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Page 2 of 14 Milluzzo et al. Metab Target Organ Damage 2024;4:5 https://dx.doi.org/10.20517/mtod.2023.43

INTRODUCTION
Diabetes mellitus (DM) and cancer are widespread diseases with a worrisome impact on public health
systems. Currently, DM affects more than one in ten adults: the prevalence of DM is estimated to be about
540 million cases worldwide, rising to 780 million in the next two decades . Likewise, the International
[1]
Agency for Research on Cancer reported 19.3 million new cases of cancer and 10 million cancer-related
[2]
deaths in 2020 and the global cancer burden is expected to be 28.4 million cases within 2040 . The growing
prevalence of these diseases led to an increase in subjects affected by both T2D and cancer, and
epidemiologic observations indicated that up to 20% of patients with cancer are also affected by DM, mainly
type 2 (T2D) . In particular, subjects with diabetes have an increased risk for liver, breast, pancreas,
[3]
[4,5]
colorectal, bladder, and endometrium cancer . These diseases share some of the involved risk factors and
have a complex, multifactorial, not fully understood etiopathogenesis . Insulin resistance and
[6,7]
hyperinsulinemia induce cell growth favouring cancer progression and aggressiveness, mediated by the
overexpression in tumoral tissue of the isoform A of the insulin receptor that has mostly mitogenic
effects .
[6,8]

Anticancer drugs could have several harmful effects on cancer patients with diabetes. Indeed, the most
common chemotherapies, together with reduced attention to diabetes management following cancer
diagnosis, could directly and indirectly (increasing glycaemia) affect glucose metabolism and the course of
diabetes-related micro- and macro-vascular complications [9,10] .

Diabetic retinopathy (DR), occurring in about 30%-40% of diabetic individuals, is one of the most frequent
microvascular complications of DM, and the most frequent cause of new cases of blindness in adults aged
20-74 years in developed countries . The main determinants of DR are diabetes duration, glucose control,
[11]
hypertension, and dyslipidaemia [12-14] . Moreover, unhealthy lifestyles (unbalanced diet, low level of physical
activity, tobacco consumption), genetic and epigenetic mechanisms could contribute to the onset and
progression of DR [15-17] .

Retinal damage induced by cancer drugs includes a wide spectrum of disorders, reflecting the anatomical,
physiological, and biochemical features of this tissue. The retinal neurovascular unit, composed of blood
vessel, pericytes, neurons, and glia, is dysfunctional in DR and could represent a frail, target site for cancer
[18]
drugs complications . The knowledge of the retinal adverse effects is mandatory to address a personalised
cancer treatment, in particular in subjects with diabetes, often affected by other comorbidities and vascular
complications. Additionally, the prediction of cancer treatment ocular side effects may provide the
opportunity to develop intervention strategies to recognize the tissue damage early before the occurrence of
the visual impairment. Few data exist regarding the impact of anticancer chemotherapies on diabetes
vascular complications, as well as no specific recommendations on their management in cancer patients are
available.

In this review, we summarise the current evidence regarding the effect of the different anticancer therapies
on the DR course. A literature search was conducted on PubMed, Embase, Web of Science, including
studies from inception to date. We found case reports/series, observational, prospective, registry, and pre-
registering trials, while no randomised controlled trials focused on the retinal effects of anticancer drugs in
diabetes subjects were available. We aimed to provide clinicians with some advice for the best management
of these patients, and to prevent the risk of retinal injury, vision loss, impaired quality of life, and public
health expenses.