Ocular Toxicity From New Oncology Agents: Safety Review

As use of targeted cancer and immunotherapies has increased, duration of therapy and use of multiple agents concurrently, ocular toxicity has become a major clinical problem. Many of these therapies have the potential to improve survival and induce remission but also can cause anything from transient discomfort to vision-threatening inflammation or retinopathy. Accurate identification and timely multidisciplinary management of these complications are essential.

Why It Matters

Many small molecule agents and monoclonal antibodies, targeted agents and immune therapies, are being developed and studied to kill or inhibit cancer cells by attacking specific signaling pathways. In addition to their intended effects, some of these compounds affect the cornea and conjunctiva, the uveal tract, the retina, the retinal pigment epithelium, and the optic nerve. Small perturbations in key immune and vascular homeostatic pathways that operate in these structures can result in serious eye toxicity. This ocular toxicity can manifest as painful symptoms, vision loss, or serious, irreversible tissue damage. This international symposium brings together clinical and basic researchers from around the world to discuss the current state of this problem and future directions.

Cancer and its treatments have visual side effects which can interfere with daily activities and decrease quality of life. Fatigue and nausea are often considered “part of the ride” of cancer treatment, yet vision changes can produce sudden onset and acute anxiety, as these symptoms interfere with independence, mobility, work, or caregiving. Patients report mild dry eye or blurry vision, feeling of grittiness or sensitivity to light, which interfere with reading, watching TV, computer work, or sleep. These symptoms can be long-term and cause patients to forgo, skip, delayed or withhold doses of prescribed cancer therapy without the knowledge of their medical oncology team.

How new oncology agents lead to eye complications

Targeted cancer therapies can cause changes in the physiological properties of the tumor and affect the retina and choroid in ways that lead to fluid leakage and inflammation. In some cases, findings of inflammation in the retina such as subretinal fluid have been noted in patients on MAPK pathway inhibitors, including the MEK inhibitors and BRAF inhibitors. Some of these findings have been transient; however, in some cases they have recurred in the same eye upon re-exposure to the same drug. Patients on these therapies should be aware of eye symptoms and monitored accordingly.

With the increasing use of Fibroblast Growth Factor Receptor (FGFR) inhibitors, particularly for the treatment of certain malignancies, there has been growing concern regarding the potential effects of these agents on the retina and the ocular surface. Patients taking FGFR inhibitors can be asymptomatic or complain of visual disturbances. On imaging of the ocular tissue, patients taking these agents can be found to have unsuspected effects. The ocology team is becoming increasingly familiar with what were previously rare adverse effects of these agents on the eye. This conference will discuss the common complaints and imaging findings seen in patients taking FGFR inhibitors as well as an overview of appropriate management.

Immune checkpoint inhibitors can cause immune-related inflammation in almost any part of the eye. Immune-related adverse events (irAEs) caused by CTLA-4, PD-1, and PD-L1 blockade can occur at any time during or after treatment. Patients may present with dendritic ulcers or severe dry eye due to severe inflammation of the surface of the eye, as well as with more severe ocular inflammation (uveitis, scleritis, episcleritis). In addition, some patients have developed immune-related optic neuritis, retinal vasculitis, or macular edema. These conditions usually require treatment with corticosteroids or other immunosuppressive therapy. Presentation is typically unpredictable, occurring as early as the first month of treatment, but more often after several months of therapy.

Why early recognition matters

Some eye toxicities are reversible with simple treatment – but ignoring eye symptoms can result in irreversible vision loss. Most eye dryness/irritation, macular edema, or fluid is amenable to supportive care, topical drops, or watchful waiting while on cancer therapy. Severe uveitis, retinal vascular occlusion, optic neuritis, or detached retinas, on the other hand, can cause rapid vision loss and therefore require prompt evaluation.

Issues related to eye symptoms in patients with cancer can be complex and demanding. The term “eye symptoms” is non-specific yet highly relevant in the oncology setting. While a patient with new onset blurred vision may have primary dry eye, require refraction due to chemotherapy or radiation effects, have progression of a pre-existing cataract, have retinal fluid or optic nerve involvement secondary to cancer, all of these issues require timely assessment and management. Additionally, patients with benign floaters and flashes may have secondary posterior uveitis or a retinal tear that requires immediate diagnosis. Oncology teams need simple triage rules to distinguish same-day versus delayed evaluation, and imaging versus observation.

Balancing cancer control with vision protection

Decisions to either continue or withdraw life-prolonging therapy in children with cancer who are experiencing visual threatening toxic effects to their sight are difficult and complex. The anticipated benefits and risks of continuing potentially curative antineoplastic therapy versus the risks and benefits of stopping cancer treatment to preserve vision must be considered. This statement provides a framework for making informed and shared decisions with families based on the child’s and family’s values, the child’s prognosis, the severity and irreversibility of the treatment effects on vision, and the probability that treatment to preserve vision will compromise oncologic outcomes.

Ocular inflammation can be challenging to manage as often immunosuppression rather than immunity to tumour is required. Topical corticosteroids are used frequently to treat inflammation involving the anterior segment of the eye, often with little systemic absorption. In more severe cases, treatment with periocular or systemic corticosteroids alone or in conjunction with other immunomodulatory agents is often necessary. Patients on therapy with immune checkpoint inhibitors have a systemic immune suppression versus anti-tumour immune activation opposing effect to management by the medical oncology teams and close coordination of care is indicated. A discussion of the respective risks and appropriate monitoring is also indicated.

System-level implications

Management of ocular toxicity associated with cancer treatment adds significant cost and complexity to oncology pathways. The need for initial screening tests, emergency hospital referral, urgent reading of imaging, and follow up consultations all put additional pressure on resources and the ophthalmology service. A practical approach to address these challenges within existing constraints is required. From a health system perspective, the goal is not to carry out unnecessary tests on all patients, but rather to promptly identify toxicity when it occurs, prevent serious, potentially permanent vision loss, and avoid costly and time-consuming vision rehabilitation and associated long-term disability.

Who It Affects

Patients taking certain targeted and/or immune therapies have the highest risk for clinically significant ocular events. Patients taking MAPK pathway inhibitors (e.g. BRAF and MEK inhibitors) and FGFR inhibitors as well as other kinase inhibitors are at risk for retinal changes (e.g. fluid), inflammatory eye disease and toxic effects to the ocular surface. Immune checkpoint inhibitors (e.g. PD-1, PD-L1, CTLA-4 inhibitors) are associated with immune-mediated, multi-compartmental inflammation affecting the ocular surface, cornea, conjunctiva, lacrimal gland, uvea, retina and optic nerve.

Patients at higher risk

Chemotherapy toxicity will likely have a greater effect on vision in the older patient and in the patient with significant prior ocular disease. Patients with glaucoma, age-related macular degeneration, diabetic retinopathy or prior retinal detachment may notice a marked decrease in visual function. It is helpful to record the patients pre-treatment visual function for later comparison when changes in vision are suspected to be related to chemotherapy.

Patients on combination or sequential therapy are at increased risk of severe severe adverse effects due to their treatment regimen. Patients receiving combination therapies are exposed to an increased inflammatory burden; have an increased risk of overlapping toxicities; and face greater challenges in determining causality of adverse effects. The duration of therapy given for combination regimens extends the period during which ocular toxicity symptoms manifest, and allows for the manifestation of delayed immune-mediated effects or cumulative ocular surface damage in some affected individuals.

Patients with a history of autoimmune disease or prior immune-related adverse effects should also be considered to be at potential risk. While most such patients with underlying diseases have not experienced ocular toxicity associated with immune activation, the unpredictable course of most autoimmune diseases makes it prudent to have all patients monitor for symptoms of ocular toxicity and have an early evaluation by an ophthalmologist as indicated.

Clinical teams involved

Oncologists/hematologists and their associated advanced practice providers should be aware of the early warning signs of these ocular toxicities and know the appropriate timing of referral for urgent evaluation. Many of these toxicities present first to the oncology clinic before the eye clinic evaluation. For the nurses triaging in the oncology setting, it is helpful to have a list of common toxicities and accompanying concise scripts and triage pathways for the patient callers and observers.

Ophthalmologists, optometrists and sub-specialists in ophthalmology are often required for diagnosis and imaging, as well as patient management. Community eye clinicians, such as general ophthalmologists, optometrists and opticians are often the first point of contact for a patient presenting with symptoms related to the eye. They can then refer the patient on to a retina specialist or a medical and surgical ocular immunology specialist as necessary. Pharmacists are able to identify drugs and classes of drugs which may cause eye symptoms, check for possible interactions and advise patients and prescribers on the various pharmacological options that are available.

Health systems, payers, and policy stakeholders

For health systems and insurers, appropriate coverage decisions and efficient workflow for screening, monitoring and imaging services are a major concern. If baseline exams and OCT imaging are not covered or difficult to schedule, patients may not receive timely care and allow significant vision loss to occur before seeking treatment. For regulators and safety programs, consistent and accurate reporting of adverse events is critical to update labeling, identify at risk patients and provide better clinical guidance to the community as post-market evidence continues to emerge for newer and widely used therapies.

What Changes

Integration of ocular safety pathways into cancer care pathways should not be left to chance. With more novel oncology agents entering the mainstream treatment armamentarium, the standard of care is evolving to include adequate education, risk-based counseling, and timely multidisciplinary collaboration between oncologists and eye care providers.

1) More Baseline and symptom triggered ophthalmic assessments are being conducted.

For patients on investigational therapy deemed to be at higher risk for serious adverse effects, a targeted eye history and baseline eye exam can be incredibly valuable. By performing a baseline eye evaluation, clinicians can obtain important information about the patient’s pre-existing dry eye, cataract, glaucoma, history of prior retinal disease and visual acuity. The baseline eye exam also serves as a comparison exam should the patient reports symptoms such as eye irritation, vision change, or vision disturbances as the patient begins investigational therapy. Logistically, a targeted baseline eye exam may be appropriate for patients on certain drug classes associated with retinal toxicity or with severe immune-mediated inflammation.

The evaluation for symptom triggered treatment of acute acute postoperative shed virus endophthalmitis should be expedient, organized and consistent. In addition to recent surgical history, there are several practical red flags that would bring a patient in for same-day or urgent ophthalmology evaluation (e.g. sudden vision loss, new visual field flashes or a “shower of rain” of floaters, severe eye pain, prolonged or increasing photophobia, marked redness, double vision or a new field defect). In contrast, patient reported symptoms such as mild dryness or occasional blurry vision would require timely evaluation, but would not require immediate evaluation and could be scheduled off of a regularly scheduled follow-up.

2) Multidisciplinary management becomes the norm

Both oncology and ophthalmology staffs should make their communication more efficient and use the same criteria for making certain patient management decisions when developing joint plans of therapeutic care for patients with Moor’s disease. A joint treatment plan should include a system for measuring the severity of certain Moor’s disease complications, choices between topical and systemic therapy for Moor’s disease, timing of cancer treatment, cessation or adjustment of cancer treatment for patients with Moor’s disease, expected alleviation of symptoms, the person responsible for calling the patient with specific results, and the duration of alleviation of symptoms prior to recurrence.

In many cases, protocols can help avoid unnecessary delays and treatment discontinuations by managing certain ocular toxicities between courses of chemotherapy without the need for a treatment hold. Many of these ocular toxicities can be monitored with imaging studies and ocular examinations on a schedule outlined by the protocol. In addition, protocols may also outline supportive care measures such as preservative-free artificial tears for patients with dry eye, or topical steroid or anti-inflammatory drops for certain retinal findings. For cases of immune-mediated inflammation, protocols will outline the appropriate tapering schedule for steroids, monitor for side effects and determine when to add or increase other immunosuppressive medications.

3) New models of care delivery are necessary to address issues of access.

In low resource ophthalmology settings timely triage and referral to appropriate specialists is crucial to prevent vision loss. Utilizing tele-triage referral systems and fast track referral protocols as well as a hub-and-spoke teleophthalmology approach which utilizes Tele-conferencing and/or patient-based symptom questionnaires and imaging allows for rapid identification of those patients who require urgent evaluation in person. This is particularly important for oncology patients in fully integrated pathways, where wait time to scheduling can lead to vision threatening disease progression. Additionally, clear scheduling protocols to ensure direct appointments to timely evaluation and care are also critical.

Timing is everything when it comes to discussing diagnostic imaging in the management of retinopathy. OCT images are often shown to the team and can reveal evidence of retinal fluid or structural damage, and widefield imaging and/or fluorescein angiography are often necessary to differentiate between a vascular versus inflammatory cause of the retinopathy. Any delays in authorization for imaging can add a layer of uncertainty as to whether to continue or defer certain oncology medications.

4) Safety monitoring and reporting need strengthening

Accurate and consistent capture of adverse events is important for appropriate risk stratification and effective labeling and guidance. In oncology this would include capture of ocular symptoms and findings as well as relevant imaging and management data, and this information can be captured through the use of registries or a structured reporting system. In addition to uncovering important patterns between adverse events and drug combinations, as well as patient specific factors that increase the risk of adverse events, the monitoring system can help to identify treatment(s) that will allow continued cancer therapy while limiting vision threatening consequences of treatment-induced toxicity.

Frontline health care workers such as physicians, nurses, and other personnel could greatly benefit from the use of electronic health record decision support, such as alerts indicating exposure to highly toxic pesticides, prompting health care providers to educate patients or family members about specific pesticide-related symptoms, and assisting with appropriate referrals to prevent missing the critical window for early intervention. In addition, templates to collect patient- reported ocular and other pesticide-related symptoms and a severity scale could aid in effective inter-professional communication.

5) Practical clinical considerations that improve real-world safety

Clear, simple, consistent information is key to enabling patients to understand and use it effectively. This may include information about their specific symptoms, our after-hours call arrangements, the effect of certain medication on an upcoming appointment and patients should be encouraged to bring these to their attention. Written information and a number of checklists are available to assist in this area.

Treatment decisions for ocular surface disease and/or inflammation should be organized first around vision threatening disease and then allow as little disruption as possible to the child’s and family’s oncology treatment plan. Mild inflammation may resolve with lubricants and simple environmental modifications. However, more severe inflammation will often require the use of topical steroids with close follow-up for measurement of intraocular pressure as well as monitoring for cataract development. More severe inflammation involving the posterior segment and/or optic nerve typically requires systemic therapy and coordination with the oncology team in order to most effectively protect vision and cancer outcomes.

This article is designed to assist in identification and referral for appropriate care, and NOT to encourage patients to discontinue cancer treatment. Patients displaying any oral and facial changes who feel that they are urgent in nature should first be evaluated by the patient’s oncologist or doctor of choice.

References:

https://pmc.ncbi.nlm.nih.gov/articles/PMC12815813/