Ocular side effects of anticancer agents used in the treatment of gynecologic cancers

Abstract

The treatment landscape of gynecologic cancers has expanded in recent years to include targeted and immune-based therapies. These therapies often have ocular side effects not seen with conventional chemotherapies, some of which can cause significant visual impairment if not recognized in a timely fashion. Clinicians must know how to appropriately identify, mitigate, and treat these ocular adverse events. Management often involves working with an interdisciplinary team of eye specialists, and it is important to know when to refer patients for specialized care. Proactive identification of eye specialists, especially in rural and community settings where access to care can be limited, may be necessary. Here, we discuss the management of common ocular toxicities seen with novel anticancer agents used to treat gynecologic cancers.

1. Introduction

The treatment landscape of many cancers has changed dramatically in the last decade. While previously chemotherapy was the mainstay of systemic cancer treatment, targeted therapies and immunotherapies have emerged, ushering in a new treatment era with improved survival outcomes. Targeted therapies and immunotherapies have now been approved for the treatment of cervical, ovarian, and endometrial cancers [1–3]. Although these agents are purported to have less off-target toxicity compared to conventional chemotherapies [4,5], they are often associated with significant on-target, off-tumor toxicity. The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) have published guidelines on how these toxicities can be managed [5,6].

Targeted therapies and immunotherapies can cause ocular adverse events that may require multidisciplinary care by a team of eye specialists [7]. Given the increasing use of these agents, clinicians must have a good understanding of the unique ocular toxicities associated with their use. Established referral networks are required, particularly in community and rural settings where access to eye specialists may be limited. In this narrative review, we discuss common ocular toxicities seen with novel anticancer agents used to treat gynecologic cancers. We review ocular monitoring, preemptive mitigation strategies, and management of eye toxicities, as well as highlight when urgent referral to an eye specialist is required.

2. Antibody-drug conjugates

Antibody-drug conjugates (ADCs) are comprised of a target-specific monoclonal antibody chemically linked to a potent anticancer agent [8,9]. There are currently 11 anticancer ADCs approved by the US Food and Drug Administration (FDA), including 3 for gynecologic cancers (tisotumab vedotin-tftv, mirvetuximab soravtansine-gynx, famtrastuzumab deruxtecan-nxki), and 2 for other indications but which have been studied in gynecologic cancers (ado-trastuzumab emtansine and sacituzumab govitecan-hziy). Ocular toxicity from ADCs varies according to the target antigen, antibody, linker, and cytotoxic payload (ie, highly toxic cargo) [10–12]. Although eye toxicity is common and usually easily managed, it is important the healthcare team and the patient are aware of the need for prompt ophthalmic evaluation when new ocular symptoms and/or signs present, as these may warrant dose interruption, reduction, or discontinuation of the ADC, in addition to early intervention with supportive measures.

Tisotumab vedotin-tftv binds to tissue factor on target cells and, upon internalization, releases monomethyl auristatin E (MMAE), a microtubule-disrupting agent, resulting in cell cycle arrest and apoptotic cell death [11]. Tisotumab vedotin received full approval from the FDA in April 2024 for the treatment of persistent/recurrent cervical cancer that progressed on or after chemotherapy [11]. On the innovaTV 204/GOG-3023/ENGOT-cx6 trial, half of patients experienced eye toxicity, mostly low grade, including conjunctivitis (26%), dry eye (23%), and keratitis (11%) [11]. All patients in the trial followed a standardized eye care plan, which included steroid eye drops prior to start of infusion and for 72 h after, ocular vasoconstrictor eye drops prior to infusion, eye cooling pads during the entire infusion, preservative-free lubricating drops at the start of treatment to 30 days after end of treatment, and avoidance of contact lens. Following the above mitigation strategies, only two patients (2%) had grade 3 events (ulcerative keratitis), one of whom required a corneal transplant, although the relative benefit of each measure was unclear. Median time to onset of the first event was 1.4 months (interquartile range, 0.7–2.0), and median time to resolution of each event was 0.7 months (interquartile range, 0.3–1.6) [11]. In the phase 3 study of tisotumab vedotin versus investigator’s choice chemotherapy in recurrent or metastatic cervical cancer, 50.4% of patients experienced ocular side effects, 3.2% of which were grade ≥ 3. The most common were conjunctivitis (30.4%), keratitis (15.6%), and dry eye (13.2%), and 5.6% of patients discontinued treatment due to ocular adverse events [13]. In a phase 2 study examining tisotumab vedotin in combination with carboplatin, pembrolizumab, or bevacizumab for recurrent or metastatic cervical cancer, grade ≥ 3 ocular side effects were rare, occurring in 6.1% of patients (ulcerative keratitis in the tisotumab vedotin and carboplatin arm only) [14]. Collectively, across clinical trials, grade 3 ocular events occurred in 3.3% of patients, including severe ulcerative keratitis in 1.2% of patients, prompting close ocular monitoring for this drug, which is now required by the FDA [15].

The monoclonal antibody for mirvetuximab soravtansine-gynx is directed against folate receptor α (FRα) and connected through a cleavable linker to the maytansinoid DM4 payload, a potent tubulin-targeting antimitotic agent [16,17]. Mirvetuximab soravtansine-gynx was granted full FDA approval in March 2024 for patients with FRα-high expressing platinum-resistant ovarian cancer who have received up to 3 prior therapies [12]. In the SORAYA study, ocular adverse events included blurred vision (41%, all grades; 6%, grade 3; 0%, grade 4), keratopathy (29%, all grades; 8%, grade 3; 1%, grade 4), and dry eye (25%, all grades) [12]. Median time to onset was 1.3 months (range, 0.0–9.9) and 1.5 months (range, 1.1–8.6) for blurred vision and keratopathy, respectively. Overall, 11% of patients required dose reductions for ocular toxicity; although, only 1 patient (< 1%) required treatment discontinuation because of an ocular treatment-emergent adverse event. No corneal ulcers or corneal perforations were identified, and no patients had permanent ocular sequelae at data cutoff [12].

The FORWARD 1 study, a phase 3 study of mirvetuximab soravtansine-gynx versus chemotherapy in 366 patients with platinum-resistant ovarian cancer, reported similar rates of ocular toxicity. Blurred vision (42%, all grades; 2.5%, grades ≥ 3) and keratopathy (32.5%, all grades; 1.2%, grades ≥ 3) were the most frequent adverse events leading to dose delays and/or reductions, which occurred in 19.8% of patients [18]. The phase 3 MIRASOL study reported a rate of 56% of ocular toxicity across all grades, with 14% being grade 3 [16].

Up to 40% of patients treated with these ADCs experience corneal toxicity, which is commonly described as corneal epithelial microcysts. Microcyst-like epithelial changes (MECs) develop in the epithelial layer of the cornea. These spherical cysts do not stain with fluorescein dye and are best visualized with a parallelepiped slit lamp beam or indirect illumination (Fig. 1). Ocular dryness with resulting corneal staining and refractive error changes can occur. Hyperopic shifts are seen in early treatment, while myopic changes are more common in later treatment [8]. The resulting decreased vision from corneal staining and refractive shifts generally reverse with cessation of the ADC. The mechanism for the development of MECs is not well understood. Recent literature suggests that the ADC enters the corneal epithelial cells, causing them to become apoptotic (observed as MECs), and then eventually shed and be replaced by new epithelial cells [19].

Fig. 1.

Corneal microcyst-like epithelial changes (blue arrow) in a patient with antibody-drug conjugate-related keratopathy.

There is no treatment for MECs, and they are often observed in the absence of visual changes. MECs typically resolve within weeks to months following cessation of the ADC. Symptoms of dry eyes and keratopathy can be very bothersome to patients and often require input from an eye care specialist. Treatment of dry eye includes preservative-free artificial tears at least 3 times daily, and if needed, cyclosporine ophthalmic solution, emulsion, and/or lifitegrast ophthalmic solution. Blepharitis can be treated with lid hygiene and warm compresses. Treatment of uveitis or conjunctivitis includes corticosteroid drops. The use of contact lenses is not recommended given concern that the ADC will sit in the tear film and absorb into the contact lens, exacerbating any keratopathy; although, this has not been formally studied. Contact lenses may still be used under the supervision of an eye care provider. There are similar concerns regarding the use of punctal plugs. If vision is severely impacted with or without moderate-to-severe keratopathy, the ADC should be held, or on a case-by-case basis, the dose reduced, as deemed appropriate by the oncologist.

Baseline eye examination is critical to ensure the cornea is healthy and to note any other ocular pathology. Patients should be educated thoroughly on possible ocular side effects (including blurred vision and dry eye) prior to starting an ADC. Changes to the cornea are generally reversible and rarely cause permanent changes in vision. Both tisotumab vedotin-tftv and mirvetuximab soravtansine-gynx have FDA black box warnings requiring ocular toxicity monitoring at baseline, and for tisotumab vedotin-tftv prior to each cycle for the first 9 cycles and as clinically indicated, and for mirvetuximab soravtansine-gynx prior to every other cycle for the first 8 cycles and as clinically indicated thereafter [15,20].

Patients on tisotumab vedotin-tftv are required to instill vasoconstricting eye drops immediately prior to each infusion and corticosteroid drops on days 1 to 3 (starting prior to infusion and continuing through day 3 of each treatment cycle), as well as to use cooling eye pads during the infusion [15]. Patients on mirvetuximab soravtansine-gynx are required to use corticosteroid drops on days 1 through 8 of each treatment cycle (1 drop in each eye 6 times daily starting the day prior to each infusion for 5 days, and then reducing to 4 times daily for another 4 days) [20]. The use of lubricating preservative-free eye drops is recommended for both ADCs. Patients should be educated to wait at least 10 min after administering medicated eye drops before using lubricating eye drops. These recommendations are summarized in Table 1.

Table 1. Medications, adverse events, and management.

Class	Names	Ocular toxicity	Pre-treatment	During treatment	End of treatment	Mitigation	Management
Antibody-drug conjugates	Mirvetuximab soravtansine-gynx	Keratopathy MECs Dry eye Uveitis (< 1%)	Baseline eye exam required (comprehensive eye exam, including slit lamp, visual acuity and dilation)	Eye exam required every other cycle for first 8 cycles, and as indicated thereafter.	Not required, but patient may need to be followed until resolution of ocular symptoms, if any	Corticosteroid drops on days −1 to 8 of each treatment cycle (1 drop in each eye 6 times daily starting the day prior to each infusion for 5 days, and then reducing to 4 times daily for another 4 days * ) Lubricating drops	Treat dry eye with preservative free artificial tears. Withhold for grade ≥ 2 ocular toxicity until improvement and resume at same or reduced dose Discontinue for grade 4 toxicities Treat uveitis with topical steroid drops. Check intraocular pressure with use of topical steroids. Additional information found here .
	Tisotumab vedotin-tfv	Conjunctivitis Keratopathy MECs Dry eye		Eye exam required before each cycle for first 9 cycles, and as clinically indicated. dose (usually every 3 weeks), and then as clinically indicated thereafter.		Vasoconstricting eye drops immediately prior to each infusion * Corticosteroid drops days 1–3 (starting prior to the infusion and continuing through day 3 of each treatment cycle) * Cooling eye pads during the infusion * Lubricating drops	Treat dry eye with preservative free artificial tears Withhold for grade ≥ 2 ocular toxicity until improvement and resume at the same or reduced dose Treat conjunctivitis with topical steroids. Check intraocular pressure with use of topical steroids. Blepharitis: lid hygiene and warm compresses Additional information found here .
	Sacituzumab govitecan	Ocular toxic effects (unspecified)	No baseline eye exam required	As clinically indicated, if visual symptoms occur		Not required	Dry eye/keratopathy: preservative-free artificial tears
	Ado-trastuzumab emtansine	Increased lacrimation Dry eye Conjunctivitis
	Fam-trastuzumab deruxtecan-nxki	Dry eye
ALK inhibitors	Crizotinib Brigatinib	Trailing lights Flashes Photopsia	No baseline eye exam required	As clinically indicated, if visual symptoms occur	Not required, but patient may need to be followed until resolution of ocular symptoms, if any	Not required	Grade 1: continue drug. Ocular symptoms known to improve over time Hold for grade 2 or 3 ocular toxicity unless resolves to grade 1 Discontinue for grade 4
BRAF inhibitors	Vemurfenib Encorafenib Dabrafenib	Uveitis Dry eye Conjunctivitis Squamoproliferative lesions When used in combination with MEK inhibitors: Macular edema, retinal vein occlusion	Baseline eye exam is preferred (comprehensive exam including dilation)	Every 3–6 months and/or at onset of visual symptoms	Not required, but patient may need to be followed until resolution of ocular symptoms, if any	Not required	Dry eye: artificial tears Uveitis: topical, periocular, or intraocular corticosteroids in addition to cessation, pause, or continue drug therapy at a lower dose Squamoproliferative lesions: surgical excision
VEGF inhibitors	Pazopanib	Retinal detachments	Baseline eye exam is not required	As clinically indicated, if visual symptoms occur	Not required, but patient may need to be followed until resolution of ocular symptoms, if any	Not required	Withhold for ocular toxicities until improvement and resume at the same or reduced dose
HER2 monoclonal antibody	Trastuzumab Pertuzumab	Dry eye Conjunctivitis Crystalline keratopathy Corneal ulcers Blurred vision	Baseline eye exam is not required	As clinically indicated, if visual symptoms occur	Not required, but patient may need to be followed until resolution of ocular symptoms, if any	Not required	Dry eye: artificial tears Conjunctivitis: topical steroids
Immune checkpoint inhibitors	Pembrolizumab Dostarlimab Nivolumab Avelumab Cemiplimab	Anterior and posterior uveitis Conjunctivitis Keratitis Retinopathy/retinitis Orbital myositis Optic neuritis	Baseline eye exam is not required	At onset of visual symptoms	Not required, but patient may need to be followed until resolution of ocular symptoms, if any	Not required	Immediate evaluation by ophthalmology and if inflammation detected, topical periocular or oral steroids may be started. This may be escalated to other immunomodulation
MEK inhibitors	Trametinib Cobimetinib Selumetinib Binimetinib	MEK inhibitor-associated retinopathy Retinal vein occlusion	Baseline eye exam is preferred (comprehensive exam including dilation)	Every 3–6 months and/or at onset of visual symptoms	Not required, but patient may need to be followed until resolution of ocular symptoms, if any	Not required	MEK inhibitor-associated retinopathy: continue drug and monitor carefully unless specified otherwise by drug company instructions. Retinal vein occlusion: anti-VEGF injections and likely permanent discontinuation of drug
SERMs	Tamoxifen Toremifene	Corneal deposits Macular edema Cataracts	Baseline eye exam is preferred (comprehensive exam including dilation)	At onset of visual symptoms or every 6–12 months during treatment	Not required but patient may need to be followed until resolution of ocular symptoms, if any	Not required	Corneal deposits: continuation of drug is safe Macular edema/retinal deposits: discontinuation of the drug if changes in vision. Cataracts: may require surgery
Aromatase inhibitors	Anastrozole Letrozole Exemestane	Dry eyes Uveitis Crystalline retinopathy Macular edema Retinal detachment	Baseline eye exam is not required	At onset of visual symptoms	Not required, but patient may need to be followed until resolution of ocular symptoms, if any	Not required	Dry eye: artificial tears and lubricants Uveitis: topical corticosteroids Macular edema: immediate cessation of therapy and referral to an ophthalmologist Retinal detachment: immediate cessation of therapy and referral to an ophthalmologist
PARP inhibitors	Niraparib Olaparib Rucaparib	Blurred vision related to hypertension/ posterior reversible encephalopathy	Baseline eye exam is not required	At onset of visual symptoms	Not required, but patient may need to be followed until resolution of ocular symptoms, if any	Not required	Hold drug. Treat any hypertension. May require evaluation by an ophthalmologist

ALK, anaplastic lymphoma kinase; VEGF, vascular endothelial growth factor; MEK, mitogen-activated protein kinase; SERM, selective estrogen receptor modulator; PARP, poly ADP-ribose polymerase; MEC, microcyst-like epithelial change.

^*These mitigation strategies are recommended per the US Food and Drug Administration although there is not sufficient evidence to suggest these measures have an impact on incidence or severity of ocular side effects.

Results of the eye examination, including ocular toxicity grading, and any new ocular symptoms must be reported to the oncologist prior to each treatment. Topical steroids have ocular side effects, such as elevated intraocular pressure (which can be vision-threatening in approximately 5% of patients if left untreated) and cataracts; therefore, it is advisable to include an eye care professional on the treating team.

Other ADCs used in the treatment of gynecologic cancers cause ocular toxicity less often and therefore do not require baseline eye examinations or close monitoring during treatment. Ado-trastuzumab emtansine links trastuzumab coupled via a noncleavable thioether linker to 3 to 4 molecules of the maytansine derivative DM1 [21]. It is currently FDA approved for patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, and a previous study investigating its use in other populations found that 8 of 10 patients with ovarian or uterine cancer achieved stable disease [21]. Increased lacrimation (3.9%), dry eye (3.9%), blurred vision (4.5%), and conjunctivitis (3.9%) have been reported with adotrastuzumab emtansine [22].

Fam-trastuzumab deruxtecan-nxki, another anti-HER2 ADC, consists of a humanized anti-HER2 monoclonal antibody linked to a topoisomerase I inhibitor payload through a tetrapeptide-based cleavable linker. It is approved for the treatment of metastatic, HER2-positive breast cancer [23], and recently, the DESTINY study demonstrated efficacy in HER2-low breast cancer [23]. This ADC is now listed in the NCCN Compendium based on results of the phase 2 DESTINY-PanTumor02 study, which included patients with HER2-positive cervical, endometrial, or ovarian cancer [24]. On April 5, 2024, fam-trastuzumab deruxtecan-nxki received accelerated tumor-agnostic FDA approval for unresectable or metastatic HER2-positive (immunohistochemistry 3+) solid tumors. Fam-trastuzumab deruxtecan-nxki has been associated with an 11% incidence of dry eye, 0.4% of which were grade ≥ 3 [25]. Blurred vision and visual impairment occurred in 3.5% to 4.9% of patients across trials [25].

Sacituzumab govitecan-hziy consists of SN-38 (an active metabolite of irinotecan), a topoisomerase I inhibitor, coupled to the humanized antitrophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody hRS7 IgG1κ through the cleavable CL2A linker [26]. It is FDA approved in breast and urothelial carcinomas. A phase 2 study investigated its use in patients with recurrent endometrial carcinoma overexpressing Trop-2 [26]. Ocular toxicity was noted in 5% and 4% of participants in the sacituzumab govitecan-hziy arms of the phase 3 ASCENT (metastatic triple-negative breast cancer) [27] and TROPHY-U-01 (locally advanced or metastatic urothelial carcinoma) studies, respectively [28].

3. Additional HER2 inhibitors

HER2 is part of the epidermal growth factor receptor (EGFR) family, which includes epidermal EGFR/HER1, HER2, HER3, and HER4 [29]. These oncoproteins play a role in controlling cell growth, survival differentiation, and migration. HER2 (ERBB2) is amplified in 17% to 33% of carcinosarcomas, in uterine serous carcinoma, and in a subset of high-grade endometrioid endometrial tumors [30]. There are numerous HER2-targeted therapies approved by the FDA, mostly for the treatment of breast cancer, including lapatinib, trastuzumab, pertuzumab, neratinib, margetuximab, tucatinib, and fam-trastuzumab deruxtecan-nxki. Combination carboplatin, paclitaxel, and trastuzumab is recommended as first-line systemic therapy for stage III/IV HER2-positive uterine serous carcinoma and HER2-positive carcinosarcoma [2]. Trastuzumab, fam-trastuzumab deruxtecan-nxki (discussed above), and pertuzumab have had documented ophthalmic side effects, while lapatinib, neratinib, magetuximab, and tucatinib have no documented ocular side effects in the literature or by the FDA [31].

Trastuzumab has been associated with dry eye, increased lacrimation (21%), conjunctivitis (2.5%), blurry vision, crystalline keratopathy, and corneal ulcers [9,31,32]. In a systematic review by Huillard et al., analysis of agency labels identified rare but devastating ocular events after trastuzumab treatment, including macular ischemia, retinal detachment, retinal hemorrhage, retinal artery occlusion, and retinal vein occlusion [9,32–34]. The FDA reported a 14% incidence of increased lacrimation in trials of pertuzumab for the treatment of breast cancer [35]. Two incidences of blurry vision in Chinese patients following pertuzumab administration have also been reported [36]. Topical treatment with autologous serum was described in a case report as a treatment strategy to manage trastuzumab-related corneal ulceration [32].

4. Anaplastic lymphoma kinase inhibitors

Anaplastic lymphoma kinase (ALK) inhibitors are tyrosine kinase inhibitors used to treat ALK-positive non-small cell lung cancer and rare solid tumors with ALK translocations, including uterine inflammatory myofibroblastic tumors. Examples of FDA-approved ALK inhibitors include alectinib, brigatinib, ceritinib, lorlatinib, and crizotinib [2].

Crizotinib has been shown to cause visual disturbances in 65% of patients, including trailing lights, flashes, and brief image persistence [37]. Onset begins within the first week of treatment and episodes last for approximately 1 min. The symptoms of photopsia are similar to those of an impending retinal detachment, and patients should be examined by an eye care professional to ensure no retinal abnormalities are present. There is no known treatment for these visual symptoms, but they often improve over time on the ALK inhibitor. Discontinuation of crizotinib is recommended in the event of severe vision loss. Brigatinib should be held for Common Terminology Criteria for Adverse Events (CTCAE) version 5 grade 2 or 3 ocular toxicity until vision loss resolves to grade 1, and drug should be discontinued for grade 4 toxicity [38].

5. BRAF inhibitors

BRAF inhibitors are approved for the treatment of BRAF v600E-mutant melanoma [39]. These agents selectively target BRAF kinase, interfering with the mitogen-activated protein kinase (MAPK) signaling pathway, which regulates the proliferation of melanoma cells [39,40]. These drugs are now often prescribed in combination with MEK inhibitors, thereby increasing the probability of ocular toxicity. Examples of FDA-approved BRAF inhibitors include vemurafenib, dabrafenib, and encorafenib. These agents are also used in low-grade serous ovarian cancer [41–43]. In addition, dabrafenib used in combination with trametinib (a MEK inhibitor) showed activity in recurrent low-grade serous ovarian cancer for BRAF-V600E-positive tumors, and is a guideline-approved treatment [39,44]. BRAF inhibitors can also be used to treat BRAF v600E-mutant vulvar or vaginal melanoma [45].

A retrospective review of clinical study reports found that ocular toxicities occurred in 22% of patients who received vemurafenib [46]. The most common ocular toxicities were uveitis (ranging from anterior to posterior) and dry eye/conjunctivitis, which occurred in approximately 4% to 9% and 2% of patients, respectively [46,47]. A total of 3 patients discontinued vemurafenib during the study period due to ocular adverse events, which included unilateral ischemic central retinal vein occlusion (1 patient), diplopia (1 patient), and persistent ocular hyperemia and conjunctivitis that continued after the study (1 patient) [46]. These agents may also cause cutaneous squamous cell carcinoma, verruca vulgaris lesions, and keratoacanthoma on the eyelid (Fig. 2) [48].

Fig. 2.

Eyelid verruca in a patient treated with a BRAF inhibitor. This figure was published in Cancer, 121(1), Belum VR, Rosen AC, Jaimes N, Dranitsaris G, Pulitzer MP, Busam KJ, Marghoob AA, Carvajal RD, Chapman PB, Lacouture ME, Clinico-morphological features of BRAF inhibition-induced proliferative skin lesions in cancer patients, 60–68, Copyright Wiley (2014). Reproduced with permission.

Dry eye symptoms are generally mild and often do not require intervention or can be managed with artificial tears. Depending on the location of the uveitis, it can be treated with topical, periocular, or intraocular corticosteroids, in addition to cessation, pause, or continued drug therapy (at same or lower dose). This treatment is given under the management of an eye care professional. Any symptoms of eye redness, pain, sensitivity to light, or blurry vision should be evaluated by an ophthalmologist or optometrist, because prompt treatment of uveitis is imperative to prevent lasting consequences to vision.

Encorafenib’s label specifies it should be withheld for grade 1 or 2 uveitis that does not respond to ocular treatment, or for any grade 3 uveitis. Squamoproliferative lesions (particularly squamous cell carcinoma) should be referred for surgical excision, and patients are often able to continue drug therapy. Encorafenib’s label also specifies that ophthalmologic evaluation should be performed at regular intervals and for any new or worsening disturbances. Clinically or visually significant findings, including ocular toxicity grading, must be reported to the oncologist, as they may impact dosing and treatment.

Case reports of combined trametinib and dabrafenib therapy have described instances of uveitis, macular edema, and retinal vein occlusion [49–51]. All patients treated with BRAF inhibitors should be assessed for visual symptoms at each visit. Toxicity related to MEK inhibitors is discussed separately.

6. Vascular endothelial growth factor inhibitors

Vascular endothelial growth factor (VEGF) and angiogenesis are important promoters of cancer growth and progression. VEGF participates in the initial stage of tumor development, progression, and metastasis [52]. Bevacizumab is a recombinant humanized monoclonal IgG1 antibody directed against VEGF-A [52]. It is approved in combination with chemotherapy for patients with ovarian [52] or cervical cancer [53].

No ocular toxicity was noted in large phase 3 studies of bevacizumab. Endophthalmitis, iritis, vitritis, retinal detachment, increased intraocular pressure, and ocular hyperemia are all cited as possible side effects in the post-marketing literature [9,54]; however, these side effects appear to be associated with intravitreal administration of bevacizumab and are more likely related to the intraocular injection procedure, rather than the drug. Patients treated with bevacizumab do not need routine ophthalmological examinations, but oncologists should be aware of the above incidences and seek ophthalmological input if any changes in vision are reported.

Pazopanib, a tyrosine kinase inhibitor of VEGF receptor (VEGFR) used to treat sarcomas [2], has been associated with retinal detachment [55].

7. Immune checkpoint inhibitors

Immunotherapy has become a major pilar of cancer care in the last decade. For many patients with advanced cancer, it offers durable responses and, in some cases, possible cure. There are 3 main classes of immune checkpoint inhibitors (ICIs), which act by potentiating the immune system to attack cancer cells, including cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death-ligand 1 (PD-L1) inhibitors. There are numerous FDA-approved ICIs, including ipilimumab, tremelimumab, pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, dostarlimab and durvalumab. In gynecologic oncology, pembrolizumab, dostarlimab, cemiplimab, nivolumab, and avelumab are used most often.

By unleashing the immune system to attack cancer cells, ICIs can also cause an inflammatory reaction in healthy cells, thereby resulting in immune-related adverse events. Ocular immune-related adverse events occur in approximately 1% of patients. Inflammation of any part of the eye is possible with ICI treatment. Potential adverse events include blepharitis, conjunctivitis, keratitis, uveitis (anterior or posterior), vitritis, retinitis, orbital myositis (Graves’ ophthalmopathy), cranial neuritis, and optic neuritis (Fig. 3) [56,57].

Fig. 3.

Bilateral optic neuritis in a patient treated with immunotherapy.

Pembrolizumab, a PD-1 inhibitor, was the first drug to be granted tumor-agnostic approval from the FDA. It is approved for the treatment of recurrent tumor mutational burden–high solid tumors and mismatch repair-deficient endometrial cancer [58,59]. Pembrolizumab was approved in June 2024 as a first-line regimen for recurrent and/or metastatic endometrial carcinoma in combination with paclitaxel and carboplatin, and is also FDA approved as a second-line regimen for mismatch repair-proficient tumors in combination with lenvatinib (VEGFR1, VEGFR2, and VEGFR3 kinase inhibitor) [59,60]. In PD-L1-positive cervical carcinoma, pembrolizumab is also used in the first-line setting in combination with platinum-based chemotherapy. More recently, it was approved in combination with chemoradiotherapy for locally advanced stage III/IV disease. [61] Pembrolizumab has been associated with anterior and posterior uveitis, conjunctivitis, retinopathy, and inflammatory orbital disease (Graves’ disease, myasthenia gravis) [31,62].

Dostarlimab is also a PD-1 inhibitor approved in combination with carboplatin and paclitaxel for first-line and subsequent-line systemic therapy for endometrial carcinoma [2,59]. It is also approved as a biomarker-directed therapy in mismatch repair-deficient/ microsatellite instability-high ovarian and endometrial carcinomas. No ocular adverse effects were reported in large clinical trials, but the FDA label for dostarlimab lists uveitis, iritis, and other ocular inflammatory toxicities as potential side effects [63,64]. Nivolumab, another PD-1 inhibitor, is approved for the treatment of melanoma [58]. Dry eye, uveitis, and optic neuritis are the most commonly reported ocular adverse events with use of nivolumab [31,62]. Uveitis has been cited as a possible adverse event with the anti-PD-L1 inhibitor avelumab [31]. Cemiplimab is a PD-1-blocking monoclonal antibody [65] recommended for the treatment of cervical cancer in the second-line setting [1]. While its FDA label warns of possible uveitis, iritis, other ocular inflammatory toxicities, and retinal detachment, a phase 3 study in recurrent cervical cancer including 604 patients did not report ocular adverse events [65].

Treatment of anterior segment inflammation includes topical corticosteroid drops (i.e., prednisolone acetate ophthalmic suspension 4 times daily in both eyes). Treatment of posterior segment inflammation, including optic neuritis, involves systemic steroid treatment with a slow taper (i.e., treatment of optic neuritis in a 60 kg patient may begin with 1 mg/kg [60 mg] prednisone by mouth for 2 weeks, then 40 mg for 2 weeks, then decrease by 10 mg for 2 weeks, then keep at 5 mg or 2.5 mg for 2–4 weeks each). Multiple sclerosis-dosed IV methylprednisolone may also be used to treat optic neuritis. Taper is dependent on response to treatment and should be co-managed by the oncologist and ophthalmic team. Prolonged courses of steroids warrant pneumocystis jirovecii pneumonia prophylaxis. If there is no improvement in ocular condition, the drug should be discontinued. Before attributing the ocular condition to drug toxicity, other inflammatory/infectious etiologies should be ruled out with bloodwork, such as sedimentation rate, C-reactive protein, herpes simplex virus 1/2 titer, rheumatoid factor, QuantiFERON-TB, rapid plasma reagin, antineutrophil cytoplasmic antibody and Lyme titers, if applicable, and any case of orbital or optic nerve involvement should have magnetic resonance imaging of brain and/or orbits.

Patients who develop blurred vision, pain, or redness should be seen promptly, including dilated fundus examination. Special attention to the anterior chamber and vitreous will help detect subtle inflammation. Clinically or visually significant findings, including ocular toxicity grading, must be reported to the oncologist, as it may impact dosing and treatment.

8. Mitogen-activated protein kinase inhibitors

MEK inhibitors work by blocking the MAPK pathway, which is often dysregulated in human cancers. These drugs are used to treat BRAF v600E-mutant melanoma, histiocytic neoplasms, and neurofibromatosis type 1. Many MEK inhibitors are now used in combination with BRAF inhibitors for the treatment of certain cancers, increasing the probability of ocular toxicity; for example, MEK inhibitors are being used in low-grade serous ovarian cancer, both alone and in combination with BRAF inhibitors. Examples of FDA-approved MEK inhibitors include trametinib, cobimetinib, selumetinib, and binimetinib.

MEK inhibitor-associated retinopathy (MEKAR) is an ocular phenomenon associated with MEK inhibitor use. It may occur within the first week of the first dose of MEK inhibitor therapy. MEKAR is characterized by bilateral, yellow-grey elevations of the retina, circular in configuration without inferior tracking [66]. Optical coherence tomography (OCT) can reveal fluid between the interdigitation zone and retinal pigment epithelium in varying configurations (Fig. 4). Overall, 48% of patients with MEKAR will report blurred vision and/or metamorphopsia or seeing a “bubble” in their vision [66]. Retinal vein occlusion can also occur, with an incidence of 0.2%; predisposing risk factors include glaucoma, methylenetetrahydrofolate reductase polymorphism, uncontrolled hypertension, and diabetes mellitus [66,67].

Fig. 4.

Optical coherence tomography (OCT) reveals fluid between the interdigitation zone and retinal pigment epithelium in varying configurations, in a patient with MEK inhibitor-associated retinopathy (MEKAR). This figure was published in Ophthalmology, 124(12), Francis JH, Habib LA, Abramson DH, Yannuzzi LA, Heinemann M, Gounder MM, Grisham RN, Postow MA, Shoushtari AN, Chi P, Segal NH, Yaeger R, Ho AL, Chapman PB, Catalanotti F, Clinical and Morphologic Characteristics of MEK Inhibitor-Associated Retinopathy: Differences from Central Serous Chorioretinopathy, 1788–1798, Copyright Elsevier (2017). Reproduced with permission.

In patients who present with MEKAR, the drug label instructions should be followed for ocular toxicity. Specifically, trametinib and cobimetinib should be withheld in a patient with MEKAR, but the patient may resume the drug if fluid resolves within 3 to 4 weeks [66]. Patients taking binimetinib must pause the drug only if they develop MEKAR that causes unusually significant vision symptoms; however, patients with MEKAR may continue the drug and be monitored every 2 to 3 weeks. Retinopathy typically resolves even as patients remain on drug.

Patients who develop retinal vein occlusion may require treatment with intravitreal anti-VEGF injections and will typically need to discontinue the drug. Patients should be monitored regularly and should be seen immediately if there is a change in vision. As with other types of agents, it is critical that clinically or visually significant findings, including ocular toxicity grading, are reported to the oncologist since they can impact dosing and treatment.

9. Selective estrogen receptor modulators

Selective estrogen receptor modulators (SERMs) regulate estrogen action by binding to estrogen receptors (ERs) and exert agonistic or antagonistic effects depending on the target tissue [68]. SERMs are typically used to treat cancers such as ER-positive breast cancer or metastatic breast cancer. Examples of FDA-approved SERMs include tamoxifen and toremifene. Tamoxifen may also be used in ovarian cancer [69–71]. SERMs are known to have deleterious effects in endometrial cancer due to the agonistic effect of SERMs in endometrial cells [72]; however, SERMs are also useful in endometrial cancer, specifically in recurrent or metastatic endometrial stromal sarcomas and low-grade endometrioid cancer [73–75].

Asymptomatic corneal deposits may occur in patients using SERMs, although the incidence is < 0.7% [76]. The development of cataracts has also been associated with these drugs (3.7% for toremifene and 3.2% for tamoxifen) [76]. Although rare, this drug class may also cause irreversible refractile retinal deposits, more commonly as the total cumulative dose reaches 100 g [77], which can lead to macular edema and affect vision [78].

If corneal deposits occur, continuation of the drug is likely safe but follow-up with an ophthalmologist is advised. There is no proven treatment for macular edema associated with tamoxifen other than discontinuation of the drug. Patients with macular edema should be monitored regularly, and immediately if they experience changes in vision. Clinically or visually significant findings, which include ocular toxicity grading, should be reported to the oncologist immediately since dosing and treatment may be affected.

10. Aromatase inhibitors

Aromatase inhibitors are another type of endocrine therapy, most commonly used in the treatment of ER-positive breast cancer or metastatic breast cancer in postmenopausal women or premenopausal women with ovarian suppression [79]. They act by inhibiting the action of aromatase, which converts androgens to estrogen. Examples of FDA-approved aromatase inhibitors include anastrozole, letrozole, and exemestane. In the context of gynecologic oncology, aromatase inhibitors are used in recurrent or metastatic endometrioid endometrial and ovarian cancers, low-grade serous ovarian cancer, and endometrial stromal sarcomas [70,79].

Ocular surface disease, including corneal epithelial changes, blepharitis, and keratitis, have been reported with all 3 of the aforementioned aromatase inhibitors [80,81]. Aromatase inhibitors most frequently cause dry eye symptoms associated with meibomian dysfunction [80,81], although there have been reports of more severe events such as retinal detachment, recurrent uveitis, crystalline retinopathy, and macular edema [80,81].

Dry eye symptoms can be managed with artificial tears and lubricants and typically do not interrupt continuation of therapy. In the case of more severe events, patients are advised to stop the causative aromatase inhibitor. Although ocular side effects are rare with these drugs, it is imperative that patients are counselled on the possibilities of such side effects and the importance of alerting their clinician as soon as they occur.

11. Poly ADP-ribose polymerases inhibitors

Poly ADP-ribose polymerase (PARP) inhibitors are a family of proteins involved in DNA damage repair, especially in repair of single-stranded breaks [82]. When a DNA replication fork encounters a persistent single-stranded break, it may stall and result in either fork collapse or the formation of a double-stranded break. These double-stranded breaks cannot be repaired by the defective homologous recombination pathway in BRCA-mutated cells, resulting in cell death [82].

Niraparib, olaparib, and rucaparib are PARP inhibitors approved for the treatment of ovarian cancer. Very little ocular toxicity has been reported with PARP inhibitors [31]. In a phase 1 trial of olaparib in patients with relapsed chronic lymphocytic leukemia, T-prolymphocytic leukemia, or mantle-cell lymphoma, 1 patient developed an eye infection [83]. The label for niraparib warns that patients may experience blurred vision as a symptom of posterior reversible encephalopathy syndrome, which occurs in 0.1% of patients [84,85].

12. Conclusion

Ocular toxicity is increasingly seen in patients treated for gynecologic cancers as newer targeted agents emerge. It is crucial to conduct baseline ocular examinations when appropriate and diligently monitor patients throughout their treatment, following the outlined protocols. Failing to promptly identify ocular toxicity can result in significant and enduring consequences. Educating patients about potential side effects and emphasizing the significance of reporting any visual changes to their oncology team are essential. Managing severe ocular toxicity necessitates consultation with eye care specialists.

HIGHLIGHTS.

• Novel targeted and immunological agents may cause ocular toxicity.

• Eye examination and mitigation strategies are required for some of these agents.

• Prompt recognition and appropriate management of ocular adverse events are imperative.