More than meets the eye: the ocular toxicities accessory to anticancer therapies

Cancer is the second leading cause of death in the United States with over 1.9 million new cancer cases and 609,000 deaths estimated to occur in this country alone in 2022 [1]. As a result, cancer is a major public health priority with a staggering amount of research funding and over 3000 US FDA-approved clinical trials (in phases II and III) investigating a wide array of cancer treatments [2]. Over the last two decades, cancer therapy has been revolutionized by the development of immunotherapy and targeted anticancer therapy. These novel therapeutics feature a broad range of mechanisms of action ranging from upregulating the immune system’s innate antitumor surveillance to targeting the path ways responsible for cellular growth and proliferation. The development of these novel therapeutics has both revolutionized the treatment of cancer and massively broadened the oncologist’s armamentarium. These medications are not only used alone but are now frequently used as part of combination therapy, such as the combination of immunotherapy and radiotherapy, which has improved outcomes in metastatic melanoma [3]. The development of these novel therapeutics and treatment strategies has led to a remarkable improvement in survival rates in some of the previously most refractory malignancies.

As these novel therapeutics have become increasingly incorporated into the oncologist’s treatment pathways, a number of wide-ranging adverse effects have been recognized, including unique, class-specific side effects, many of which can affect the eye. To name a few, immune checkpoint inhibitors have been associated with various forms of uveitis, some of which require drug discontinuation [4–6]. MEK inhibitors have been associated with retinal vein occlusion and MEK-associated retinopathy [7]. BRAF inhibitors can cause a retinal vein occlusion and retinal vasculitis [5,6]. Antigen–antibody drug conjugates, such as belantamab mafodotin, have been associated with keratopathy [5]. These drugs, like many other targeted anticancer agents, require collaboration between ophthalmologists and oncologists to successfully manage the associated side effects. This editorial focuses on the current and future issues ophthalmologists and oncologists face with the proliferation of novel therapeutics, with a proposal for the next steps to address areas of need. It is imperative that ophthalmologists and oncologists recognize ocular side effects, provide appropriate vision-preserving treatment and balance the risks of systemic treatment discontinuation. To best serve our patients, ophthalmologists should have a greater role in medical oncology clinical trial design, the creation of standardized side effect grading systems, and ultimately FDA labeling of these medications.

Current & future issues with management of ophthalmic side effects of targeted anticancer therapy

A growing body of anticancer medications have known ocular side effects that require patients to undergo baseline screening and monitoring for ocular toxicity. Recently, there has been a significant increase in anticancer drug approvals by the FDA, from 4% of all approved drugs in the 1980s to 27% in 2018 [8]. As an ever-increasing number of anticancer drugs have been investigated in clinical trials and subsequently approved, numerous ophthalmic side effects have emerged, which have primarily been managed by ophthalmologists and oncologists in academic settings. From the clinical trial stage to post-approval, the management of ocular toxicity of anticancer drugs is littered with difficulties for all stakeholders. As providers who regularly work in multidisciplinary management teams for patients affected by cancer, we need to not only identify and clearly define such issues but also provide solutions to help manage these side effects and deliver safer care.

Clinical trials serve as the foundation for establishing drug side effect profiles and monitoring strategies. Critical questions that routinely occur in clinical trial design regarding ocular adverse effects are the following: How are ophthalmic adverse events quantified? How are ophthalmic side effects managed, specifically regarding dose modifications or discontinuation of the offending agent? The input of ophthalmologists on clinical trial design is imperative to help address these questions. Greater granularity of ophthalmic side effects in the clinical trial stage facilitates inherently better FDA labeling, including protocols for surveillance, treatment and discontinuation. Engaging ophthalmology in a multidisciplinary partnership from the inception of clinical trial design helps alleviate the nebulous risk–benefit profile when a patient experiences an ocular adverse effect through greater collaboration by domain experts.

Increased ophthalmology engagement enables improved clinical trial design and definition of ophthalmic side effects, which may require subspecialty-specific terminology and detail to create objective grading systems distinct from those used for other systemic adverse events. This segues into the other core issue, as currently no universal standardized ophthalmic side effect grading system exists. Utilizing a standardized system developed by ophthalmologists from the clinical trial design stage would enable greater granularity in reporting and surveillance, which is essential for FDA labeling. The most useful grading system would be objective, based on evidence and/or consensus expert opinion, and simple such that community comprehensive ophthalmologists can accurately grade toxicity without the need for screening by subspecialists in the absence of active side effects. The system should be individualized for different side effects or affected parts of the eye to consider what might require intervention, what level of side effect would cause irreversible damage and what is vision-threatening. Side effects such as keratopathy, uveitis and optic neuropathy would have vastly different grading criteria and would require unique testing for screening exams. The lack of such a standardized system currently shrouds comparisons across both trials and the literature, limiting insight into a holistic picture of a drug’s ocular side effect profile. Intrinsically, this adds greater complexity to evaluating such side effects when the drug is approved, as ophthalmologists who see these side effects lack a concise criterion upon which to evaluate. For example, the FDA package insert for belantamab states ‘withhold until improvement and resume at same or reduced dose or consider permanently discontinuing based on severity’ and documents a grade 1–4 scale based on mild/moderate or severe superficial keratopathy [9]. The distinction among mild, moderate and severe superficial keratopathy can be subjective, and in this case a subjective opinion is tied to a temporary hold or even permanent discontinuation of the medication [9]. Without clear, standardized ocular adverse effect grading systems, patients will unfortunately bear the burden as both false positives and false negatives can lead to mortality and morbidity, respectively.

The lack of standardized systems increases barriers to care, as community ophthalmologists and oncologists will continue to relegate targeted anticancer therapy, and the ocular toxicity associated with them, to tertiary referral centers,as the ramifications of medication discontinuation or side effect management are steep.Standardized systems would enable community ophthalmologists and oncologists to expand access to these revolutionary anticancer therapies to more patients while ensuring the side effect burden could be safely managed through screening protocols and clear side effect classifications. Community ophthalmologists would be better suited for longitudinal management of established patients, as they can be screened before symptoms manifest and can be meticulously monitored to document natural progression and required treatment for side effects without limited access to care and the travel burden associated with visits to tertiary centers.

Looking to the future, all the previously mentioned issues will continue to compound as the number of anticancer agents increases and treatments are utilized in a personalized fashion. Standard criteria for approaching ophthalmic side effects will be tremendously valuable, as a concrete system could be widely applied to the plethora of new drugs that are being approved even before most ophthalmologists become familiar with the typical side effect profiles of any given new medication. By establishing clear and concise prescribing information through FDA labeling, targeted anticancer therapy can escape relegation to tertiary care centers to be readily accessible for patients elsewhere who desperately need these medications.

Conclusion

The list of targeted anticancer agents is ever-expanding, suggesting that ophthalmologists will likely encounter patients with these adverse effects at some point in their careers. With this growing list comes a critical need for strong partnerships among medical oncologists, ophthalmologists, patients and the FDA. With high stakes for patient survival and for the impact of vision-threatening side effects on quality of life, ophthalmologists need to be involved in clinical trial design, the creation of standardized side effect grading systems and ultimately FDA labeling of these medications [10]. Simplified ophthalmic screening protocols and clear side effect classification will be especially important to allow community ophthalmologists and oncologists to safely provide these lifesaving treatments and required ophthalmic screening closer to home. By fostering strong, multidisciplinary partnerships at the early stages of drug development and maintaining these relationships through clinical trial phases and FDA approval, we can improve safe access to innovative cancer treatments with appropriate ophthalmic side effect monitoring for all patients in need.