Markedly increased ocular side effect causing severe vision deterioration after chemotherapy using new or investigational epidermal or fibroblast growth factor receptor inhibitors

Abstract

Background: We sought to describe corneal epithelial changes after using epidermal (EGFR) or fibroblast growth factor receptor (FGFR) inhibitors as chemotherapy and to clarify incidence and prognosis. Materials: Retrospective chart review. Results: Among 6871 patients and 17 EGFR or FGFR inhibitors, 1161 patients (16.9%) referred for ophthalmologic examination. In total, 1145 patients had disease-related or unrelated ocular complications. Among 16 patients with treatment-related ocular complications, three patients had treatment-related radiation retinopathy and one patient showed treatment-related corneal ulcer. Finally the authors identified that, in 12 patients, three EGFR inhibitors and two FGFR inhibitors caused corneal epithelial lesions. Vandetanib, Osimertinib, and ABT-414 caused vortex keratopathy in nine patients, while ASP-5878 and FPA-144 caused epithelial changes resembling corneal dysmaturation in three patients. The mean interval until symptoms appeared was 246 days with vandetanib, 196 days with osimertinib, 30 days with ABT-414, 55 days with ASP-5878, and 70 days with FPA-144. The mean of the lowest logarithm of minimal angle of resolution visual acuity results of the right and left eyes after chemotherapy were 0.338 and 0.413. The incidence rates of epithelial changes were 15.79% with vandetanib, 0.5% with osimertinib, 100% with ABT-414, 50.0% with ASP-5878, and 18.2% with FPA-144. After excluding deceased patients and those who were lost to follow-up or still undergoing treatment, we confirmed the reversibility of corneal lesions after the discontinuation of each agent. Seven patients showed full recovery of their vision and corneal epithelium, while three achieved a partial level of recovery. Although patients diagnosed with glioblastoma used prophylactic topical steroids before and during ABT-414 therapy, all developed vortex keratopathy. Conclusions: EGFR and FGFR inhibitors are chemotherapy agents that could make corneal epithelial changes. Contrary to the low probability of ocular complication with old EGFR drugs, recently introduced EGFR and FGFR agents showed a high incidence of ocular complication with severe vision distortion. Doctors should forewarn patients planning chemotherapy with these agents that decreased visual acuity could develop due to corneal epithelial changes and also reassure them that the condition could be improved after the end of treatment without the use of steroid eye drops.

Choroidal and Choriocapillaris Morphology in Pan-FGFR Inhibitor-Associated Retinopathy: A Case Report

“…MEKi-associated retinopathy (MEKAR) was recently described separately from CSCR [ 6 ]. MEKAR is also characterized by a serous (fluid-filled) retinal detachment without choroidal involvement, secondary to MEKi therapy [ 13 , 14 , 15 ].…”

Epidermal Growth Factor Receptor Expression in the Corneal Epithelium

“…There are a number of growth factor receptors and cytokine receptors whose signaling contribute to the restoration and homeostasis of the corneal epithelium [45]. This list includes receptors for platelet-derived growth factor [46], hepatocyte growth factor (HGF) [47], colony-stimulating factor 1 [48], keratinocyte growth factor [49], fibroblast growth factor [50,51], transforming growth factor-β2 [52], nerve growth factor [53], interleukin-1 [54], and interleukin-6 [55]. However, the epidermal growth factor receptor (EGFR) stands out because in rodent models, stimulation with epidermal growth factor (EGF) can accelerate corneal epithelial wound healing up to two-fold [56,57] and the addition of EGFR inhibitors (i.e., AG1478) to wounded corneal epithelium in mice prevents wound healing [58].…”

Trichiasis and dry eye syndrome in two patients on novel fibroblast growth factor receptor inhibitor therapies

“… 6 Furthermore, corneal dysmaturation has been suspected in a number of patients exposed to the FGFR inhibitors ASP5878 and FPA144. 7 Therefore, we suggest that FGFR inhibition may predispose patients to corneal epithelial changes and subsequent dry eye syndrome due to dysmaturation and poor wound healing. Concerning ocular adnexal adverse effects, studies of other RTK inhibitors have implicated EGFR monoclonal antibodies as well as Bcr-Abl and c-Kit inhibitors in ocular adnexal disease due to expression of their respective receptors in the orbit, peri-orbit, lids, lashes, hair follicles, and capillary systems.…”