Cancer drugs and diabetic retinopathy: a dangerous, underestimated association

Anti-oestrogen

Antioestrogen is used in the management of breast cancer. Ocular side effects of hormone therapy are less frequent than other organ toxicity, although their incidence is probably underestimated^[19].

In particular, tamoxifen is an oral selective oestrogen receptor modulator used in the treatment of hormone receptor-positive breast cancer. Tamoxifen binds competitively to the cytoplasmic oestrogen receptors, entering the nucleus and inhibiting DNA synthesis, and its use is related to retinal thromboembolism^[19]. Tamoxifen penetrates the choriocapillary barrier and induces glycosaminoglycan deposition in the plexiform layers of the retina nerve fiber, determining axonal injury^[18].

A retrospective analysis of “The International Breast Cancer Study” evaluated, in a large number of subjects, the ocular toxicity related to adjuvant hormonal treatment (tamoxifen or toramifen) for breast cancer^[20] [Table 1]. The authors reported the occurrence of retinal adverse events during hormone therapy in about 1% of the cohort, although other cohorts observed a 6% incidence^[21]. The main retinal alterations include refractile yellowish deposits in the area surrounding macula, nerve, and plexiform layers. In the case of extensive deposits, macular oedema and visual acuity reduction occurred. These features regressed after tamoxifen withdrawal, although retinal deposits were permanent. The cumulative dosage of tamoxifen and duration of treatment could predict the risk for retinal damage, with the deposits occurring as the cumulative dosage approaches 100 g^[19].

Few data are available on the risk for onset or progression of retinopathy in diabetic subjects treated with tamoxifen [Table 1]. Moussa and colleagues observed the onset of superficial retinal haemorrhages, exudates and macular oedema, in a 52-year-old woman who presented with blurry vision, a history of well-controlled T2D, and breast cancer previously treated with tamoxifen^[22].

Similar retinal alterations were reported by Bommireddy and colleagues in a 52-year-old, non-diabetic woman who, at the time of visual impairment, was taking for about 5 years, 20 mg/day of tamoxifen to treat a grade 2, invasive lobular breast cancer^[23]. Although the incidence of ocular toxicity during hormonal therapy is low, subjects treated with tamoxifen should be alerted of this possible side effect to promptly ruling out an ophthalmic evaluation in case of visual injury^[20].

Androgen deprivation therapy

Anti-androgen drugs represent the standard of care for the treatment of prostate cancer both in adjuvant therapy and for the treatment of recurrence or biochemical failure^[24].

Gonadotropin-releasing hormone agonists, as well as steroidal (cyproterone acetate) and nonsteroidal anti-androgens (flutamide, bicalutamide, and nilutamide), have a detrimental effect on body weight, fat composition, and insulin sensitivity, determining in diabetic subjects a worsening of glucose control^[4,25,26]. The risk for DR is tightly related to the level of glucose control and insulin resistance; nevertheless, very limited evidence is available on the influence of anti-androgen on retinal health. In a large retrospective cohort observing 5,336 men newly diagnosed with localised prostate cancer and affected by pre-existing T2D, no significant increased risk for DR was reported in the group treated with androgen deprivation therapy. These men were treated with gonadotropin hormone-releasing hormone (GnRH) analogues (leuprolide, goserelin, or triporelin) or GnRH antagonists (abarelix or degarelix), with or without an oral anti-androgen (flutamide, bicalutamide, or nilutamide)^[24]. Recently, we retrospectively evaluated the retinal short-term effects of cancer drugs in 168 patients with different cancer types (mean age 55.7 years) and previously diagnosed T2D (mean diabetes duration 9.3 years)^[10,15]. In the subgroups of subjects (6% of the study cohort) treated for prostate cancer with anti-androgens, we did not observe an increased risk for short-term adverse retinal outcomes^[10,15]. Further prospective, larger studies are necessary to better investigate these findings.

Classical cytolytic chemotherapy

Alkylating agents, anti-microtubule agents, antimetabolites, and topoisomerase inhibitors are currently used for the treatment of many cancers and could be associated with various degrees of hyperglycaemia in patients previously not affected by diabetes^[27]. A toxic effect of these drugs on retinal tissue has been occasionally observed in subjects with and without diabetes mellitus [Table 1]. In a real-world retrospective study including cancer patients also affected by T2D for an average of 9 years, the use of alkylating agents and topoisomerase inhibitors was related to a seven- and nine-fold increase, respectively, of short-term retinal worsening^[15]. This risk was more pronounced in obese subjects.

The combined treatment with alkylating agents and taxanes is common in various solid malignancies. Some reports described the different degrees of retinal toxicity due to the contemporary use of carboplatin and paclitaxel. Matsuyama and colleagues described the case of a 59-year-old man with good diabetes control (glycated haemoglobin 5.8%) and treated with both paclitaxel and carboplatin for a non-small cell lung cancer, who experienced severe visual loss due to a large number of bilateral soft exudates, retinal ischaemia, and haemorrhages. This retinal injury was resistant to laser photocoagulation and disappeared after stopping cancer treatment^[28]. The case of paclitaxel and carboplatin retinal damage was described in a non-diabetic 70-year-old female affected by cervical cancer: bilateral mild decreased vision appeared four weeks after initiating chemotherapy, including 4 cycles of paclitaxel (175 mg/m²) and carboplatin. Retinal examination showed an early ischemic retinopathy and cotton wool spots. Both symptoms and retinopathy signs disappeared after drugs cessation^[29].

Several mechanisms, not fully clarified, have been proposed to explain how alkylating agents induce retinal ischemia. In particular, thrombosis could be related to the platelet activation mediated by phospholipase A2 increased activity^[29].

Paclitaxel was reported to determine symptomatic cystoid macular oedema in a 49-year-old woman with ovarian cancer, probably due to its detrimental effect on the blood-retinal barrier: oedema appeared after more than one year since paclitaxel treatment (cumulative dose of 1,680 mg) and regressed with drug’s discontinuation^[30]. Chelala and colleagues found an increased central macular thickness, without significant macular oedema nor reduced visual loss, in 25 subjects affected by different solid cancers treated with various protocols (4EC-4T, 3FEC/3T, or 4TC) including paclitaxel or docetaxel^[31].

Few reports described retinal damage in paediatric subjects treated with alkylating agents in combination with topoisomerase inhibitors, in particular etoposide^[32] [Table 1]. Hilliard and colleagues reported two cases of new-onset blurry vision after 4 months after cisplatin (40 mg/m²/day) and etoposide (100 mg/m²/day) initiation. Fundus examination showed a bilateral mild diffuse optic nerve pallor and retinal granular pigmentation^[32]. The authors explained the ocular toxicity by the reduced renal clearance of platinum and increased plasma level.

Kwan and colleagues described the case of cisplatin-related retinal toxicity in a 31-year-old male after ten weeks of treatment (20 mg/m²/day, cumulative dose 528 mg) for testicular cancer^[33]: fundus oculi and fluorescein angiographic examinations revealed some cotton wool spots and scattered intraretinal haemorrhages near the macula at both eyes and retinal neovascularization at the left eye. Visual acuity did not improve after laser photocoagulation and the cessation of the chemotherapy^[33].

The multidrug chemotherapy regimens usually used for cancer treatment make it difficult to explore the exact role of each drug on the onset of retinal adverse events. In this regard, an interesting report described the case of a 58-year-old diabetic man suffering from bladder cancer who developed, after 4 months of treatment with gemcitabine - antimetabolites molecule - and alkylating agents, microaneurysms, capillary leakage, cotton wool spots, haemorrhages, thickening of the macula, and mild retinal oedema in both eyes^[34]. The treatment discontinuation led to an improvement in the retinal injury. However, the cancer relapsed, gemcitabine was reintroduced in monotherapy, and retinopathy appeared again after a month. The clinical improvement observed after gemcitabine withdrawal and the retinopathy relapse after the second exposure to the drug seem to indicate the causal role of gemcitabine in the onset of retinopathy^[34].

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)^[35]. Macular oedema appeared at the end of the second cycle and regressed three 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; nevertheless, they could determine adverse effects, including retinal toxicity^[18].

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%^[36] [Table 1]. The term 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^[39]. Subretinal fluid spontaneously resolved despite continuation of pimasertib. Diabetes, hypertension, and dyslipidaemia were additional risk factors for more severe events with retinal vein occlusion and visual impairment^[36]. 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, continuously for 28 days^[40]. 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].

The combination of MAPK and BRAF inhibitors, namely trametinib and dabrafenib, determined, in a 39-year-old woman with metastatic melanoma, the onset of multiple serious retinal detachments and severe acute granulomatous panuveitis two weeks after the treatment starting^[42]. The recovery of a good visual acuity was obtained after two weeks since drugs discontinuation and corticosteroids administration, although an extensive extra-macula retinal fibrosis remained^[42].

The pathogenesis of MEKAR is unclear. There is evidence that the MAPK/MEK pathway regulates tight junctions in retinal epithelial cells, and thus anticancer drugs modulating these pathways could interfere with fluid transport determining retinal oedema^[36,37]. Other possible pathogenetic mechanisms include the generation of antibodies against the retinal pigment epithelium cells, found in the serum of subjects treated with binimetinib^[40].

Tyrosine-kinase inhibitors (TKIs) are known to increase the risk for renal (asymptomatic albuminuria or nephrotic syndrome) and cardiovascular (hypertension and myocardial ischemia) adverse events^[4]. Few studies evaluated the risk of TKIs to determine retinal injury^[19] [Table 1]. In particular, imatinib, used in subjects affected by chronic myelogenous lymphoma and gastrointestinal stromal cancers (400-800 mg/day), has been rarely (less than 1% of treated subjects) associated with the onset of retinal haemorrhages and macular oedema, usually resolved after imatinib discontinuation^[43,44]. The ocular events mostly occurred in patients treated with high doses of imatinib (600–800 mg/day). Some of these studies also recruited subjects affected by diabetes^[44]. Retinal necrosis and oedema were observed in rabbits after the intraocular injection of imatinib^[45].

Molecules inhibiting the angiogenesis of cancer cells by targeting the vascular endothelial growth factor (VEGF) signalling are widely used in the treatment of a variety of malignancies. Fraunfelder and colleagues explored the “National Registry of Drug-Induced Ocular Side Effects” to investigate the association between the use of three oral VEGF inhibitors, namely pazopanib, sorafenib, and sunitinib, with the onset of ocular adverse events^[46] [Table 1]. Macular oedema or retinal bleeding occlusion and detachments were observed in 15% of the cases after 2-3 months since the drug initiation. The authors assumed that the changes in vascular permeability and the occurrence of microemboli and microvascular events are responsible for the retinal damage. This large number of serious retinal adverse events associated with oral VEGF inhibitors suggests a close monitoring of eye health in treated subjects.

Recent studies reported the retinal side effects associated with fibroblast growth factor receptor 2 inhibitors (FGFR). A multicentre, open-label, single-arm, phase 2 study investigated the efficacy and safety of infigratinib (125 mg/day, orally administered for 21 days of 28-day cycles), a fibroblast growth factor receptor 2 inhibitor, in 108 subjects affected by cholangiocarcinoma. Central serious retinopathy-like and retinal pigment epithelial detachment-like events occurred in 17% of the enrolled subjects. The median time to first onset of ocular side effects was 39 days. No information about the effect of infigratinib on DR is reported^[47]. The occurrence of asymptomatic bilateral subretinal fluid, detected on optical coherence tomography scans, was observed in a phase 2 trial of subjects treated with an oral FGFR inhibitor (AZD4547) for malignant pleural mesothelioma^[48]. All patients received twice-daily dosing of 80 mg AZD4547 on a nominal 3-weekly cycle. The subretinal fluid emerged between 3 and 19 weeks following the first dose of the drug, did not require any dose interruptions or reductions, and disappeared after the last dose.

In the last decade, therapies targeting the immune response against cancer cells have taken a crucial role in the treatment of metastatic melanoma, non-small-cell lung cancer, renal cell carcinoma, bladder carcinoma, head and neck cancer, and lymphomas^[4]. These medications upregulate the immune system and could determine autoimmune-like side effects in several organs, including the pancreas, thus inducing acute, severe hyperglycaemia with diabetic ketoacidosis observed in 76% of cases^[49]. The ocular side effects related to anticancer target therapies occurred, within weeks to months since the beginning of therapy, in approximately 1% of patients^[50]. Some reports described the occurrence of optic neuropathy and retinal 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 metastatic non–small cell lung cancer^[52]. 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 proteins. After nivolumab discontinuation and glucocorticoid treatment, the visual symptoms improved^[52].

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 activator inhibitor-1) and is known to induce capillary diameter reduction and leakage^[53]. 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)^[54] [Table 1]. Thus, the molecule was discontinued for three months and one month after its reintroduction, the visual symptoms worsened again, suggesting its involvement in the retinal damage. Visual impairment was reported in 2% of subjects treated with trastuzumab^[54].