Balancing Vision and Cancer Treatment: Perspectives on Modern Cancer Therapeutics and the Eye

Modern oncology care has been fundamentally reshaped by the advent of immunotherapy and targeted cancer therapy. Immune checkpoint inhibitors (ICIs), targeted kinase inhibitors and antibody-drug conjugates (ADCs) all have improved survival outcomes, transforming many cancers that once carried a uniformly poor prognosis into more manageable and, in some cases, chronic disease. The recent article by Dong et al. ‘Ophthalmic Adverse Events of Systemic Immunotherapy and Targeted Cancer Therapy: A Review’ presents a comprehensive overview of these novel agents including the secondary ocular adverse events that frequently occur [1]. Among the many ophthalmic adverse events reported, ocular surface disease (e.g., keratitis) and uveitis are the two most prominent categories. It is important to note that many agents have the potential to cause ocular adverse events in both of these categories, as the authors, in fact, described for the ICIs and many of the targeted kinase inhibitors. The review highlights corneal toxicity (specifically microcystic epithelial changes) as a hallmark of ADCs such as mirvetuximab, belantamab and tisotumab. However, oncologists and ophthalmologists should recognise uveitis as a potential adverse event as well in this category. Tsui et al. recently published a series on ocular adverse events in the setting of mirvetuximab, and although keratopathy was most frequent, anterior uveitis occurred in 25% of patients [2]. Anecdotally, among our patients, one of the authors has cared for a patient with a severe Vogt-Koyanagi-Harada (VKH)-like response after initiation of mirvetuximab. Although ophthalmic adverse events associated with ADCs and targeted therapies are largely attributed to direct toxicity and off-target effects in ocular tissues, the inflammatory adverse events observed with immune-activating therapies (ICIs) arise through fundamentally different mechanisms. The underlying principle of the ICIs is to stimulate the host immune system to recognise and eliminate cancer cells. As a result, immune-related adverse effects such as uveitis are not only frequent but may represent a marker of success of the drug [3]. Both a biological plausibility and empirical evidence demonstrate that the development of uveitis is a marker of a robust immune response correlating with improved oncologic outcomes. A nearly 6000 patient cohort by Chew et al. showed that in patients treated with ICIs, those who developed uveitis had a greater than twice median survival length (1008.5 days compared to 444.0 days), suggesting uveitis development as a marker of survival benefit [3]. Therefore, in the case of ICIs in particular, uveitis should not be thought of as merely a complication or drug toxicity, but also a signal that the drug is working. The development of ocular toxicity during cancer therapy creates a delicate balance between continuing a potentially lifesaving therapy while preserving vision and quality of life. This challenge is particularly complex in the setting of immunotherapy, where inflammatory toxicities such as uveitis may reflect effective immune activation. As these are novel agents, oncologists and ophthalmologists are still attempting to outline the best path to manage this balance. One clinician may have a low threshold to hold or permanently discontinue a medication if it is affecting vision, whereas another may view treating severe uveitis, keratitis or ocular surface disease as necessary over halting a lifesaving medication. This uncertainty can compromise patient outcomes. As such, a multicenter interspecialty consensus group including ophthalmologists and oncologists was formed to better define ocular adverse effects and to provide guidelines for when to decrease, hold or rechallenge a medication [4]. Although initially developed specifically for ADCs, the consensus findings are certainly applicable to all forms of immunotherapy. These guidelines provide clear objective clinical findings with dose modification recommendations. The goal of this editorial is not to summarise the guidelines, and we direct the reader to this consensus publication. Ultimately, drug interruptions are minimised for manageable toxicities when ‘treating through’ is safe, whereas cases with severe ocular inflammation that may cause permanent vision loss should have drug reduction or discontinuation. We certainly agree with the nuanced approach advocated by Dong et al., which favours collaborative decision-making among oncologists ophthalmologists, and patients rather than sole reliance on rigid decision-tree algorithms. The decision to continue or to stop therapy must be an individualised calculation of the patient's specific goals and potential treatment options. For instance, among our patients, one of the authors recently cared for a patient who developed panuveitis with cystoid macular edema and retinal vasculitis after commencement of an ICI for metastatic melanoma. When discussing her goals, the patient frankly stated, ‘I would rather die than lose any vision’. Furthermore, her recent scans showed good regression of the metastatic lesions. For this patient, although she did not complete the recommended course of immunotherapy, the drug was held and was not rechallenged after a discussion of risks and benefits between the patient and her care team. Alternatively, a patient receiving potentially life-saving treatment without any alternative drug option may require continuation despite severe uveitis. Many ocular adverse events can be effectively treated without discontinuing anticancer therapy. Uveitis in particular has several treatment options. When the decision is made to continue therapy in the setting of uveitis, we advocate prioritising local treatment when possible over systemic corticosteroids. This is especially relevant for patients receiving ICIs, where systemic corticosteroids may blunt immune activation and have been associated with worse oncologic outcomes when used at high doses for immune-related adverse events [5]. In contrast, this concern may be less pronounced with targeted therapies and ADCs, whose efficacy is not primarily immune-mediated. Nevertheless, systemic corticosteroids still warrant careful consideration and interdisciplinary collaboration because of infection risk, metabolic complications and potential drug interactions with certain targeted agents. Local therapies, including topical, periocular and intravitreal corticosteroids, can control inflammation while limiting systemic immunosuppression, though they carry risks such as the development of cataract and glaucoma. Although uveitis may improve after completion of immunotherapy, this is not universal. In our experience, some patients develop persistent immune-mediated inflammation that continues even after treatment has ended, occasionally requiring prolonged ocular treatment or systemic immunomodulatory therapy, a pattern also highlighted by Dong et al. These cases underscore that management is rarely straightforward and there is no one correct approach. Every case can be complex; frequent patient monitoring is required, and different treatment strategies are often necessary depending on the patient's uveitis and oncologic state. We therefore emphasise the importance of ongoing communication between the patient, oncologist and ophthalmologist to weigh systemic oncologic options alongside the severity of ocular disease, in order to preserve vision and quality of life in accordance with the patient's goals. T.K.L., T.M.J. and D.A.G. have an unrestricted departmental grant from Research to Prevent Blindness. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.