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Page 8 of 14 Milluzzo et al. Metab Target Organ Damage 2024;4:5 https://dx.doi.org/10.20517/mtod.2023.43

Higashide and colleagues described the case of a 60-year-old diabetic subject affected by retinopathy and
neovascular glaucoma who developed anaemia and cystoid macular oedema during the oral treatment, for
advanced gastric cancer, with S-1, consisting of 5-fluorouracil prodrug combined with 5-chloro-2,4-
dihydroxypyridine and potassium oxonate (100 mg/day for 48, 26, and 32 consecutive days with an interval
of about three weeks) . Macular oedema appeared at the end of the second cycle and regressed three
[35]
months after S-1 discontinuation. The authors speculated that the retinal hypoxia due to DR worsened for
the S-1-induced anaemia, which resulted in the onset of macular oedema, suggesting the need for great
attention for the onset or progression of DR in subjects with multiple comorbidities.

Targeted anticancer therapy
Targeted cancer therapies, intended for modulators of specific molecular pathways responsible for the
growth and survival of cancer cells, are more specific and less toxic than classical cytotoxic chemotherapy;
[18]
nevertheless, they could determine adverse effects, including retinal toxicity .

The mitogen-activated protein kinase (MAPK) pathway is involved in the regulation of gene expression,
mRNA stability and translation, cell proliferation and differentiation, stress response, apoptosis, and
survival, thus playing a leading role in oncogenesis .
[36]

In patients treated with mitogen-activated protein kinase (MEK) inhibitors, the occurrence of ocular
adverse events, including asymptomatic to severe disturbances, is reported up to 90% [Table 1]. The term
[36]
MEKAR (MEK inhibitor-associated retinopathy) describes the retinal adverse events related to the
administration of MEK inhibitors, namely retinal vein and central artery occlusion, and separation of the
neurosensory retina .
[36]

Some reports described the occurrence of outer retinal layer separation in subjects treated with selumetinib
or pimasertib for astrocytoma and ovarian cancer, respectively. Visual symptoms appeared six months after
starting selumetinib and a few days after the administration of pimasertib (60 mg/day), with a spontaneous,
without visual sequelae, resolution of the retinal detachment after drugs discontinuation [37,38] . Interestingly,
the retreatment with selumetinib determined the relapse of these findings.

Recently, a prospective study involving eight patients treated with pimasertib (60 mg twice a day,
continuously for 21 days) for metastatic cutaneous melanoma observed, within the first month after the
start of medication, the onset of asymptomatic sub-retinal fluid in all patients, and foveal involvement in six
of them . Subretinal fluid spontaneously resolved despite continuation of pimasertib. Diabetes,
[39]
hypertension, and dyslipidaemia were additional risk factors for more severe events with retinal vein
[36]
occlusion and visual impairment . Van Djik and colleagues analysed the ocular outcomes of binimetinib in
35 subjects affected by cutaneous or uveal melanoma, treated with 45 mg of oral binimetinib twice a day,
[40]
continuously for 28 days . Serious retinal events occurred in 77% and 60% of subjects with cutaneous and
uveal melanoma, respectively, affecting the fovea in 85% of these cases. These injuries appeared between a
few hours to 26 days (median, 14 days) after the start of binimetinib evaluated by OCT. Nevertheless, only
23% of subjects experienced mild and reversible visual symptoms (blurred vision or dark flecks), which
generally disappeared within one week despite continuation of the drugs, suggesting that binimetinib
discontinuation is not necessary .
[40]

A retinal involvement related to binimetinib was also reported in a phase one study investigating the
efficacy and safety of the molecule in Japanese subjects with solid cancers .
[41]