Retinal vein occlusions (RVOs) are a group of vision-threatening disorders with the second-highest rate of retinal vascular blindness after diabetic retinopathy (1) and a worldwide prevalence of approximately 0.1–0.5% (1–3). Those whose obstruction occurs before the major bifurcation of the central retinal vein fall into the clinical entity of central retinal vein occlusions (CRVOs), characterized by engorgement and tortuosity of the retinal veins in all quadrants with retinal hemorrhages, cotton wool spots (CWSs), swelling of the optic disc, and macular edema (ME) (4). Instead of venous compression at the arteriovenous crossing site often observed in branch RVOs (5), thrombosis of the central retinal vein posterior to the lamina cribrosa is typically the cause of CRVO (6).

Advancing age, hyperlipidemia, hypertension (HTN), and primary open-angle glaucoma are well-established systemic and ocular risk factors for CRVO, while diabetes mellitus (DM) is less so (6, 7). Other conditions are less commonly associated with CRVO, including sleep apnea, homocystinuria, stroke, and thrombophilia, which should be given special attention, especially for younger patients (8, 9).

CRVO, though uncommon, is recognized as a severe adverse event related to the use of targeted anti-cancer drugs, especially for mitogen-activated protein kinase kinase (MEK) and human gene that encodes a protein (BRAF) inhibitors, usually for the treatment of metastatic melanoma (10, 11). It is even more rarely reported in the use of tyrosine kinase inhibitors (TKIs) and fibroblast growth factor receptor (FGFR) inhibitors (12), providing sporadic evidence for the retinal toxicity of these drugs. Herein, we report the case series of three CRVO patients on regular regimens of TKIs as part of targeted therapies for metastatic malignancies, all of whom were otherwise healthy with no or well-controlled systemic conditions.

TKIs function by inhibiting corresponding kinases from catalyzing downstream phosphorylation (13). Since being approved in 2001 by the Food and Drug Administration (FDA) of the United States, TKIs have greatly improved the life expectancy of numerous cancer patients. They are highly potent in stabilizing tumor progression with fewer side effects compared to cytotoxic chemotherapeutic agents (14). Currently, TKIs are designed to target multiple pathways for cumulative antitumor efficacy. Although most TKIs are designed to be highly selective, other targets can be covered unexpectedly (14), which partially explains the ocular side effects of targeted therapy (15).

Cases reporting CRVO and other retinal vascular abnormalities related to the use of TKIs are summarized in Table 1 (16–21). Since 2012, several cases have been reported sporadically, four of which were CRVO. Of these cases, two were related to the use of sorafenib (16, 17), three were related to axitinib (19–21) and one was related to regorafenib (18). Interestingly, the TKIs used in previously reported cases (Table 1) and in our patients all belong to vascular endothelial growth factor receptor (VEGFR)-associated multitargeted TKIs (22), which target multiple receptors of endothelial cells, including VEGFR, platelet-derived growth factor receptor, FGFR, c-Kit, and c-Met. These TKIs block the kinase activity and the downstream transduction pathways involving angiogenesis, proliferation, migration, and cell survival (23), significantly improving the overall survival of some types of solid malignancies, including RCC and hepatocellular carcinoma. Some of these pathways, including the VEGF pathways, are shared by normal retinal tissues, contributing to retinal toxicity. Agents targeting VEGF pathways have been reported to increase the risk of ocular and systemic thromboembolic events (TEs), partially contributed by the dysregulation of endothelial cells and a decrease in prostaglandin-I 2 (PG-I 2) and nitric oxide (NO) (24). On the other hand, with endothelial cell death, exposure to phospholipid and extracellular matrix increases the tendency for thrombosis (25).

It may seem paradoxical to relate RVO to the systemic use of anti-VEGF agents, as intravitreal injection of anti-VEGF agents is the first-line therapy for RVO. In fact, local vascular toxicity has been observed with intravitreal injections. In patients with diabetic retinopathy, anti-VEGF agents showed enlargement of the foveal avascular zone, with no efficacy in improving retinal perfusion in some studies (26, 27). In patients with RVO, aggravation of retinal perfusion and development of the new non-perfusion area and CWSs after intravitreal injections were reported (28, 29). In addition, side effects of the posterior segment, such as RVO (18), ME, and central serous retinopathy, have been reported with systemic anti-VEGF agents (30), which are consistent with the results of animal experiments showing decreased local blood flow secondary to retinal vascular endothelial cell dysfunction with systemic anti-VEGF treatment (31). Bevacizumab, a commonly used anti-VEGF agent in systemic chemotherapy, is also the first generation of anti-VEGF agents for intravitreal injections. It increases the risk of venous thromboembolism development in cancer patients (32), and RVO is reported as an adverse effect when combined with chemotherapy for metastatic colorectal cancer (33). Although the underlying mechanism has not been fully elucidated, these observations justify the causal relationship between anti-VEGF agents and RVO.

Theoretically, hypercoagulation and thrombosis, which are commonly observed in patients with malignancies (34), seem to increase the risk of CRVO. However, up to now, the direct causal relationship between malignancies and CRVO was not well-established (35), and the results of previous studies were not consistent. The study by Kim et al. (36) identified an increased risk of subsequent cancer in patients with RVO. In other studies, thrombosis of retinal veins was not identified as a significant clinical marker for occult cancer (37), and RVO did not show an increased frequency of thrombophilia (38). The study by Toft-Petersen et al. (39) established the association between cancer and RVO, but the authors stated that the relationship reflects common risk factors instead of causal relationships. In addition, primary malignancy may trigger the elevation of anticardiolipin and antiphospholipid, resulting in RVO (40).

In fact, TEs related to the use of TKIs in other systems are not scarce. Cardiotoxicity is a known adverse effect of TKIs targeting VEGFR (41). Pantaleo et al. (42) reported coronary artery stenosis in a 58-year-old man on regular sorafenib for metastatic RCC (mRCC) for 2 years, whose cardiac function was normal and with no common cardiovascular risk factors. Axitinib was reported in relation to the cerebrovascular accident (CVA) (21, 43) and pulmonary embolism (43). The exact mechanism of TKI-related endothelial dysfunction has not been elucidated, yet due to the vital role of VEGF signaling pathways in the maintenance of retinal endothelial cell homeostasis and function, it is a fair guess that blockade of VEGF results in abnormal vascular integrity, which may increase the tendency for embolisms. Additionally, animal studies of sunitinib-related cardiac side effects suggest the impairment of mitochondrial function and the compromise of cellular energy homeostasis might be involved in TKI-related toxicity (41).

It should be extremely cautious to establish the cause of CRVO with targeted therapy. An important reason is that severe adverse events such as CRVO alter the treatment protocols of oncologists, which may influence the prognosis of systemic malignancy. Most patients in previous literature and in our case series were otherwise healthy, with normal lab results and well-controlled or no systemic comorbidities. Particularly, Li et al. (17) reported a 42-year-old man with no comorbidities. Jenkins et al. (20) reported bilateral hemorrhagic and ischemic retinopathy in a 62-year-old woman who was on a regular regimen of axitinib, another kind of TKI, for metastatic RCC. She was otherwise healthy, with no systemic or ocular comorbidities. Her retinal condition significantly improved with the cessation of axitinib without ocular treatment. Other reported cases mostly had well-controlled comorbidities such as HTN and hyperlipidemia. For these patients, RVO could hardly be explained other than the use of systemic TKIs, despite the presence of primary malignancies.

In addition to apatinib, camrelizumab, a programmed cell death receptor 1 (PD-1) inhibitor, was used in combination with our third patient. A synergistic antitumor effect of immunotherapy and anti-angiogenesis is well-recognized and often used as neoadjuvant therapy (44). Up to date, only one case of CRVO was reported with anti-PD-1 therapy (45), which is rarer than TKI. Although the possibility of camrelizumab-induced CRVO cannot be excluded, it is likely that apatinib contributes more to the disease onset in this patient.

All our patients developed CRVO during the use of systemic anti-VEGF agents, namely TKIs. The initial treatment of the third patient was local anti-VEGF agents, but the ME did not resolve, compromising faith in intravitreal anti-VEGF agents. On the other side, the poor responses to anti-VEGF agents indicate that TKIs might be the trigger of the retinal toxic reactions, resulting in CRVO. In comparison, IDI demonstrated good efficacy as the initial treatment or after the regimen switch, implicating the role of inflammation over VEGF in the pathogenesis of TKI-induced CRVO. In the setting of retinal endothelial injuries that might be related to the blockade of VEGF signaling pathways by systemic TKIs, IDI may be preferred in future patients with similar presentations.

Our study had the inherent limitations of a case series with a small sample size. The exact mechanism of the retinal toxicity of TKIs cannot be elucidated at this point, and the contribution of malignancy to CRVO is hard to evaluate. In addition, we lacked a control group to compare the efficacy of anti-VEGF agents and IDIs. However, to the best of our knowledge, this may be the first review on the topic of CRVO related to the use of systemic TKIs. Since the condition is rare, joint efforts should be made to reveal the incidence of CRVO and retinal toxicities in patients on systemic TKIs for metastatic malignancies.

In this case series report, all patients diagnosed with CRVO on TKIs received dexamethasone implant treatment and obtained a fluid-free macula until the last visits, indicating intravitreal injection of IDIs may be preferred over anti-VEGF agents. Oncologists should be aware of the possibility of CRVO in patients on TKIs for metastatic malignancies and inform them of the potential retinal toxicity. Regular screening by a retinal specialist is necessary.

ML: Data curation, Formal analysis, Methodology, Writing – original draft. LS: Data curation, Writing – original draft. RD: Writing – review & editing. YC: Writing – review & editing. CW: Conceptualization, Data curation, Funding acquisition, Supervision, Writing – review & editing.