body sensation. (See 'Epidermal growth factor receptor (EGFR) inhibitor' below and 'Fibroblast growth factor receptor (FGFR) inhibitors' below.)
Lubrication with artificial tears can help with comfort. Mechanical epilation of the abnormal eyelashes can temporarily solve the problem, providing sometimes dramatic relief. Electrolysis, radiofrequency epilation, cryotherapy, and surgical resection are alternative options, although they are less likely to be necessary, as reported side effects tend to resolve after cessation of therapy.
Cicatricial eyelid changes — Cicatricial (scarring) changes to the eyelid, such as ectropion (picture 4), can prevent good eyelid closure and potentially result in exposure keratopathy, leading to symptoms of dry eye. This condition is reported with epidermal growth factor pathway inhibitors, fluorouracil, and pemetrexed. (See 'Epidermal growth factor receptor (EGFR) inhibitor' below and 'Fluoropyrimidines' below and 'Pemetrexed and eye edema' below.)
Referral to an ophthalmologist is recommended for management. In the interim, patients may be prescribed an ocular lubricant.
Chalazia and other eyelid masses — Chalazia (picture 5 and picture 6) have been reported with the proteasome inhibitor bortezomib. Large, painful, inflamed, erythematous and nodular lesions appear over days on the upper or lower lids. Conservative management with warm compresses and lid hygiene, antibiotic and steroid ophthalmic ointments, and systemic tetracycline has been mildly successful, and management is difficult. Incision and drainage can help treat the lesion, but chalazia can recur as long as the drug is continued. (See 'Bortezomib and eyelid disorders' below.)
Other eyelid lesions, such as verruca vulgaris, keratoacanthomas, and squamous cell carcinomas, have been reported with the use of sorafenib and the BRAF inhibitors vemurafenib and dabrafenib. Squamoproliferative lesions that develop during chemotherapy with these agents should be treated similarly to lesions that develop in patients not receiving the drug (usually with complete surgical excision). Patients are usually able to continue the drug, but close clinical follow-up during treatment is warranted. (See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy", section on 'Squamoproliferative lesions' and 'BRAF inhibitors' below and 'Tyrosine kinase inhibitors' below.)
Periorbital edema — Periorbital edema is a common complaint in patients treated with imatinib. Large lower-eyelid festoons (redundant folds of lax skin and orbicularis oculi muscle that hang below the lower eyelid) are rarely reported with this agent. These lesions can prevent proper eyelid closure, and they can be very difficult to manage. Referral to an oculoplastics specialist is recommended. (See 'Imatinib' below.)
Epiphora and nasolacrimal duct obstruction — Epiphora (excess tearing), with or without nasolacrimal duct or canalicular obstruction, has been associated with fluoropyrimidines and docetaxel, especially when administered weekly. Imatinib has also been associated with epiphora. Referral to an ophthalmologist for probing and irrigation of the nasolacrimal system is the most reliable method to rule out duct obstruction in these cases. Prophylactic silicone intubation is appropriate for patients with progressive ductal stenosis to prevent permanent complete closure and the need for much more involved surgery, and worse outcomes . (See 'Epiphora and docetaxel' below and 'Fluoropyrimidines' below and 'Imatinib' below.)
Orbital inflammation — Inflammation of the orbit (sometimes referred to as being similar to Graves ophthalmopathy, although rarely true Graves ophthalmopathy) has been reported with the immune checkpoint inhibitor ipilimumab . It can cause eye pain with eye movement, orbital congestion (conjunctival injection and chemosis), proptosis of the eye, exposure keratopathy, ophthalmoplegia and diplopia, strabismus, potential optic neuropathy, and blindness. This is an emergency, and prompt evaluation with a specialist is recommended. Before getting to the specialist, maneuvers that can be undertaken are checking for complete eyelid closure to protect the cornea and prevent exposure keratopathy, and starting a topical ophthalmic lubricant gel right away. Evaluate for optic neuropathy by looking for decreased visual acuity, an afferent pupillary defect, color desaturation testing, and constriction on visual fields on confrontation. Extraocular muscle movements and symptoms of diplopia should be checked as well.
Retina — Several chemotherapy drugs have been reported to affect retinal vasculature, causing retinal vein and artery occlusions, intraretinal hemorrhages and cotton wool spots, choroidal neovascularization (a form of macular degeneration), toxicity to the retinal pigment epithelium leading to pigmentary retinopathy, accumulation of fluid under the retinal pigment epithelium (central serous retinopathy), as well as intraretinal (cystoid macular edema) and subretinal damage (serous retinal detachments). Chemotherapy agents can also accumulate in the retinal pigment epithelium, causing refractile retinal deposits. Photoreceptors can also be affected, leading to impaired night vision .
Retinal vein and artery occlusion — Occlusions of the retinal artery or vein, which have been reported with interferon and mitogen-activated protein kinase (MEK) inhibitors, cause blurred vision and painless acute vision loss, which can be profound. (See 'Interferon' below and 'Mitogen-activated protein kinase inhibitors' below and 'Carmustine and retinal damage' below.)
Retinal ischemia from artery occlusion >90 minutes generally causes irreversible vision loss. No treatment has been definitively shown to be effective to prevent the vision loss once it occurs. Recommendations include immediate cessation of therapy and referral to a retina specialist. (See "Central and branch retinal artery occlusion".)
For retinal vein occlusions, referral to a retina specialist is indicated for consideration of intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors to optimize vision. (See "Retinal vein occlusion: Treatment", section on 'Vascular endothelial growth factor inhibitors'.)
Macular edema, central serous retinopathy, and serous retinal detachment — Cystoid macular edema is defined as multiple cyst-like (cystoid) areas of fluid appearing in the central retina (macula) and causing retinal swelling or edema. It presents with painless blurry vision or metamorphopsia (distortion of lines; for example, straight lines appear wavy).
Multiple chemotherapy agents have been associated with macular edema, including tamoxifen, trastuzumab, vemurafenib, interferon, imatinib, cytarabine, taxanes, and cisplatin. (See 'BRAF inhibitors' below and 'Tyrosine kinase inhibitors' below and 'Tamoxifen and toremifene' below and 'Platinum analogs' below and 'Taxanes' below and 'Interferon' below.)
When cystoid macular edema results from uveitis (as, for example, with vemurafenib), photophobia can also present if there is active associated inflammation. (See 'Uveitis and ocular inflammation' above and 'BRAF inhibitors' below.)
MEK inhibitors are all associated with retinopathy as a class effect, although the terms used to describe this toxicity are varied. Symptomatic patients may complain of blurred vision, altered color perception, shadows, light sensitivity, metamorphopsia and/or glare. Symptoms generally resolve either spontaneously or after discontinuation of therapy. (See 'Mitogen-activated protein kinase inhibitors' below.)
Serous retinal detachments (as have been seen with trastuzumab, and inhibitors of fibroblast growth factor receptor [FGFR]) are associated with painless vision loss. (See 'Human epidermal growth factor receptor 2 (HER2) inhibitors' below and 'Fibroblast growth factor receptor (FGFR) inhibitors' below.)
In severe cases, patients complain of a dark curtain-like effect coming from any direction, with or without photopsia (flashes of light). Prompt evaluation by an ophthalmologist is recommended for all patients with visual changes while receiving chemotherapy. Resolution of serous retinal detachments can occur with cessation of treatment.
Pigment changes, cotton wool spots, and hemorrhages — Retinal pigmentary changes, cotton wool spots, and mild intraretinal hemorrhages are signs of damage to various layers of the retina. Usually, the cotton wool spots and intraretinal hemorrhages are signs of inner retinal damage, while the pigmentary changes are associated with outer retinal damage. Cotton wool spots reflect ischemic damage, while intraretinal hemorrhages and pigmentary changes can be due to either ischemia or other causes, such as inflammation. Reports range from asymptomatic to mild painless blurriness of vision. Visual prognosis depends on the agent. (See 'Carmustine and retinal damage' below and 'Interferon' below.)
Reports of retinal deposits from tamoxifen range from asymptomatic to mild painless blurriness of vision. The nature of these deposits is unclear. They may represent potential changes to the retinal structure (ie, postinflammatory or degenerative changes) or drug deposits. Pigmentary changes are generally irreversible, but visual disturbance can resolve with cessation of therapy. Follow-up with an ophthalmologist for monitoring is recommended. (See 'Tamoxifen and toremifene' below.)
Optic nerve — Reports of optic neuropathy from chemotherapies include optic nerve edema, optic neuritis, optic atrophy, and idiopathic intracranial hypertension with associated cranial nerve palsies and optic nerve edema. In some cases, different authors have used different words to describe the same toxicity.
Optic nerve edema — Optic nerve edema has varying presentations: asymptomatic to mild-moderate blurriness of vision, enlarged blind spot, and constriction of visual field. Several agents have been associated with optic nerve edema, including imatinib, taxanes, mitotane, and methotrexate. Drug-induced intracranial hypertension, such as that associated with oxaliplatin and all-trans retinoic acid (systemic tretinoin), can also cause optic nerve edema and is associated with blurry vision, headaches, visual field constrictions, and nausea/vomiting. (See 'Platinum analogs' below and 'All-trans retinoic acid' below.)
Regardless of its etiology, edema of the optic nerve head can be seen on examination of the fundus. Magnetic resonance imaging (MRI) of the head and lumbar puncture with opening pressure can help to exclude structural defects raising intracranial pressure and to assess for the presence of intracranial hypertension.
Management of the drug is discussed below. (See 'Imatinib' below and 'Platinum analogs' below and 'All-trans retinoic acid' below and 'Mitotane and retinopathy' below and 'Visual changes' below and 'Low-dose methotrexate and optic neuropathy' below.)
Optic neuritis — Optic neuritis, as has been reported with imatinib, is associated with moderate to severe vision loss, color vision loss, and pain with eye movement. Optic neuritis that is due to ischemia, however, may be nonpainful. Examination of the optic nerve head can sometimes show either optic disc swelling, if it involves the anterior portion of the optic nerve, or no swelling, if it involves the posterior portions. An MRI with contrast and dedicated orbital cuts can help with diagnosis. Patients may have an afferent pupillary defect if one optic nerve is involved more than the other. (See 'Imatinib' below.)
Atrophy — Optic nerve atrophy that follows an ischemic injury can result from chronic optic nerve edema or optic neuritis, or represent an idiopathic drug toxicity (interferon, cisplatin, vincristine, low-dose oral methotrexate). It presents with a slow progressive vision loss. An afferent pupillary defect can be seen if the relative damage of one nerve is more severe than that of the other. The optic nerve head may appear pale on examination. (See 'Interferon' below and 'Platinum analogs' below and 'Vincristine' below and 'Low-dose methotrexate and optic neuropathy' below.)
Etiologies and clinical features of nonarteritic anterior ischemic optic neuropathy are discussed in detail elsewhere. (See "Nonarteritic anterior ischemic optic neuropathy: Epidemiology, pathogenesis, and etiologies" and "Nonarteritic anterior ischemic optic neuropathy: Clinical features and diagnosis".)
TOXICITY PROFILE OF SPECIFIC AGENTS
Molecularly targeted agents
Epidermal growth factor receptor (EGFR) inhibitor — Agents targeting the EGFR (including the monoclonal antibodies cetuximab, panitumumab, and amivantamab, and the small-molecule EGFR inhibitors erlotinib, gefitinib, and mobocertinib) have some of the highest frequencies of ocular side effects.
●Cornea and anterior segment
•Multiple different ocular toxicities are reported with cetuximab, most of which affect the anterior segment. These include corneal erosions , eyelash trichomegaly [17-21], keratitis (inflammation of the cornea) , conjunctivitis, eyelid dermatitis, and blepharitis [19,23].
•Panitumumab-related ocular toxicities include conjunctivitis, conjunctival hyperemia, corneal perforation and keratitis (including ulcerative keratitis) , epiphora, and eyelid irritation.
•Reported ocular toxicities in patients treated with erlotinib include conjunctivitis and eyelid changes such as entropion, ectropion, and trichomegaly, although early episcleritis and corneal epithelial defects with associated infectious keratitis are reported.
•Clinical trials with gefitinib have reported mostly dry eye, blepharitis, conjunctivitis, and visual disturbances such as hemianopia, blurred vision, and photophobia, but corneal erosions, trichomegaly, and punctate keratopathy have also been reported .
•A clinical trial of mobocertinib reported ocular toxicity in (including dry eye, eye pruritus, eye discharge, blepharitis, trichiasis, conjunctival hemorrhage, blurred vision, and corneal edema) in 11 percent; none were grade 3 or worse.
•Poor healing of the outermost epithelial layer of the cornea is reported with all EGFR inhibitors, leading to dry eyes  and persistent corneal epithelial defects and erosions [9,10,27,28]. This can cause significant blurriness of vision  and can increase risks of bacterial keratitis . Standard treatment with frequent artificial tears, bandage contact lens, and patching can be tried , but good results are infrequent. Epithelial defects are reversible with cessation of treatment . The decision to continue therapy must individualized, taking into account the risks and the availability of alternative treatments. Consistent follow-up with an ophthalmologist is recommended if the patient is to continue the EGFR inhibitor, in order to manage symptoms and monitor for signs of superinfection. (See 'Corneal epithelial defects' above.)
Corneal thinning and melts that are sterile (culture negative) are more rare with this class of agents (and are reported most often with erlotinib), but they are potentially more severe, as corneal perforation can result [10,24,29]. Cyanoacrylate glue can temporize the thinning . Cessation of the offending medication can halt progression of thinning, but ultimately, corneal transplantation may be necessary. Given the potential for severe vision loss, we recommend establishing regular follow-ups with an ophthalmologist in any patient who develops ocular symptoms (blurred vision, dry eyes, burning or stinging of the eyes) while receiving an anti-EGFR agent.
Keratitis is also reported with amivantamab, which is a bispecific antibody that targets both the EGFR and the MET receptor. In a safety population of 129 patients treated with the drug, 0.7 percent developed keratitis . Other symptoms included dry eye, conjunctival redness, blurred vision, ocular itching, visual impairment, and uveitis (0.3 percent). The United States Prescribing Information for amivantamab recommends prompt referral of patients with eye symptoms to an ophthalmologist, and dose modification guidelines are provided based upon symptom severity.
●Anterior uveitis – Rare cases of severe anterior uveitis are reported in association with erlotinib [31,32]. Drug discontinuation and management with topical corticosteroids is usually effective. Rechallenge with erlotinib caused recurrence of uveitis in one patient . Referral to an ophthalmologist during an acute episode is recommended. If an alternative anticancer agent is not available, the risks must be weighed against the benefits of continued therapy in a discussion that involves the patient, the oncologist, and the ophthalmologist. (See 'Uveitis and ocular inflammation' above.)
●Orbit and periorbital tissue – All EGFR inhibitors have been associated with dysregulated hair cycles leading to hypertrichosis or alopecia; changes in hair color, growth rate, and texture; and trichomegaly [17-21]. In a prospective study of 30 patients receiving cetuximab or erlotinib, the incidence of trichomegaly was 17 to 23 percent . Trichiasis with eyelashes directed at the cornea has been reported [9,34,35], in some cases causing corneal ulcer [35,36], which is vision threatening and needs immediate treatment. This is particularly hazardous in patients who also have concurrent nonhealing corneal epithelium, as was reported in one case . (See 'Trichiasis and trichomegaly' above.)
Periocular skin changes are also relatively common, including edema, erythema, and blepharitis [9,10,19,23,26,36,37]. Periocular tissue may also be affected [9,10,17-19,26,33,36-44]. Chronic inflammation leads to hyperpigmentation and cicatricial changes, such as ectropion, which can lead to poor eyelid closure, exposure keratopathy, and tearing [10,36,37,45].
These side effects are generally mild and reversible when treatment is discontinued. Symptomatic management is usually successful and permits ongoing treatment with the anti-EGFR agent. However, an ophthalmologic evaluation is recommended to ensure that the cornea is not compromised. (See 'Blepharitis and meibomian gland dysfunction' above and 'Cicatricial eyelid changes' above.)
Human epidermal growth factor receptor 2 (HER2) inhibitors — Trastuzumab is a monoclonal antibody directed against HER2; it is used for treatment of HER2-ovexpresssing breast and gastric cancers. Ado-trastuzumab emtansine is an antibody-drug conjugate composed of trastuzumab, a thioether linker, and a microtubule inhibitor, DM1. (See "Systemic treatment for HER2-positive metastatic breast cancer" and "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Trastuzumab-based treatment' and "Initial systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'HER2-overexpressing adenocarcinomas'.)
●Cornea and anterior segment – Dry eyes and the associated symptoms of tearing, mild blurriness of vision, and conjunctival injection were reported in 35 of 112 patients (31 percent) in a phase II study of the conjugate agent ado-trastuzumab emtansine . Trastuzumab has also been associated with conjunctivitis.
Symptom management with frequent artificial tears is usually successful and permits ongoing treatment. This is not a vision-threatening condition, and cessation of therapy is usually not necessary. (See 'Dry eyes' above.)
●Retina – Trastuzumab has rarely been associated with macular edema, macular ischemia, and serous retinal detachment, which can lead to severe vision loss . Medication should be stopped immediately, and referral to a retina specialist is recommended. (See 'Macular edema, central serous retinopathy, and serous retinal detachment' above.)
BRAF inhibitors — Vemurafenib, dabrafenib, and encorafenib are orally available, potent inhibitors of the kinase domain in mutant BRAF (a serine-threonine kinase); all are approved for treatment of metastatic melanoma with a BRAFV600 mutation. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Toxicities of BRAF and MEK inhibitors'.)
Several ocular toxicities are reported with all three agents:
●Dry eyes/conjunctivitis – A review of 568 patients enrolled in vemurafenib phase I clinical trials showed that dry eyes occurred in 2 percent and conjunctivitis occurred in 2.8 percent . Symptoms are generally mild, and cessation of therapy is usually not necessary. (See 'Dry eyes' above and 'Conjunctivitis' above.)
●Uveitis – Vemurafenib has been associated with uveitis (incidence of 4 percent in a review of phase I clinical trials ). Uveitis was diagnosed at a median of 117 days after starting treatment and was mild/moderate in this series. All cases were successfully managed by topical, periocular, or intraocular corticosteroid treatment. Some had dose reduction, but all were able to continue therapy. (See 'Uveitis and ocular inflammation' above.)
Another study showed a higher incidence (7 out of 78 patients developed uveitis) and wider range of severity, ranging from mild anterior uveitis to severe panuveitis complicated by retinal detachment or macular edema . The majority had clinical improvement with cessation of vemurafenib and were able to be managed with local corticosteroids. A few recurred upon rechallenge. (See 'Macular edema, central serous retinopathy, and serous retinal detachment' above and 'Uveitis and ocular inflammation' above.)
There are at least three case reports of posterior uveitis and bilateral panuveitis in patients treated with dabrafenib in conjunction with the mitogen-activated protein kinase (MEK) inhibitor trametinib [50-52]. In one report, uveitis resolved upon cessation of both drugs, with no sequelae . Uveitis has responded to pulsed or topical steroid therapy [51,52].
All patients receiving a BRAF inhibitor should be assessed for visual symptoms at each visit. The majority of cases can be managed successfully; prompt evaluation and management by an ophthalmologist are recommended if uveitis is suggested by clinical symptoms in patients receiving BRAF inhibitors. In mild cases, drug treatment can be continued. If there is no improvement on local therapy, treatment discontinuation is an option, as is using pulsed corticosteroids. Severe cases of panuveitis warrant discontinuation of therapy.
In contrast to the other BRAF inhibitors, the United States Prescribing Information for encorafenib contains a specific recommendation to perform an ophthalmologic evaluation at regular intervals and for any new or worsening disturbances. Encorafenib should be withheld for up to six weeks for grade 1 or 2 uveitis that does not respond to specific ocular therapy, or for any grade 3 uveitis (table 2). If improved, resume at the same or a reduced dose; if not improved, discontinue permanently.
●Squamoproliferative lesions – Clinically significant cutaneous side effects are common with vemurafenib, including squamous cell carcinomas and keratoacanthomas. Eyelid squamous cell carcinoma and verruca vulgaris lesions frequently occur as well . Squamoproliferative lesions are also reported with the related agent dabrafenib, but eyelid neoplasms are not specifically reported.
Most lesions develop during the first three months of therapy and may occur in sun-protected sites. Biopsy and excision by a specialist who can excise the lesions, reconstruct defects, and prevent poor eyelid closure to protect the eye are recommended. Patients are usually able to continue treatment without dose adjustment. (See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy", section on 'Squamoproliferative lesions' and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Toxicities of BRAF and MEK inhibitors'.)
Mitogen-activated protein kinase inhibitors — Trametinib and cobimetinib, which are inhibitors of the MEK enzymes MEK1 and MEK2, have significant clinical activity in melanoma patients whose tumor contains a BRAFV600 mutation; these MEK inhibitors are now largely used for treatment of advanced melanoma in combination with BRAF inhibitors, which also are associated with ocular toxicity. (See 'BRAF inhibitors' above and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Toxicities of BRAF and MEK inhibitors'.)
●Retinal vein occlusion – Retinal vein occlusion (RVO) is an uncommon but potentially severe side effect reported in initial clinical trials of several MEK inhibitors, including cobimetinib and trametinib. Across all clinical trials, the incidence with trametinib was 0.2 percent (4 of 1749 individuals) [55-58]. Predisposing factors include glaucoma, uncontrolled hypertension, and diabetes mellitus. In at least one case, dosing adjustment from a continuous to an intermittent schedule reduced the frequency of RVO . (See 'Retinal vein and artery occlusion' above.)
At least one series suggests an association of MEK inhibitor-associated RVO with hyperhomocysteinemia, an inborn error of metabolism that predisposes to venous thromboembolism . These scant data indicate a potential role for hyperhomocysteinemia screening prior to initiation of MEK inhibitor therapy, but more data are needed. (See "Overview of the causes of venous thrombosis", section on 'Hyperhomocysteinemia'.)
For patients who develop an RVO, referral to a retina specialist is indicated; intravitreal injection of vascular endothelial growth factor inhibitors may be needed to optimize vision in the right setting. (See "Retinal vein occlusion: Treatment".)
●Retinopathy – Retinal events other than RVO have been reported for all MEK inhibitors tested in a clinical setting, and they are considered to represent a class effect. Various terms have been used to describe these side effects, which are based upon a combination of clinical findings and nonspecific symptoms, including serous retinopathy, central serous retinopathy, subfoveal retinal detachment, macular edema, visual disturbance, retinopathy, chorioretinopathy, and blurred vision [55,61-71]. All of these clinical findings correspond to the same clinical entity, and the umbrella term "MEK inhibitor-associated retinopathy" has been introduced to clarify this confusing area.
The incidence of MEK inhibitor-associated retinopathy ranges from 5 to 75 percent [68,72,73]. In a phase III trial of vemurafenib alone or with cobimetinib, retinopathy was reported more frequently with combined treatment (26 versus 3 percent), and over one-half of cases were asymptomatic and discovered during routine monitoring [71,74]. MEK inhibitor-associated retinopathy usually presents acutely within the first week of the first dose. The clinical examination of mild presentations is typically characterized by small, multifocal and bilateral subretinal detachments, which may be accompanied by subretinal fluid (image 1) . Moderate cases may be characterized by only multiple subretinal detachments. More severe cases may develop intraretinal fluid or cysts, and a disarrangement of the outer retinal layers. The clinical presentation is often but not always bilateral and is most often symmetric .
Symptoms vary widely; in many cases, patients are asymptomatic . Symptomatic patients may complain of blurred vision, altered color perception, shadows, light sensitivity, metamorphopsia, and/or glare. Symptoms generally (but not always ) resolve either spontaneously or after discontinuation of therapy [61,62,71].
The United States Prescribing Information for trametinib and cobimetinib recommends ophthalmological examination at regular intervals during therapy and at any time a new or worsening visual disturbance is reported. Trametinib should be withheld for documented retinal detachment, and restarted at a lower dose if resolution is documented within three weeks. If no improvement after three weeks, recurrence, or RVO, discontinue use of the drug . For cobimetinib, interrupt therapy for serous retinopathy until visual symptoms improve. Resume at a reduced dose only if symptoms improve over four weeks. For recurrent symptoms or any RVO, discontinue the drug permanently.
Fibroblast growth factor receptor (FGFR) inhibitors — Several inhibitors of FGFR (including ponatinib, dovitinib, erdafitinib, pemigatinib, and infigratinib) are in clinical trials for a variety of malignancies. Erdafitinib has now been approved for the treatment of advanced urothelial cancers that harbor certain FGFR mutations, and both pemigatinib and infigratinib are approved for previously treated advanced cholangiocarcinomas that harbor FGFR2 gene alterations. (See "Treatment of metastatic urothelial cancer of the bladder and urinary tract", section on 'FGFR mutation negative' and "Systemic therapy for advanced cholangiocarcinoma", section on 'FGFR inhibitors for FGFR fusion-positive tumors'.)
All of these drugs appear to be associated with a similar type of serous retinopathy (foci of subretinal fluid) to that seen with the MEK inhibitors [72,76-80], possibly because the FGFR pathway intersects with the MEK pathway.
●In the phase II BLC2001 trial, which included 87 patients with locally advanced or metastatic urothelial cancer that had susceptible FGFR2 or FGFR3 mutations, ocular toxicity from erdafitinib resulting in a visual field defect was reported in 25 percent, with a median time to first onset of 50 days . Grade 3 symptoms, defined as involving the central field of vision causing vision worse than 20/40 or >3 lines of worsening from baseline, were reported in 3 percent of patients. Dry eye symptoms occurred in 28 percent of patients during treatment and were grade 3 in 6 percent. Ocular symptoms resolved in 13 percent and were ongoing at the study cutoff in 13 percent.
●In the phase II FIGHT-202 trial, serous retinal detachment due to subretinal fluid accumulation occurred in six (4 percent) of 146 patients treated with pemigatinib; all events were grade 1 or 2, except for one grade 3 event that was deemed unrelated to therapy . Only one patient required dose interruption because of this adverse event.
●In the PACE trial, ocular toxicities occurred in 30 percent of 449 patients; 3.6 percent experienced a serious or severe toxicity. The most frequent reported toxicities were dry eye, blurred vision, and eye pain . Retinal toxicity occurred in 3.6 percent, and the most frequent were macular edema, retinal vein occlusion, retinal hemorrhage, and venous floaters.
The United States Prescribing Information for erdafitinib recommends that all patients receive dry eye prophylaxis with ocular lubricants as needed. Monthly ophthalmologic examinations (including an assessment of visual acuity, slit lamp examination, fundus examination, and optical coherence tomography [OCT]) are recommended during the first four months of treatment and every three months thereafter, with urgent reevaluation at any time for visual symptoms. It is recommended that the drug be withheld when serous retinal toxicity occurs, regardless of vision, and permanently discontinued if it does not resolve in four weeks or if it is grade 4 in severity (ie, visual acuity 20/200 or worse in the affected eye). However, there were no data provided on the percentage of patients whose symptoms resolved within four weeks. There are also recommended dose modification guidelines for patients who develop ocular adverse reactions.
The United States Prescribing Information for pemigatinib recommends ophthalmologic examining including OCT prior to initiation of therapy, every two months for the first six months of treatment and every three months thereafter, and urgently at any time for visual symptoms. Specific dose modifications based on symptomatology and finding on serial examination are provided. A similar recommendation for ophthalmologic examining including OCT prior to therapy, at one and three months, and every three months thereafter is made in the United States Prescribing Information for infigratinib. The United States Prescribing Information for ponatinib suggests a comprehensive eye examination at baseline, and periodically during treatment.
Immune checkpoint inhibitors — Checkpoint inhibitors, which are immunomodulatory antibodies that are used to enhance the immune system function, have substantially improved the prognosis for patients with advanced melanoma and a number of other malignancies. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation".)
The primary targets for checkpoint inhibition include:
●Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) – Ipilimumab, an anti-CTLA-4 antibody, is approved for use in patients with advanced melanoma. It prolongs overall survival in advanced melanoma by increasing T-cell-mediated adaptive immunotherapy, but this is accompanied by numerous autoimmune toxicities, including colitis, hepatitis, thyroid function abnormalities, vitiligo, and hypophysitis. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)
●Programmed cell death-1 (PD-1) and programmed cell death-1 ligand (PD-L1) receptors – Multiple antibodies against PD-1 and PD-L1 have shown great promise in multiple malignancies. Nivolumab and pembrolizumab, both of which target PD-1, and atezolizumab, avelumab, and durvalumab, which target PD-L1, have been approved in multiple indications (eg, melanoma, renal cell carcinoma, non-small cell lung cancer, head and neck cancer, urothelial carcinoma, Hodgkin lymphoma, Merkel cell carcinoma), and these agents are being evaluated in a wide range of other indications.
Ipilimumab — There are a variety of ocular events reported in patients treated with ipilimumab, including conjunctivitis, episcleritis, uveitis, and orbital inflammation (Graves-like ophthalmopathy).
Inflammation in the eyes presenting as anterior panuveitis [84-87] and episcleritis  are reported in patients taking ipilimumab, but the incidence is less than 1 percent. Symptoms can include photophobia, pain, dryness of the eyes, and blurred vision . Vision loss is typically mild to moderate.
Ipilimumab has rarely been associated with bilateral severe uveitis, which can lead to exudative retinal detachment in a mode similar to that seen with Vogt-Koyanagi-Harada syndrome (VKH). This can be vision threatening and should prompt immediate drug discontinuation [88,89]. (See 'Uveitis and ocular inflammation' above.)
Treatment with topical corticosteroid drops has controlled anterior uveitis, and vision usually improves. As patients typically have concurrent systemic autoimmune toxicities, systemic corticosteroids have also typically been used in these cases. While the uveitis appears to be manageable with corticosteroids, cessation of therapy must be considered in the setting of systemic autoimmune toxicity. The United States Prescribing Information for ipilimumab provides guidance for management of immune-mediated ocular toxicity:
●Administer corticosteroid eye drops (eg, 1 percent prednisolone acetate suspension) to patients who develop uveitis, iritis, or episcleritis.
●Permanently discontinue ipilimumab for immune-mediated ocular disease grade 2 to 4 that is not improving to grade 1 within two weeks while receiving topical therapy, or that requires oral immunosuppressive therapy.
●If uveitis occurs in combination with other immune-mediated adverse reactions (eg, cutaneous [vitiligo, poliosis, alopecia], auditory [tinnitus], or neurologic [cerebrospinal fluid pleocytosis, meningismus] [89,90]), consider a VKH-like syndrome, which has been observed in patients treated with ipilimumab  and may require treatment with systemic steroids to reduce the risk of permanent vision loss.
Management guidelines for uveitis/iritis, episcleritis, and blepharitis caused by immune checkpoint inhibitor immunotherapy (including ipilimumab), which in some cases differ from those in the United States Prescribing Information, are also available from the American Society of Clinical Oncology (ASCO). (See 'ASCO guidelines for counseling and management' below.)
Ipilimumab has also been implicated in the development of orbital inflammation, which has been described as Graves-like orbitopathy, but only rarely is this truly thyroid-related [92,93]. Symptoms include proptosis, diplopia, exposure keratopathy, ophthalmoplegia (inability to move the ocular muscles), and enlargement of extraocular muscles, potentially compressing the optic nerve. A computed tomography (CT) scan of the orbits is helpful and will show enlargement of the extraocular muscles, classically with sparing of the tendon insertions. Lab studies with thyroid-stimulating hormone (TSH), thyroxine (T4), antithyroid peroxidase (TPO), and thyroglobulin antibodies are often positive (reflecting the association of ipilimumab with immune-mediated thyroiditis and hypothyroidism), but development of orbital inflammation can occur in euthyroid patients without positive serologies . This condition is uncommon but severe and can be vision threatening. Prompt evaluation by a specialist is recommended to evaluate for orbital congestion, optic neuropathy, or exposure keratopathy. Acute treatment with systemic corticosteroids is recommended. Severe cases warrant cessation of therapy; however, it should be noted that the mean plasma half-life of ipilimumab is long (359 hours; 15 days) . (See 'Orbital inflammation' above and "Clinical features and diagnosis of Graves' orbitopathy (ophthalmopathy)".)
Anti-PD-1 and PD-L1 agents — Intraocular inflammation (uveitis) following treatment with pembrolizumab, nivolumab, or cemiplimab is a rare but clinically important event, described in approximately 1 percent of treated patients [95-97]. Ocular inflammation (uveitis, iritis) is also reported in fewer than 1 percent of patients receiving therapy with the anti-PD-L1 blocking antibodies avelumab, durvalumab, and atezolizumab [98,99].
Although the available data are limited, the risk of eye disorders may be aggravated when drugs of both checkpoint inhibitor classes are combined . As use of these agents increases, there are more cases of patients developing autoimmune retinopathy.
With all checkpoint inhibitors, concerns for autoimmune disease (including myasthenia gravis), thyroid eye disease, uveitis (including punctate inner choroidopathy/multifocal choroiditis, also called white dot syndrome or birdshot-like chorioretinopathy ), and exacerbation of paraneoplastic syndromes (including melanoma-associated retinopathy) need to be considered.
For patients receiving the anti-PD-1 antibodies nivolumab or cemiplimab, if uveitis occurs in combination with other immune-mediated adverse reactions (eg, cutaneous [vitiligo, poliosis, alopecia], auditory [tinnitus], or neurologic [cerebrospinal fluid pleocytosis, meningismus]) [102-104], consider a VKH-like syndrome, which has been observed in patients treated with cemiplimab alone, nivolumab alone, or nivolumab in combination with ipilimumab and may require treatment with systemic steroids to reduce the risk of permanent vision loss.
ASCO guidelines for counseling and management — Specific guidelines for counseling patients about ocular side effects and which ocular symptoms should be reported to the health care provider, and recommendations for ophthalmology referral and management of uveitis/iritis and episcleritis in patients treated with immune checkpoint inhibitors are available from the ASCO (table 3) .
Anaplastic lymphoma kinase inhibitors — Visual disturbances have been seen in up to 65 percent of patients treated with crizotinib in the phase II studies [106,107]. The main complaints are trailing lights, flashes, and brief image persistence, primarily associated with the transition from dark to light [46,107-110]. Uncommon visual manifestations included photophobia, decreased visual acuity, and blurred vision. Optic neuropathy and blindness have been reported, although they may have been related to prior whole-brain radiation therapy . Across all clinical trials, the incidence of grade 4 visual field defect with vision loss was 0.2 percent (4 of 1719) .
Onset typically begins in the first week of starting crizotinib; symptoms tend to recur daily, last up to one minute, and generally have little to no impact on daily activity . Similar symptoms have been reported with three other anaplastic lymphoma kinase inhibitors (ceritinib, brigatinib, and lorlatinib), but their overall incidence (all grade) is less than 15 percent.
The mechanism is unclear. Detailed ophthalmological assessment in over 200 patients from phase II experience with crizotinib did not demonstrate any objective abnormalities associated with visual symptoms .
No therapies are known to help. Symptoms often improve with length of time receiving therapy , and treatment cessation is usually not needed. The United States Prescribing Information for crizotinib recommends discontinuation of the drug in patients with new onset of severe visual loss (best corrected vision less than 20/200 in one or both eyes). The decision to resume therapy must be individualized, weighing the risks of visual loss with the potential benefits of treatment discontinuation to the patient. The United States Prescribing Information for brigatinib recommends withholding the drug for grade 2 (symptomatic, with moderate decrease in visual acuity [no worse than 20/40]; limiting instrumental activities of daily living [ADL]) or grade 3 (symptomatic, with marked decrease in visual acuity [worse than 20/40 but not 20/200]; disabling; limiting self-care ADL) visual loss until resolved to grade 1 (asymptomatic), and restarting at a reduced dose; they recommend permanent discontinuation for grade 4 visual loss (blindness [20/200 or worse] in the affected eye).
Tamoxifen and toremifene — The selective estrogen receptor modulators tamoxifen and toremifene have been associated with asymptomatic corneal deposits [114,115]. A meta-analysis of three studies shows incidence is 0.7 percent for toremifene and 0.3 percent for tamoxifen . Corneal pigmentation was reversible upon cessation of drug [117,118]. Continuation of therapy is likely safe if corneal deposits are found. Periodic follow-up with an ophthalmologist to monitor deposits is recommended. (See 'Corneal deposits' above.)
Cataracts have been reported in association with both drugs (3.7 percent for toremifene and 3.2 percent for tamoxifen ). Surgical lens replacement is recommended when cataracts become visually significant. Since cataracts are well treated surgically, patients may not have to discontinue treatment because of this side effect. (See 'Cataracts' above.)
Tamoxifen was first reported to be associated with irreversible refractile retinal deposits in women taking high doses of the drug for metastatic breast cancer . Subsequently, reports were also noted with tamoxifen given at standard doses for adjuvant therapy of breast cancer (20 mg daily), although this side effect appears to be rare [119,120]. Retinal deposits occur more often as total cumulative dose reaches 100 grams.
Macular edema is often associated with these deposits, which are typically located in the paramacular region [121-126]. Significant vision loss occurs in only a subset of these patients. Macular edema and vision loss may resolve with discontinuation of therapy, but the pigmentary changes and the retinal deposits persist. We recommend referral to a specialist to evaluate for evidence of refractile deposits or macular edema at any evidence of visual symptoms. Therapy may need to be discontinued as prolonged macular edema is likely damaging to the retina. No proven treatment for macular edema associated with tamoxifen has been described besides cessation of tamoxifen itself. (See 'Pigment changes, cotton wool spots, and hemorrhages' above.)
Tyrosine kinase inhibitors — Several ocular toxicities are reported with a variety of tyrosine kinase inhibitors (TKIs) targeting different receptors.
Imatinib — The TKI with the greatest frequency of ocular side effects is imatinib, which targets the KIT, Platelet-derived growth factor receptor (PDGFR), and BCR-ABL tyrosine kinases:
●Mild/moderate periorbital edema is a common side effect of imatinib , shown to occur in 70 out of 147 (47.6 percent) patients taking imatinib in a phase II clinical trial for gastrointestinal stromal tumors . Another retrospective review of imatinib (in clinical trials from a single center) showed 73 of 104 (70 percent) with periorbital edema . Usually, conservative-management topical steroids and diuretics can control symptoms, and therapy doesn't need to be stopped. If symptoms are intolerable and therapy is stopped, rechallenge results in recurrence of symptoms in approximately one-half of patients . Occasionally, dramatic periorbital edema impairs function  and requires surgical treatment. (See 'Periorbital edema' above.)
Another major ocular complaint is epiphora [127,129,131], which has been attributed not to nasolacrimal duct obstruction but to poor lid apposition to the globe from periorbital edema and conjunctival chalasis . Improvement typically occurs with cessation of therapy. (See 'Epiphora and nasolacrimal duct obstruction' above.)
●Imatinib has also been associated with spontaneous subconjunctival hemorrhage, which occurred in absence of systemic bleeding tendencies or bone marrow suppression. This occurred in 10 patients (11 percent) . There was recurrence in six patients, but no other ocular sequelae ensued. Although aesthetically displeasing, this condition is benign, and cessation of treatment is not necessary. (See 'Conjunctival hemorrhage' above.)
●Imatinib is associated with rare incidences of retinal hemorrhages in the first few months after starting treatment [129,133-135]. These are usually reversible. Cystoid macular edema and optic nerve edema have also been reported rarely [136-140]. Referral to a retina specialist is recommended. No effective treatments have been reported. Cessation of medication may be necessary in severe cases. (See 'Retina' above.)
●Rare cases of optic neuritis have been reported in association with imatinib use [136,139,141]. Vision loss varied from mild to severe on initial presentation but eventually improved almost to baseline with cessation of therapy [139,141]. Discontinuing treatment should be considered. However, this decision must be individualized, taking into account the availability of an alternative therapy and the risks versus benefits of treatment discontinuation versus continuation. In one case, rechallenge was associated with worsening vision, but in another, rechallenge was well tolerated [139,141]. (See 'Optic nerve' above.)
Vandetanib — The multikinase inhibitor vandetanib, which targets the EGFR, vascular endothelial growth factor receptor (VEGFR), and RET and SRC kinases, has been reported to cause corneal verticillata (deposits) [11,28,142]. Incidence is rare, and symptoms are generally mild. Blurriness and glare have been managed symptomatically with artificial tears. One case reported that dose reduction improved symptoms, but corneal findings persisted. Follow-up with an ophthalmologist is recommended to monitor the corneal findings, but given the mild effects on vision, cessation of treatment is not usually necessary.
Nilotinib — Nilotinib is a selective TKI that targets BCR-ABL, KIT, and PDGFR. It was associated with mild dry eye symptoms in three out of nine patients in a phase II clinical trial . Nilotinib has also been associated with a case of xanthomas of the eyelids, but these were probably related to systemic elevation of cholesterol, which seemed to be "unmasked" by the initiation of nilotinib . These lesions are benign but should alert the clinician to the need for a systemic workup.
Ponatinib — Ponatinib is a third generation TKI that targets BCR-ABL, and several other receptors, including FGFR. Ocular toxicities are reported in 30 percent of patients receiving the drug for refractory CML, but the specific molecular target responsible for these toxicities is not established. Ocular toxicity from this agent is described in more detail above. (See 'Fibroblast growth factor receptor (FGFR) inhibitors' above.)
Sorafenib — Sorafenib is a multitargeted TKI that targets KIT, PDGFR, and VEGFR-1, 2, and 3. It has been associated with the development of squamoproliferative lesions, such as keratoacanthomas and squamous cell carcinomas, that can affect the eyelid. The risk and natural history are not well defined.
Squamoproliferative lesions that develop during sorafenib therapy should be treated similarly to lesions that develop in patients not receiving the drug (usually with complete surgical excision). However, spontaneous regression of keratoacanthomas has been reported after discontinuation of the drug and also in a few patients who continued therapy. Definitive guidelines for continuing versus discontinuing sorafenib in patients who develop squamous cell carcinoma or keratoacanthomas while on therapy have not been established. Close clinical follow-up during treatment is warranted. (See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy", section on 'Squamoproliferative lesions'.)
Pexidartinib — Pexidartinib is an oral kinase inhibitor that targets colony stimulating factor 1 receptor (CSF1R); it is approved for advanced tenosynovial giant cell tumor. (See "Treatment for tenosynovial giant cell tumor and other benign neoplasms affecting soft tissue and bone".)
Eye edema (including periorbital edema, eye edema, and eyelid edema) was reported in 30 percent of 61 patients treated with pexidartinib in one trial; it was severe (grade 3 or worse) in 1.6 percent .
Bruton tyrosine kinase inhibitors — Ibrutinib is a Bruton tyrosine kinase (BTK) inhibitor used for the treatment of hematologic malignancies. Several ophthalmic side effects have been reported, including blurred vision, dry eye, increased lacrimation, and uveitis [146,147]. Ocular side effects have not been reported in patients treated with a second BTK inhibitor, acalabrutinib.
Antibody-drug conjugates — Antibody-drug conjugates can be very toxic to the cornea. Many trials and prescribing information prohibit contact lens wearers from wearing their contact lenses during therapy because of concerns that the antibody drug might get into high concentration in the contact lens and exacerbate drug-related corneal toxicity.
●Belantamab mafodotin – Belantamab mafodotin is an anti-B-cell maturation antigen humanized immunoglobulin G antibody conjugated to the microtubular disrupting agent monomethyl auristatin; it is approved for relapsed and refractory multiple myeloma. In a pooled safety population of 218 patients who received the drug, corneal epithelial changes (keratopathy) were the most common toxicity, occurring in 76 percent of patients, the majority of whom had clinically relevant visual acuity changes . The keratopathy was grade 1 or 2 in 29 percent, and grade 3 or 4 in 46 percent. Corneal ulcers were reported. The majority developed during the first two treatment cycles. Other ocular adverse reactions included blurred vision (27 percent) and dry eye (19 percent). Most cases of ocular toxicity reversed with dose reduction or delay, and the use of artificial tears.
The drug is available only through a restricted access program under a Risk Evaluation and Mitigation Strategy because of the risks of ocular toxicity; prescribers and patients must be enrolled, and comply with training and monitoring requirements. The United States Prescribing Information for belantamab mafodotin advises an ophthalmologic examination (visual acuity and slit-lamp) at baseline, prior to each dose, and promptly for worsening symptoms. Patients should use a lubricant eye drop at least four times daily starting with the first infusion, and continuing until the end of treatment. Ophthalmic topical corticosteroids are often helpful; in our experience, topical (ophthalmic) cyclosporine is not. Contact lenses should be avoided during treatment unless directed by an ophthalmologist. Recommendations for dose modification based on corneal toxicity are provided.
●Enfortumab vedotin – Enfortumab vedotin is a nectin-4-directed antibody microtubule inhibitor drug conjugate that is approved for metastatic refractory urothelial cancer. (See "Treatment of metastatic urothelial cancer of the bladder and urinary tract", section on 'Enfortumab vedotin'.)
In the initial clinical trial, involving 125 patients treated with enfortumab vedotin, ocular disorders included dry eye in 29 (23 percent), blurred vision in 19 (15 percent), and increased lacrimation in 18 (14 percent) . In an analysis of 310 patients treated with the drug, ocular disorders occurred in 46 percent, and the majority involved the cornea, including keratitis, blurred vision, limbal stem cell deficiency, and other events associated with dry eye .
The United States Prescribing Information for enfortumab vedotin recommends artificial tears for prophylaxis of dry eyes, and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Options for symptomatic ocular disorders include ophthalmic topical steroids, dose interruption, or dose reduction. In our experience, ophthalmic topical cyclosporin is not helpful.
●Tisotumab vedotin – Tisotumab vedotin is a tissue factor-directed antibody and microtubule inhibitor drug-conjugate approved for use for those with recurrent or metastatic cervical cancer with disease progression on, or after, chemotherapy. (See "Management of recurrent or metastatic cervical cancer", section on 'Second-line therapy'.)
In a pooled analysis of 158 patients who received at least one dose of tisotumab vedotin, eye disorders included conjunctival adverse reactions in 37 percent (conjunctivitis, conjunctival abrasion, erosion, hyperemia, scar, or hemorrhage), dry eye or increased lacrimation (29 percent), corneal adverse reactions in 21 percent (keratitis, keratopathy, corneal erosions, and corneal bleeding), and periorbital adverse reactions in 16 percent (blepharitis, meibomianitis, eye pruritus, entropion, trichiasis, chalazion, and meibomian gland dysfunction) . There were no cases of grade 3 or 4 ocular toxicity.
The United States Prescribing Information for tisotumab vedotin advises an ophthalmic examination (including visual acuity and slit lamp examination) at baseline, prior to each dose, and as clinically indicated. All patients should receive topical corticosteroid and vasoconstrictor eye drops prior to each dose, and use eye cooling pads during drug infusion. In addition, patients should administer lubricating eye drops for the duration of therapy, and 30 days after treatment discontinuation. Patients should avoid wearing contact lenses during treatment, unless directed by an ophthalmologist. Dose modification guidelines based on the severity of ocular toxicity are provided.
Traditional chemotherapy agents
Bortezomib and eyelid disorders — Bortezomib, a proteasome inhibitor, is associated with case reports of severe meibomian gland disease and development of chalazia on multiple lids [152-154]. Several were severe enough to prompt discontinuation of bortezomib or at least temporary withholding of the drug. Rechallenge resulted in recurrence of chalazia for the majority of patients . Management of bortezomib-induced chalazia is relatively unsatisfactory with standard treatment regimens, which include warm compresses, lid hygiene, topical and oral antibiotics [152,155] and steroids, and surgical incision and drainage. Patients present with multiple chalazia on the upper and lower lids, and traditional medical management is only minimally effective. Surgical treatment may be impractical due to the multiplicity of lesions and the increased risk of scarring and lid malposition. There is a high rate of recurrence. In general, symptoms are reversible on discontinuation of the drug. (See 'Blepharitis and meibomian gland dysfunction' above and 'Chalazia and other eyelid masses' above.)
Ultimately, the decision to stop or continue bortezomib must be individualized. The benefits of continuing the drug (versus switching to an alternative potentially effective therapy) must be weighed against the risks and consequences of ongoing ocular toxicity. Optimally, this decision should be made jointly by the patient, the oncologist, and the ophthalmologist. Notably, chalazia and meibomian gland dysfunction have not been reported with the second-generation proteasome inhibitor carfilzomib.
Epiphora and docetaxel — Excess tearing (epiphora) is reported in 21 to 86 percent of patients who receive docetaxel for metastatic cancer or in the adjuvant setting for treatment of early breast cancer [156-159]; some, but not all, of these patients have obstruction of the nasolacrimal system. Longer duration of therapy and higher cumulative doses are associated with worse disease severity. Weekly dosing is also associated with a higher frequency and severity of epiphora and with a higher risk for obstruction of the nasolacrimal system than every-three-week dosing [157,160,161]. In one study, while 30 out of 71 patients who developed epiphora with weekly dosing required surgery for obstruction of the nasolacrimal system, only 3 out of 71 of those who developed epiphora with every-two-to-three-week dosing required surgery . Surgery in the weekly dosing group also tended to be more complicated. Patients who develop epiphora while receiving weekly therapy also tend to resolve less rapidly after treatment discontinuation [160,161]. (See 'Epiphora and nasolacrimal duct obstruction' above.)
Given the potential for severe, symptomatic, and irreversible obstruction of the nasolacrimal system over time , we recommend referral to a lacrimal specialist for evaluation and possible early preventive treatment for all patients who develop epiphora during docetaxel treatment. There may be benefit for early temporary silicone intubation for patients with progressive canalicular stenosis, to prevent permanent complete closure of the canaliculi and the need for much more involved surgery, and worse outcomes [13,162].
Visual changes — Paclitaxel is associated with transient scintillating scotomas during infusion in approximately 20 percent of patients [119,164-166]. These symptoms last approximately 15 minutes to 3 hours and occur mostly at the end of the infusion [165,167]. This was associated with visual-evoked potential changes [164,166], suggesting abnormalities in the optic nerve pathway. The mechanism of these changes is unclear, but the hypothesis is either transient ischemia or neurotoxic effects of taxanes. (See 'Optic nerve' above.)
Docetaxel has been associated with a rare case of toxic optic neuropathy, causing constriction of visual fields, loss of visual acuity, and loss of color vision . Optic nerve edema and disc hemorrhages were present, and complete lab work and imaging was otherwise negative. Treatment with intravenous corticosteroids with oral taper was used. Vision and visual fields gradually improved over three months. (See 'Optic nerve' above.)
While the scintillating scotomas reported with paclitaxel are a mild, non-vision-threatening, reversible condition, prolonged optic nerve edema is potentially vision threatening and, at least in the one case, was reversible upon cessation of therapy. There is not sufficient evidence to say whether corticosteroids help or whether cessation of therapy is enough. Referral to a neuro-ophthalmologist is recommended with repetitive instances of scotomas and promptly with vision loss.
Cystoid macular edema — There are case reports of mild/moderate bilateral cystoid macular edema without evidence of leakage on retinal imaging both with paclitaxel and docetaxel [169-173]. Edema resolved with cessation of therapy [170,172,174]. Acetazolamide has been used and reported in a few cases to help with edema [169,173].
For patients with a viable alternative to the use of a taxane, we recommend discontinuation of the taxane and referral to a retina specialist to manage the ocular findings. If no effective treatment alternative exists, the benefits of continuing the taxane must be weighed against the risks and consequences of ongoing ocular toxicity. Optimally, this decision should be made jointly by the patient, the oncologist, and the ophthalmologist. (See 'Macular edema, central serous retinopathy, and serous retinal detachment' above.)
Fluoropyrimidines — Fluoropyrimidines are used widely for a variety of different cancers, and their use is frequently associated with ocular side effects:
●Fluorouracil (FU) is commonly associated with excess tearing (30 to 50 percent [175-177]). The causes are multifactorial, including ocular surface disease, dry eyes, and canalicular stenosis or obstruction of the nasolacrimal system [175-185]. Canalicular stenosis is reported in 4 to 15 percent of treated patients [175,177,178], and this has required canalicular stenting with silastic tubing, dacryocystorhinostomy, or occasionally, conjunctivodacryocystorhinostomy [179,181,182,184]. (See 'Epiphora and nasolacrimal duct obstruction' above.)
●FU-induced eyelid dermatitis and lid margin inflammation can lead to cicatricial changes that cause poor apposition of the lids (eyelid ectropion 1.9 percent) [175,183] and eyelid margin fusion , leading to evaporative dry eye and reflexive tearing. (See 'Cicatricial eyelid changes' above.)
●Other reported ocular toxicities from FU-based therapies include eyelid conjunctival hyperemia (39.4 percent), lid margin abnormalities (41 percent), corneal punctate epithelial erosions (3.2 percent), and lower eyelid punctal edema (5 percent) [175,178].
●Overall, the high rate of burning, tearing, and ocular irritation seen with FU-based therapies [176,186] is likely related to dry eye caused by toxicities to the cornea, conjunctiva, and eyelid, all of which contribute to a healthy tear film.
●The oral fluoropyrimidine capecitabine has been associated with two cases of corneal deposits with mild blurriness of vision . These deposits resolved with discontinuation of drug, and rechallenge led to recurrence. (See 'Corneal deposits' above.)
We recommend referral to an ophthalmologist and/or switching to an alternative agent if symptoms are not relieved by conservative management with lubrication (artificial tears) or if there is evidence of obstruction of the nasolacrimal system. Though no data have shown prevention of extensive stenosis with early stenting in patients treated with FU, early stenting of nasolacrimal system obstruction related to docetaxel chemotherapy has prevented far more invasive nasolacrimal surgery. (See 'Taxanes' above.)
Busulfan and cataracts — The alkylating agent busulfan has been associated with the development of cataracts in the pediatric population when used as part of treatment for leukemia. The reported incidence is around 10 of 79 (12.7 percent) in a meta-analysis  and 12.5 percent in another study . The visual significance of these cataracts is not as well described. They appear to be posterior subcapsular cataracts, and in one study, out of five children who developed cataracts in association with busulfan, one needed cataract surgery . The time to formation of cataracts ranged from one to seven years . Cataracts in the pediatric population need individualized treatment. The decision for surgical extraction of the lens depends on a variety of factors, including the visual significance of the cataract, the age of the patient, the risks for amblyopia if left untreated, the inflammatory reaction and difficult postoperative care in a child, and the changing refraction of the eye during growth, amongst other factors. As cataracts likely develop post-treatment, we recommend referral to an ophthalmologist at any sign of difficulty with vision (which, in a child, can present as difficulty with schoolwork or preference for one eye over the other).
Cytarabine and fludarabine — Cytarabine has been associated with corneal deposits that are dose dependent, with high incidences when dosing reaches 3 g/m2 but minimal at 1 to 2 g/m2 [190,191]. Patients complain of conjunctival injection, photophobia, foreign body sensation, and mild to moderate vision loss. Incidence can be as high as 85 percent . On slit lamp examination, corneal epithelial microcysts are noted. (See 'Corneal deposits' above.)
Symptoms and corneal findings are reversible with cessation of treatment, and vision usually returns back to baseline [193,194]. Prednisolone eye drops can help with symptomatic management, although benefit has not been shown in all studies. One study found no difference in grade 2/3 symptoms with or without prednisolone eye drops . Topical 2-deoxycytidine, a competitive inhibitor of cytarabine, was equally effective as topical prednisolone in a small, double-masked, randomized study of 11 patients . Ophthalmologic referral is recommended.
Rare case reports of anterior uveitis have occurred when cytarabine was used as single agent , in combination in hyper-CVAD protocol (cyclophosphamide, doxorubicin, vincristine, and dexamethasone alternating with methotrexate and high-dose arabinoside) , or in combination with gemtuzumab . Anterior uveitis resolved within a few days of treatment with topical steroids and mydriatics. We recommend prompt referral to an ophthalmologist at signs and symptoms of uveitis for treatment to prevent vision loss or future ocular complications. (See 'Uveitis and ocular inflammation' above.)
High-dose cytarabine used in the setting of induction for hematopoietic cell transplantation in conjunction with total-body irradiation has been uncommonly associated with retinal microvascular damage, including capillary nonperfusion and subsequent sequelae, such as neovascularization, vitreous hemorrhage, and macular edema . It has been suggested that ocular damage in these patients may be a consequence of the radiosensitizing potential of cytarabine . In one case report, complications from retinal ischemia eventually led to tractional retinal detachment involving the macula, with poor visual prognosis . We recommend referral to a retina specialist if there is any evidence of vision loss in order to coordinate care. Retinal imaging may better define severity of retinal nonperfusion and need/benefit from local management versus cessation of therapy. (See 'Macular edema, central serous retinopathy, and serous retinal detachment' above.)
Fludarabine has been associated with rapid vision loss in three cases in the literature, all when fludarabine was administered prior to hematopoietic cell transplantation . Fundus examination showed punctate yellow flecks in the macula, and histology showed loss of retinal bipolar and ganglion cells. There is not enough evidence about reversibility to make specific recommendations. However, early referral to a retina specialist is advised. (See 'Pigment changes, cotton wool spots, and hemorrhages' above.)
Pentostatin, methotrexate, and pemetrexed — The antimetabolite pentostatin has been associated with keratitis, in which there are corneal dendritic ulcerations of similar morphology to herpes simplex keratitis (affecting 3 out of 15 patients in one study ). These lesions, however, occurred bilaterally and were associated with pain, whereas herpes keratitis doesn't usually occur simultaneously in both eyes unless the patient is immunocompromised. Decreased corneal sensation is also typical of herpetic keratitis. (See "Herpes simplex keratitis".)
Pain and photophobia may persist for several days. If a patient presents with these clinical findings, we recommend prompt referral to an ophthalmologist to help distinguish the etiology. Symptomatic management with artificial tears has been successful. In the case series discussed above, corneal healing was complete in 14 to 21 days . (See 'Corneal epithelial defects' above.)
Pentostatin has also been associated with conjunctivitis, keratoconjunctivitis, and periorbital edema [202-206]. Patients may complain of ocular pain, photophobia, burning, and itching. Treatment is usually supportive, but discontinuation of therapy may be necessary .
Therapy with high-dose methotrexate (as is used for central nervous system lymphoma and osteosarcoma treatment) is rarely associated with ocular anterior surface irritation two to seven days after starting therapy . Symptoms are usually mild and not vision threatening. (See "Therapeutic use and toxicity of high-dose methotrexate".)
Low-dose methotrexate and optic neuropathy — Methotrexate is rarely associated with toxic posterior optic neuropathy. Visual field scotomas, optic nerve edema, and optic atrophy have all been reported [209-212], predominantly after longstanding treatment with low-dose methotrexate, with or without folic acid supplementation, in the treatment of rheumatologic diseases. Recovery of vision did occur in a few cases after discontinuation of methotrexate [210,212]. We recommend cessation of therapy at the first evidence of vision loss and referral to a specialist for further management. (See "Major side effects of low-dose methotrexate", section on 'Others'.)
The optic neuropathy seen in patients treated with low-dose methotrexate has been linked to folate deficiency, either nutritional or genetic . Folate supplementation, when co-administered with methotrexate, minimizes its adverse effects  and may, therefore, prevent the development of optic neuropathy. In addition, when this condition is recognized, the nerve damage may be reversible if methotrexate is stopped and if appropriate folate supplementation is administered promptly .
Pemetrexed and eye edema — Pemetrexed, a folic acid antagonist, has been associated with lower eyelid edema, although the true incidence is difficult to ascertain. The May 2008 version of the Pemetrexed Clinical Investigator's Brochure suggested an incidence of 0.4 percent (6 cases out of 1364 treated patients) . However, the frequency of eyelid edema was 2.3 percent in a phase II clinical study of pemetrexed with concomitant cisplatin or carboplatin . The eyelid edema was attributed to pemetrexed because it was reversed after stopping pemetrexed but not carboplatin. Eyelid edema has not been associated with systemic fluid retention [214,215]. (See 'Orbit and periorbital tissue' above.)
Others report a higher frequency of adverse effects affecting the eye in patients treated with pemetrexed. In a review of 107 patients treated with four or more cycles of pemetrexed , periorbital edema (not just limited to the lower eyelid) developed in 16 (15 percent). In this series, the most common cutaneous adverse event was drug-induced conjunctivitis in 27 (26 percent), which seemed to precede an inflammatory edema of the eyelid.
Rechallenge has led to worsening eyelid edema in one case report . Chronic edema can potentially lead to lower lid laxity or cicatricial changes in the future, but given the reversibility of the condition and the generally non-vision-threatening nature of the side effect, it is likely safe to continue treatment of the malignancy, particularly if there are no other viable treatment alternatives. Artificial tears could be added to prevent any evaporative dry eye caused by lower lid sagging.
Anthracyclines and anthracenediones — Doxorubicin and epirubicin have been associated with conjunctivitis [218,219], especially following accidental ocular exposure. The incidence is 25 percent in conjunction with docetaxel  and 39 percent in conjunction with fluorouracil and cyclophosphamide . The vast majority of chemical conjunctivitis cases resolved within a day after exposure . Cautious rechallenge of therapy is probably reasonable as toxicity resolves quickly and is not vision threatening. (See 'Conjunctivitis' above.)
Mild/moderate chemical conjunctivitis was also reported in 6 percent of patients treated with combination cytarabine and mitoxantrone for refractory non-Hodgkin lymphoma . As cytarabine can also sometimes present with conjunctival injection, it is unclear whether cytarabine has a contribution to the reactions seen or whether there is a synergistic effect when both are taken together.
In general, conjunctivitis can be managed conservatively, and therapy likely does not have to be withdrawn. (See 'Conjunctivitis' above.)
Mitoxantrone has been associated with secondary acute promyelocytic leukemia [222,223]. In at least one report, this manifested as optic nerve infiltration by leukemia cells . This rare occurrence should be considered if a patient presents with optic nerve abnormalities on examination while receiving mitoxantrone. (See 'Optic nerve' above.)
Interferon — Interferons are associated with several ocular side effects; mostly these have been reported in patients receiving interferon alfa 2b, which was withdrawn from the global market in 2021. There are only scattered reports of these toxicities in patients receiving interferon alfa 2a.
●Both pegylated and nonpegylated interferon alfa-2b have been associated with development of uveitis when used in the treatment of hepatitis C viral infection [225-228]. Severe bilateral panuveitis with exudative retinal detachments has been reported, along with systemic manifestations of VKH (vertigo, skin/hair changes, hearing loss, and meningitis). Incidence is rare, but the condition is vision threatening. Prompt systemic corticosteroids and topical corticosteroid drops with prolonged taper have been tried with generally good response and control of uveitis [225-227]. Visual prognosis is uncertain and depends on the extent of ocular involvement. Referral to an ophthalmologist and a rheumatologist is recommended. (See 'Uveitis and ocular inflammation' above.)
●Interferon alfa-2b has been associated with trichomegaly of the eyelashes (irregular, elongated eyelash growth) [229-235]. No corneal decompensation has been reported. This uncommon side effect is mild and reversible after discontinuation of therapy, usually in approximately three months. (See 'Trichiasis and trichomegaly' above.)
●Interferon alfa-2b has been associated with ischemic retinopathy. On funduscopic examination, intraretinal hemorrhages and cotton wool spots are seen. These findings are most commonly described in the chronic hepatitis C literature, but they are also reported in the treatment of cancer [236-239]. Close monitoring is recommended. Incidence of vision loss varies from 15 to 86 percent [240-246]. Most cases were mild and reversible, but vision loss can be severe. Serious side effects of retinal artery and vein occlusions have been reported [238,247,248]. Fluorescein angiography has shown poor perfusion of the retina [239,249]. Treatment should be stopped, and referral to a retina specialist is recommended. (See 'Retina' above.)
●Just as interferon alfa-2b can cause ischemia to the retina, it is also associated with reports of anterior ischemic optic neuropathy. Vision loss varies from mild, nonprogressive, or reversible vision loss after cessation of therapy and starting systemic steroids [252-254] to significant loss of visual acuity and loss of peripheral visual field that is irreversible even with steroid treatment [252,255-258]. Acutely, optic nerve head swelling, an afferent pupillary defect, and color vision loss are seen. Over time, optic atrophy with optic nerve head pallor can be seen. Nonarteritic ischemic optic neuropathy has also been rarely reported [259,260] with permanent altitudinal visual field loss and moderate central visual acuity loss. A significant number of subclinical abnormalities can be seen with visual-evoked potential testing. In a prospective study, visual-evoked response was abnormal in 15 out of 74 eyes (20.3 percent). Two-thirds were reversible after stopping interferon; one-third persisted but were clinically asymptomatic . (See 'Optic nerve' above.)
Optic neuropathy is also rarely reported in patients receiving interferon alfa 2a .
It is unclear what population of people will get optic neuropathy from interferon treatment and who will have severe versus mild vision loss. Incidence is infrequent, but patients should be aware of the potential for significant vision loss. Referral to a neuro-ophthalmologist is recommended in the event of visual effects. Systemic corticosteroids are an option. (See "Nonarteritic anterior ischemic optic neuropathy: Prognosis and treatment".)
Platinum analogs — There are reports of retinal toxicity with cisplatin [263,264] and, to a lesser extent, with carboplatin and oxaliplatin. Ischemic retinopathy with cisplatin or carboplatin might be synergistic with coadministered paclitaxel [265,266]. Systemic administration of cisplatin with carmustine prior to hematopoietic cell transplantation has also been associated with retinal toxicity and vision loss, although it is not clear whether it was due to cisplatin or carmustine . (See 'Carmustine and retinal damage' below.)
Additionally, the less severe side effects of granular pigmentary deposits and altered color vision have been described with both systemic and intra-arterial cisplatin [268-272]. Color vision changes can take months to years to return to baseline. It should be emphasized that these conditions are painless. (See 'Pigment changes, cotton wool spots, and hemorrhages' above.)
Carboplatin has been associated with rare case reports of optic nerve edema with hemorrhages and macular edema [273,274]. Irreversible vision loss and optic atrophy have resulted, even with cessation of therapy. Discontinuation of the drug should be considered at any signs of vision loss, and referral to a subspecialist should be made. (See 'Optic nerve edema' above.)
Oxaliplatin has been associated with rare cases of papilledema with intracranial hypertension . Tunneling of vision was described. Treatment cessation and, in one case, initiation of oral acetazolamide led to gradual improvement in optic disc swelling and improvement in vision. The recommended workup for these patients (which includes magnetic resonance imaging [MRI] of the head) is described above. (See 'Optic nerve edema' above.)
Referral to a neuro-ophthalmologist and close follow-up to monitor the condition of the optic nerve are recommended. Discontinuation of oxaliplatin may be needed if unable to manage elevated intracranial hypertension. The decision to stop or continue oxaliplatin must be individualized. The benefits of continuing therapy (particularly where no effective treatment alternative exists) must be weighed against the risks and consequences of ongoing toxicity. Optimally, this decision should be made jointly by the patient, the oncologist, and the neuro-ophthalmologist.
Carmustine and retinal damage — Intravenous carmustine in combination with high-dose cisplatin and cyclophosphamide, used in the setting of hematopoietic cell transplantation, has also been associated with severe cases of optic disc edema, pallor, and retinopathy [267,276,277], leading to irreversible optic nerve damage and vision loss. In a prospective trial of carmustine-based chemotherapy prior to hematopoietic cell transplantation, 25 percent of the patients developed retinal cotton wool spots or retinal hemorrhages . In one case report, histopathology at autopsy showed patchy necrosis of the central nervous system and optic nerves consistent with small vessel thrombosis [267,277]. In most cases, drug administration has already been completed when the toxicity is discovered. If treatment is ongoing (for example, for systemic treatment of a brain tumor or Hodgkin lymphoma), discontinuation of therapy should be considered to prevent further potentially irreversible vision loss. Referral to and management by a retina specialist are recommended. (See 'Pigment changes, cotton wool spots, and hemorrhages' above.)
At maximally tolerated doses of 8 to 10 g daily, mitotane has uncommonly been associated with toxic retinopathy consisting of retinal hemorrhages, edema, and optic disc swelling (2 out of 139 and 3 out of 19 patients in two series [279,280]). Details on reversibility are unknown. We recommend referral to a specialist for evaluation and that consideration be given to stopping therapy if symptoms are severe and if the risks of ongoing therapy are thought to outweigh the benefits. (See 'Pigment changes, cotton wool spots, and hemorrhages' above and 'Macular edema, central serous retinopathy, and serous retinal detachment' above.)
All-trans retinoic acid — All-trans retinoic acid (tretinoin), which is used in the treatment of acute promyelocytic leukemia, is associated rarely with increased intracranial pressure and papilledema with splinter and flame hemorrhages [281,282]. Visual fields showed enlarged blind spots. Treatment with acetazolamide for increased intracranial pressure led to eventual resolution of papilledema. Final visual prognosis was good in the cases reported. Evaluation for and management of intracranial pathology are recommended in these cases. (See 'Optic nerve edema' above.)
Close follow-up with neuro-ophthalmology is recommended. Discontinuation of tretinoin may be needed if unable to manage elevated intracranial hypertension. The decision to stop or continue tretinoin must be individualized. The benefits of continuing tretinoin (particularly where no effective treatment alternative exists) must be weighed against the risks and consequences of ongoing toxicity. Optimally, this decision should be made jointly by the patient, the oncologist, and the neuro-ophthalmologist.
Tretinoin has not been associated with night blindness, but this side effect should be kept in mind given the occurrence in other members of its class, including fenretinide and isotretinoin [283-288].
Vincristine — Vincristine-based regimens are uncommonly associated with cranial nerve palsies, leading to poor extraocular movement and diplopia, and poor eyelid closure with facial nerve involvement [289-291]. There have been reports of improvement over time . Ocular involvement is likely a manifestation of known vincristine-associated neuropathy. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Vinca alkaloids'.)
Rarely, a toxic optic neuropathy is seen causing reduced vision [292,293]. With discontinuation of therapy, vision improvement has been reported . Histology showed loss of ganglion cells of the retina and atrophy of fibers of the optic nerve suggestive of direct toxicity .
We recommend discontinuation of therapy given the possibility of reversible cranial or optic nerve damage. However, the risks and benefits of stopping or continuing therapy should be made on an individual basis. Temporary monocular patching can relieve diplopia. If cranial nerve palsy is permanent, prism glasses or possibly surgical intervention can be tried. In the case of facial nerve palsy, frequent eye lubrication and possibly temporary tarsorrhaphy are recommended to prevent exposure keratopathy and complications. Referral to a specialist is recommended to follow these conditions.
SUMMARY AND RECOMMENDATIONS — Although relatively uncommon, ocular side effects from systemically administered chemotherapy (particularly targeted agents) can be severe, disabling, and irreversible. While some can be managed symptomatically while chemotherapy is continued, others can be vision threatening and warrant immediate discontinuation of the drug.
●When a patient receiving chemotherapy presents with a specific ocular sign or symptom, it is important to delineate whether the complaint is due to the malignancy itself, a paraneoplastic phenomenon, or an effect of cancer treatment. Intraocular metastasis occurs most commonly in the uveal tract and can cause overlying serous retinal detachment. A dilated fundus examination, along with ocular imaging, can help differentiate a metastasis from a drug side effect. (See 'Differentiating metastasis from drug toxicity' above.)
●Different compartments of the eye (figure 1) are preferentially affected by different agents. Presenting signs and symptoms can help localize which compartment of the eye (ie, the cornea, uvea [choroid, ciliary body, and iris], periocular and orbital tissue, retina, and/or optic nerve) is affected. (See 'Localizing the compartment affected by ocular toxicity' above.)
●Cornea and anterior segment toxicities are most common with the following agents (see 'Cornea and anterior segment' above):
•Targeted/immunotherapy agents – Epidermal growth factor receptor (EGFR) inhibitors (cetuximab, panitumumab, and erlotinib), the human epidermal growth factor receptor 2 (HER2) inhibitor trastuzumab, the BRAF inhibitor vemurafenib, the immune checkpoint inhibitor ipilimumab, small-molecule tyrosine kinase inhibitors (TKIs) targeting BCR-ABL kinase and KIT (nilotinib and imatinib), and tamoxifen. (See 'Molecularly targeted agents' above.)
●Uveitis is most common with the following agents (see 'Uveitis and ocular inflammation' above):
●Periocular toxicities are most commonly seen with the following agents (see 'Orbit and periorbital tissue' above):
●Retinal toxicities are most commonly seen with the following agents (see 'Retina' above):
•Targeted/immunotherapy agents – Ipilimumab, trastuzumab, vemurafenib, mitogen-activated protein kinase (MEK) inhibitors (trametinib, cobimetinib), erlotinib, steroid antagonists (tamoxifen and toremifene), and imatinib. (See 'Molecularly targeted agents' above.)
•Traditional chemotherapy – Platinum analogs (cisplatin, carboplatin, and oxaliplatin), antimetabolites (cytarabine and fludarabine), taxanes, mitotane, and the retinoic acid derivative all-trans-retinoic acid (tretinoin). (See 'Traditional chemotherapy agents' above.)
●Optic nerve toxicities are most common with the following agents (see 'Optic nerve' above):
•Traditional chemotherapy – Taxanes (docetaxel and paclitaxel), the vinca alkaloid vincristine, tretinoin, platinum analogs, carmustine, interferon, methotrexate, and mitoxantrone. (See 'Traditional chemotherapy agents' above.)
●Early referral to an ophthalmologist may help with management of eye symptoms.
●In the setting of ocular toxicity, the decision to stop or continue cancer therapy must be individualized. In many cases, the eye symptom can be managed symptomatically while the anticancer drug is continued. However, if vision is threatened, the benefits of continuing the specific chemotherapy drug (particularly where no effective treatment alternative exists) must be weighed against the risks and consequences of ongoing ocular toxicity. Optimally, this decision should be made jointly by the patient, the oncologist, and the ophthalmologist.
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jose S Pulido, MD, MS, MPH, who contributed to an earlier version of this topic review.