With more than 10 million deaths per year, cancer is the main cause of mortality in the developed countries(1). Beside surgery, chemotherapy and radiotherapy are the classic nonsurgical available options in the fight with this horrible disease. Unfortunately, these treatments associate high morbidity, acting nonspecifically on all cell types, including healthy tissues(2). This is the reason why, in the past 20 years, novel anticancer biological therapies have emerged. These drugs target the cancerous cells only, the impact on normal tissues being minimal(3). Through specific molecules or antibodies, biological therapy stimulates the body’s own immune system to fight against cancer cells, interfering with progression and tumor growth(3,4).
Despite the targeted mechanism, numerous side effects of biological therapy have been described, mainly regarding the digestive system, liver, skin, central nervous and cardiovascular system(5). Regarding the eye, there are very few studies on a small number of patients and do not really focus on ophthalmic side effects.
The eye is a complex structure that includes blood vessels, nerve fibers, muscles and skin. The toxic side effects of biological treatments can be found at the level of the orbit, eyelids and eyeball (from the corneo-conjunctival level to the level of the retina and optic nerve)(6). Also, we must not forget that the eye is an extension of the brain, so any cerebral side effect can affect the visual cortex or the optical pathways.
The main ocular side effects of novel anticancer biological therapies are dry eye syndrome (1-24%), uveitis (1%), and myasthenia gravis with extraocular muscle involvement(7).
Although rare (1%), the ocular side effects can have serious consequences on the quality of life and can influence the patient’s compliance with systemic therapy(8). In addition, we must keep in mind that, as biological therapies will be more and more used, side effects will be encountered and reported more frequently(9).
The main classes of biological agents approved by the Food and Drug Administration (FDA) and by the European Medicines Agency (EMA), also available in Romania, associated with ocular side effects, are: epidermal growth factor receptor inhibitors, vascular endothelial growth factor receptor inhibitors, inhibitors of specific proteins, estrogen receptor modulators, and interferons(9).
Epidermal growth factor receptor inhibitors are used to treat multiple solid tumors, mainly carcinomas – of the lung, pancreatic, colorectal, or basal cell carcinoma(10). The epidermal growth factor receptor is one of the key receptors in corneal regeneration, being expressed mainly in the corneal epithelium and endothelium(11). In the event of a corneal injury, the epidermal growth factor receptor is increasingly expressed and epithelial cells migrate to the affected area. The migrated cells also express epidermal growth factor receptors and proliferate by binding epidermal growth factor(12), which is mainly present in the tear film(13). Thus, by inhibiting the epidermal growth factor receptor, healing of the corneal epithelial defects is delayed(14), and in extreme cases it can lead to corneal perforation(10). Epidermal growth factor also stimulates the proliferation of epithelial cells at the level of the palpebral meibomian glands – so, inhibiting its effect, causes meibomitis(15). Since the epidermal growth factor receptor is also expressed in the hair follicle, its inhibition may cause trichomegaly or trichiasis(15). Studies have shown that the occurrence of side effects is dose-dependent: the higher the dose, the higher the risk of developing complications(16). Other oculopalpebral side effects associated with epidermal growth factor receptor inhibitors are blepharitis, conjunctivitis or dry eye syndrome(10). The patients complain of swollen, red eyelids, conjunctival hyperemia, or foreign body sensations. The use of artificial tears at least four times a day in patients who receive epidermal growth factor receptor inhibitors is proven to be useful as a prophylactic method(9).
Vascular growth factor receptor inhibitors are used for the treatment of renal cell carcinomas or gastrointestinal stromal tumors. Bevacizumab is a monoclonal antibody used for the treatment of colorectal carcinoma. It can cause cerebral vasospasm and a partially reversible posterior leukoencephalic syndrome, clinically manifested by cortical blindness(17). For more than 10 years, bevacizumab has been also used in ophthalmology, off-label, through intravitreal injections, for the treatment of vascular occlusive disorders and age-related macular degeneration.
Crizotinib is an anaplastic lymphoma kinase inhibitor, a tyrosine kinase, used for the treatment of non-small cell lung cancer. Ocular damage may occur as early as two weeks after the initiation of treatment(18). The main side effects are photopsia and myodesopsia(18), which are considered minor by the FDA.
Immune checkpoint inhibitors are used in the treatment of lung cancer both in early and late stages. The main immune checkpoint inhibitors are CTLA-4 (cytotoxic T lymphocyte antigen 4) inhibitors, PD-1 (programmed cell death protein 1) inhibitors and PD-L1 (programmed death-ligand 1) inhibitors. They “unlock” the immune checkpoints intended to prevent autoimmune phenomena, but this state of hyperreactivity of the nonspecific immune system causes unwanted effects. The most frequent side effects of this type of biological therapy are ophthalmoplegia (40.51%), uveitis (20.25%) and dry eye syndrome (17.72%)(19). Other immune-related side effects are conjunctivitis, corneal ulcers with perforations, corneal graft rejection, optic neuritis, retinopathy, amaurosis fugax, orbital inflammation, and giant-cell arteritis(19). Ipilimumab is a human monoclonal antibody used for the treatment of metastatic malignant melanoma. At approximately 6-12 weeks after the beginning of the treatment, pituitary gland changes may occur, mimicking Graves’ ophthalmopathy, with proptosis, extraocular muscle edema, dry eye syndrome, all most likely due to CTLA-4 receptor polymorphism(20). Side effects are remitted under systemic steroid treatment that do not reduce the effectiveness of ipilimumab therapy, but doses must be gradually reduced over several weeks, as sudden discontinuation causes symptoms to recur(21). Another rare side effect associated with ipilimumab is iridocyclitis, through an immune cross-reaction with the iris pigment epithelium(22). These patients complain of floaters and visual loss(22).
Tamoxifen is a selective estrogen receptor modulator used as an adjuvant therapy for breast cancer. The frequency of ocular side effects was reported to be between 0.6% and 12%(23). The most common side effects are crystalline retinopathy (which do not usually cause visual disturbances), macular edema and macular hole that can lead to significant vision loss(23).
Interferons are associated with multiple serious ocular side effects. Interferon-induced ischemic retinopathy can occur after approximately three months of treatment and affects more than 40% of patients(24). Typical changes are retinal hemorrhages and cotton-wool spots as a sign of nerve fiber edema. Anterior ischemic optic neuropathy was also reported in 36 patients and in 60% of cases the involvement was bilateral(25). Patients suffered visual field amputations or dramatic vision loss, reversible in only 50% of cases(25) after the discontinuation of interferon therapy. Myasthenia gravis, manifested mainly by diplopia, may also develop during interferon therapy(26).
Patients diagnosed with solid tumors at the “Dr. Carol Davila” Clinical Hospital of Nephrology, Bucharest, between January 2023 and January 2024, will be recruited to participate in this prospective observational clinical trial. The purpose is to identify structural and functional ocular changes associated with the biological therapy. The patients will be divided into two groups: patients newly diagnosed with cancer, who did not undergo any systemic cancer treatment before entering the study, and patients who have undergone cancer treatments before entering the study, in which biological therapy has an adjuvant role. All the patients will undergo a full eye examination before the biological treatment and all the systemic comorbidities will be noted. According to the latest research, most ocular side effects appear in the first three months after the initiation of treatment, so we will examine patients monthly in the first six months, then every three months in the first year. Hopefully, we will highlight the most frequent eye side effects, establish an ophthalmological follow-up protocol for the cancer patient according to the frequency, but also on the time of appearance of eye pathologies, as well as improve the therapeutic protocol for eye conditions in patients undergoing systemic anticancer treatment in Romania.
Novel anticancer biological therapies represent the main future direction for the treatment of cancer patients. However, they are new therapies, whose mechanisms of action are not fully understood. Some molecules have a well-defined safety profile, while others are newly introduced into practice, and it takes time and vigilance in reporting adverse effects. There is always the risk that side effects are not observed, especially since cancer therapies frequently associate several different molecules within treatment protocols, which causes difficulties in establishing etiological connections(9). Since the ophthalmologist cannot say whether the symptoms are caused by one particular molecule, by its association with another, or if the side effects occur only when the combined molecules target various signaling pathways, the recognition and treatment of ocular complications require a close collaboration between the oncologist and the ophthalmologist. If the side effects are serious, the therapeutic doses will be reduced. If the symptoms do not improve or get worse, the biological treatment needs to be stopped(9).
Ocular side effects of anticancer biological therapies are important. Depending on the type of the molecule used(9), they can occur in up to 70% of cases, which is precisely why periodic eye and vision examinations of patients undergoing biological oncological treatment are necessary.
Conflicts of interests: The authors declare no conflict of interests.