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Page 10 of 14 Milluzzo et al. Metab Target Organ Damage 2024;4:5 https://dx.doi.org/10.20517/mtod.2023.43

[4]
head and neck cancer, and lymphomas . These medications upregulate the immune system and could
determine autoimmune-like side effects in several organs, including the pancreas, thus inducing acute,
[49]
severe hyperglycaemia with diabetic ketoacidosis observed in 76% of cases . The ocular side effects related
to anticancer target therapies occurred, within weeks to months since the beginning of therapy, in
approximately 1% of patients . Some reports described the occurrence of optic neuropathy and retinal
[50]
detachments in subjects treated with ipilimumab (3 mg/kg), a cytotoxic T-lymphocyte 4-antigen antibody.
These side effects determined visual disturbances (scotomas or full-field vision loss) and, in subjects who
experienced optic neuropathy, improved with corticosteroids or mycophenolate mofetil [50-52] [Table 1].
These features support the hypothesis of an immune-mediated pathogenesis for the development of retinal
side effects of cancer immune therapies.

Reedy and colleagues described the case of a 64-year-old woman who developed bilateral vitreous
detachment, mild narrowing of the retinal vessels, and retinal thinning after nivolumab administration for
[52]
metastatic non–small cell lung cancer . Serology testing showed the positivity for antiretinal antibodies
against 30-kDa (carbonic anhydrase II), 35-kDa (GADPH), 38-kDA, 58-kDa (PKM2), and 112-kDa
[52]
proteins. After nivolumab discontinuation and glucocorticoid treatment, the visual symptoms improved .

Trastuzumab is a monoclonal antibody used for breast and gastric cancer due to its interference with
human epidermal growth factor receptor 2 signalling. Trastuzumab strongly reduces the expression of pro-
angiogenic (e.g., vascular endothelial growth factor, transforming growth factor-α, and plasminogen
[53]
activator inhibitor-1) and is known to induce capillary diameter reduction and leakage . Saleh and
colleagues describe the occurrence of bilateral ischemic maculopathy (macular oedema, haemorrhages, and
hard exudates), in a 50-year-old woman, three months later the trastuzumab intravenous administration (2
mg/kg) [Table 1]. Thus, the molecule was discontinued for three months and one month after its
[54]
reintroduction, the visual symptoms worsened again, suggesting its involvement in the retinal damage.
[54]
Visual impairment was reported in 2% of subjects treated with trastuzumab .
CONCLUSION
The current evidence shows that anticancer therapies are associated with different degrees of retinal
morbidity ranging from mild transient symptoms to severe, sometimes irreversible, damage. However, the
knowledge of the exact pathogenesis of cancer therapies-related retinal damage is limited and inconclusive.

Cancer subjects also affected by T2D could be more prone to develop both short- and long-term retinal
adverse effects when treated with cancer therapies, not least because T2D is often associated with other well-
known risk factors for retinal damage, namely overweight, hypertension, dyslipidaemia, and metabolic
syndrome [10,16] . Anticancer drugs may worsen glycaemic control, thus increasing the risk of retinal
worsening. Nevertheless, the exact mechanisms underlying the bad impact of these drugs on glucose levels
are unclear and often unpredictable due to the usual administration, in anticancer protocols, of multiple
molecules, often supported by glucocorticoids to reduce their side effects . Further mechanistic studies,
[4]
including cell experiments and animal models, could improve the knowledge of the detailed mechanisms
underlying the effects of anticancer drugs on retinal tissue. Pre-registering trials of anticancer molecules
reported the retinal side effects, although specific data on the diabetic population are often unavailable.

The management of these subjects is challenging for clinicians due to the lack of guidelines or standardised
protocols for the prevention and treatment of retinal damage related to cancer drugs. This review allowed us
to identify the anticancer molecules most at risk for retinal neurovascular damage. Nevertheless, other
targeted studies are necessary to better clarify how these drugs affect retinal tissues, the exposure time and