Delta Journal of Ophthalmology

REVIEW ARTICLE
Year
: 2017  |  Volume : 18  |  Issue : 3  |  Page : 117--122

Ophthalmic complications of targeted therapies: a review


Deepti Sharma 
 Department of Radiation Oncology, VMMC and Safdarjung Hospital, New Delhi, India

Correspondence Address:
Deepti Sharma
Department of Radiation Oncology, Room No. 271, Second Floor, New OPD Block, VMMC and Safdarjung Hospital, New Delhi - 110 029
India

Abstract

Recently, there has been an increase in the use of targeted therapies for cancer treatments. Nevertheless, the ocular side effects of the commonly used targeted agents are generally under-reported and not well studied in the literature. The aim of this study was to review common targeted therapies leading to ocular side effects and their management. A database search was conducted on Google scholar, PubMed and Medline using phrase words, ‘targeted therapy’, ‘ocular toxicity’, ‘antineoplastic agent’ and ‘management’. Ocular toxicity has been described with numerous approved targeted agents and also seems to be associated with several classes of agents currently being tested in early-phase clinical trials. It is important for oncologists to be aware of the potential for ocular toxicity, with prompt recognition of symptoms that require referral to an ophthalmologist. The ocular side effects of targeted therapy are clinically relevant and can be present in up to 70% of patients depending on the medication used. Because no screening protocol is recommended, ophthalmologists and oncologists should be vigilant; however, a dose reduction or cessation of therapy is only rarely necessary.



How to cite this article:
Sharma D. Ophthalmic complications of targeted therapies: a review.Delta J Ophthalmol 2017;18:117-122


How to cite this URL:
Sharma D. Ophthalmic complications of targeted therapies: a review. Delta J Ophthalmol [serial online] 2017 [cited 2017 Dec 18 ];18:117-122
Available from: http://www.djo.eg.net/text.asp?2017/18/3/117/216923


Full Text

 Introduction



Chemotherapy has been used in the treatment of cancer for several decades, although associated with well-known side effects including bone marrow, hepatic, pulmonary, cardiac, renal, and gastrointestinal toxicity. New systemic anticancer treatments, including targeted therapy, are showing promising antitumour activity but producing new adverse effects [1].

Systemic anticancer therapies can produce acute and chronic organ damage, but the eye is usually considered a protected site [2]. With the introduction of new drug, especially targeted therapy, drug-induced ocular side effects have increased [3]. Therefore, reports of drug-induced ocular toxicity must be well documented, and the other causes of these side effects should be ruled out to help establish causality.

In this article, we reviewed targeted anticancer agents that are associated with ocular toxicity, discuss the possible pathogenesis for these toxicities, and provide recommendations for monitoring and management.

A database search was conducted on Google scholar, PubMed and Medline using the phrase words targeted therapy, ocular toxicity, antineoplastic agent and ‘management’..References of all publications were also searched. All relevant publications were collected, reviewed and were analysed in detail to be summarized in this article.

 Molecular targets and ocular effects



The eye is a highly differentiated organ and has a pivotal role in the evolution of human genomics, with at least 90% of the genes in the human genome being expressed in one or more of the eye’s many tissues and cells at some point during a person’s life [4]. The complex functioning of the eye combines the neural network system with blood vessels, muscles and skin that can be affected by targeted agents, often with different receptor-specific patterns that do not occur in this form elsewhere in the body ([Table 1]) [5].{Table 1}

Epidermal growth factor receptor

Epidermal growth factor receptor (EGFR) receptors are present in ocular and periocular tissues, including the eyelids, eyelash follicles, tear glands, conjunctiva and cornea. The suppression of EGFR signalling in ocular tissues such as sebaceous glands, hair follicles, conjunctiva, tear glands, eyelid skin and the capillary system results in adverse effects such as conjunctivitis, blepharitis, dry eye, trichiasis and keratitis [6],[7].

EGFR is also expressed in corneal basal epithelial cells and is involved in corneal wound healing [8],[9]. In animal models, corneal epithelial wound healing was delayed with the administration of an EGFR inhibitor, suggesting that EGFR inhibition may decrease corneal epithelial cell proliferation [10].

Tyrosine kinase inhibitors

EGFR tyrosine kinase inhibitors (TKIs) (erlotinib, afatinib and gefitinib) are used for the treatment of non-small-cell lung cancer (NSCLC) and pancreatic cancer [11],[12]. Frequently reported ocular toxicities with erlotinib include conjunctivitis and eyelid changes such as entropion, ectropion and trichomegaly [13]. Rare ocular toxicities associated with erlotinib are episcleritis and corneal epithelial defects with associated infectious keratitis [6]. The most common ocular adverse events noted with gefitinib were conjunctivitis, blepharitis, dry eye, visual disturbances (blurred vision, hemianopia and photophobia), corneal erosions, mild superficial punctuate keratopathy and trichomegaly [14],[15].

Antibodies against epidermal growth factor receptor (EGFR)

The EGFR monoclonal antibodies (cetuximab and panitumumab), are used to treat colorectal and head and neck cancers [16],[17],[18]. Cetuximab is often associated with corneal erosions [6], poliosis, eyelash trichomegaly, punctate keratitis, conjunctivitis, eyelid dermatitis and blepharitis [19],[20],[21],[22]. Use of panitimumab is associated with ocular toxicity in 15–18% of patients. The most common adverse effects are conjunctivitis, eye and eyelid irritation, increased lacrimation and conjunctival hyperemia [23],[24].

Vascular endothelial growth factor receptor

Vascular endothelial growth factor receptor (VEGFR) inhibitors such as bevacizumab and sunitinib block VEGF-stimulated endothelial cell proliferation and migration and reduce tumour vessel permeability [25],[26].

Tyrosine kinase inhibitors

VEGF TKIs such as sunitinib, axatinib, pazopanib and vandetanib are used in the treatment of renal cell carcinoma and pancreatic neuroendocrine tumours. Although direct ocular toxicity with VEGF TKIs are rare, they are known to be associated with toxicities that lead to visual symptoms, such as hypertension and posterior reverse encephalopathy syndrome, causing blurred vision and retinopathy [27],[28]. One case of neurosensory retinal detachment was reported in a patient taking oral sunitinib for renal cell cancer [29].

Antibodies against epidermal growth factor receptor

Bevacizumab is a monoclonal antibody that is used for the treatment of colorectal carcinoma [25]. A reversible posterior leukencephalic syndrome under bevacizumab treatment has been reported [30]. There are reports of direct ocular toxicity related to intravitreal injection of these agents, including the potential for ocular inflammation [31].

BCR-ABL, platelet-derived growth factor receptor and c-kit inhibitors

Imatinib, dasatinib and nilotinib are the selective inhibitor of BCR-ABL, c-kit and platelet-derived growth factor receptor (PDGFR)-related protein tyrosine kinase [32],[33],[34]. These are approved for treatment of chronic myeloid leukaemia and gastrointestinal stromal tumour. Periorbital oedema is the most common ocular side effect associated with imatinib. This phenomenon is due to dermal dendrocytes found in the periocular soft tissues that express particular molecular targets of imatinib − namely, c-kit and PDGFR. Through the inhibition of PDGFR, imatinib may decrease the interstitial pressure and increase transcapillary transport [35],[36]. Periorbital oedema also results in lacrimal pump dysfunction and conjunctival chemosis resulting in epiphora [37],[38]. Studies have shown that the inhibition of the PDGFR signalling pathway have resulted in compromised survival of retinal ganglion cells leading to sight-threatening complications affecting the optic nerve, macula and retina [39].

AKT inhibitors

Perifosine have been used in colorectal cancer and Waldenstrom’s macroglobulinaemia. Perifosine is a phosphoinositide 3-kinase/Akt/mammalian target of rapamycin inhibitor that inhibits Akt activation in the phosphoinositide 3-kinase pathway and also affects the c-Jun N-terminal kinase pathway, which are associated with programmed cell death, cell growth, cell differentiation and cell survival.

Although the pathogenesis behind its ocular side effects is not known, it often leads to severe form of keratitis presenting as peripheral, paralimbal, ring-shaped, superficial corneal stromal infiltration and corneal ulcers that resembled the features of autoimmune keratitis [38],[40],[41].

The mitogen-activated protein kinase pathway

The mitogen-activated protein kinase (MEK) pathway is a signal transduction pathway that ultimately leads to cellular proliferation [42]. Studies have shown that MEK-induced oxidative stress in the retina leads to oedema, haemorrhage and induction of the coagulation cascade producing retinal vein occlusion (RVO) [43]. Duncan et al. [44] demonstrated that inhibition of the MEK pathway may alter permeability of retinal epithelial pigment cells and disrupt the ability to prevent fluid accumulation resulting in subretinal fluid accumulation and serous retinal detachment. RVO and macular oedema may occur when fluid blocks the vasculature that drains the retina [44]. MEK inhibition may also lead to the development of uveitis [45]. In addition to melanoma, the antitumour activity of MEK inhibitors has been observed in patients with hepatocellular carcinoma, as well as low-grade serous ovarian cancer, NSCLC and biliary cancers [46].

Trametinib is a potent and selective inhibitor of MEK-1 and MEK-2A and is Food and Drug Administration approved for metastatic melanoma carrying the BRAF V600E mutation in a phase III clinical trial [47].

It is important to note that unlike RVO, which can produce permanent visual loss, other visual disturbances associated with MEK inhibitors, such as central serous retinopathy, blurred vision and colour disturbances, are potentially reversible [46],[47],[48].

Anti-cytotoxic T-cell lymphocyte antigen-4 antibodies

Ipilimumab is a CLTA-4 monoclonal antibody that acts by increasing T-cell-mediated adaptive immunity. It is used in the management of malignant melanoma [49]. Treatment with anti-CTLA-4 antibodies has been associated with autoimmune toxicities, including colitis, hepatitis, toxic epidermal necrolysis, neuropathy, vitiligo, thyroid disease and hypophysitis [49]. Ocular events reported with ipilimumab include conjunctivitis, scleritis, uveitis and Graves’ ophthalmopathy [50]. In addition, there are two reported cases of ipilimumab-induced uveitis that resolved after the administration of corticosteroid eye drops and periocular corticosteroid injections [51].

BRAF

BRAF is a member of the Raf kinase family of growth signal transduction protein kinases. Vemurafenib and dabrafenib are two approved BRAF inhibitors that target a mutated form of the BRAF gene (V600E). Most common adverse effects due to BRAF inhibitors are photosensitivity, RVO, uveitis and macular oedema [52],[53].

Anaplastic lymphoma kinase

Crizotinib is an inhibitor of the anaplastic lymphoma kinase and cMET receptor tyrosine kinases. It is approved for use in NSCLC. Visual effects are described as photopsia (flashes), light trails or brief image persistence (i.e. postflashbulb effect) occurring particularly when transferring from low to bright light conditions. This condition often improves with length of time receiving therapy [53],[54].

Vascular disrupting agents

Vascular disrupting agents (VDAs) induce the collapse of the vascular supply that supports a tumour. Phase I studies of VDA reported dose-related transient disturbances in colour vision [55]. Given the similarities between these agents and the VEGF pathway inhibitors, there is also the potential for ocular symptoms secondary to systemic toxicities (such as hypertension) with VDAs [56].

Anti-CD40 monoclonal antibody

Dacetuzumab is a monoclonal antibody against CD40, a protein expressed on B cells. Most common adverse effect is noninfectious ocular inflammation, which may be related to CD40 being expressed by conjunctival tissues [57].

 Conclusion



Ophthalmic complications induced by targeted therapy are often underestimated and under-reported due to the priority given to other life-threatening conditions. The possible reversal of some of these side effects, if diagnosed timely, emphasizes the need for the oncologists to be aware about these ocular reactions and suggests immediate consultation with an ophthalmologist so that they can be recognized early and some ophthalmic intervention can be made before irreversible changes occur, hampering patient’s quality of life. An ophthalmic baseline examination before anticancer treatment may help detect any pre-existing ocular conditions and lead to the reduction of ocular side effects when predisposed patients are screened and examined regularly during and after anticancer therapy. Reporting of ocular adverse effects should be encouraged for definite analysis of the burden. Anticipation of various treatment-related toxicities may also provide the opportunity for pharmacists to develop intervention strategies that could minimize expected adverse effects. On the whole, oncologist and ophthalmologist should work together in order to prevent irreversible ocular toxicities of targeted agents and to determine true cause of visual disturbance.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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