Targeted Cancer Therapy and Its Ophthalmic Side Effects: A Review

The past 2 decades represent a unique era in the advancement of cancer management resulting in improved clinical outcomes. Targeted cancer therapy (TCT) refers to novel treatment modalities aimed at interfering with signaling and angiogenesis pathways associated with carcinogenesis. Although traditional chemotherapy along with radiation and surgery remain the mainstays of care, TCT is emerging as an alternative or adjunctive approach.

The goal of cancer treatment is to limit systemic toxicity while enhancing tumor treatment specificity.^[1] The concept of deploying the body's own immune system by enhancing its ability to detect cancer cells has revolutionized management and opened TCT to the forefront of modern therapy. This review briefly describes the basics of TCT and -associated ocular side effects.

We conducted an English language database search for ophthalmic side effects associated with TCT, including Medline, PubMed, and Google Scholar using the following search terms: “targeted therapy,” “immune therapy,” “ocular adverse events,” “immune-related ocular toxicities,” and “ocular toxicity.” Case reports and letters to the editor were included only if they added substantially to the content of this review. We included drugs approved by the US Food and Drug Administration (FDA) as of December 2019.

The basic concept of TCT involves manipulation of specific cellular molecules to decrease or block transformation, proliferation, and or survival of cancer cells. The main difference between TCT and traditional chemotherapy is that TCT is directed toward specific molecular targets associated with cancer whereas standard chemotherapy impacts all rapidly diving cells. In addition, TCT is cytostatic (ie, inhibit tumor cells) whereas standard chemotherapy is typically cytotoxic (ie, destroy tumor cells).^[2]

The two main categories of TCT are monoclonal antibodies and small molecules. Whereas monoclonal antibodies are delivered parenterally and act on external cell surface proteins, small molecules can be formulated as oral agents and target intracellular pathways.^[2]Table 1 summarizes the various available forms of TCT.^[3]

The immune system provides a defense against external antigens (immune surveillance).^[8] There are two main lymphocytic arms of the immune response—humoral mediated (B cell) and cell mediated (T cell). The many difference between the two is that humoral immunity is mediated via antibodies and targets extracellular antigens, whereas cellular immunity mediated via T cells and targets intracellular antigens. Cancer cells although initially recognized and destroyed by the body's normal surveillance system may evade these mechanisms (immune editing).^[9,10]

Immune editing is classically described in three phases as follows: (1) tumor elimination—where the body's immune mechanisms destroy the tumor cells before they are clinically detectable; (2) tumor quiescence (equilibrium phase)—where the antitumor cytokines (interleukin [IL]-12, interferon [IFN]-γ) balance out the tumor promoting cytokines (IL-10 and IL-23)^[11]; and (3) tumor escape—where cancer cells adopt ways to circumvent the body's immune mechanisms leading to cancer progression.^[11] This concept has led to a paradigm shift in our understanding of tumor biology providing the foundation that cancer immune surveillance could produce personalized TCT.

At some point through an individual's life up to 90% of the human genome is expressed in the eye, making it vulnerable to systemic and genetic conditions.^[11] Although the eyes are thought of as “privileged” to immune and inflammatory complications, these mechanisms are not absolute.^[12] The coexistence of neural and vascular networks targeted by TCT make them potentially more susceptible to side effects.^[13,14] Ocular toxicities are among the most common immune-related adverse events (IRAEs) following TCT.^[15]Table 2 presents all the FDA-listed ocular side effects.^[14]

TCT have inherent risk of provoking and unmasking autoimmune mechanisms and disorders in the eye and visual pathways.

Different ocular structures respond differently to various TCT. Presenting signs and symptoms can range from dry eye to conjunctivitis, burning, foreign body sensation, photosensitivity, and blurred vision. The conjunctiva may be injected, chemotic with or without discharge or blepharitis.Inflammation of the uveal tract can present as anterior, intermediate, posterior uveitis, or as panuveitis (involving all ocular compartments). Patients often present with blurred vision, floaters, eye pain, redness, photophobia, and vision loss. Other periocular changes may include ectropion, entropion, chalazia, excess tearing with or without nasolacrimal duct obstruction, and periorbital edema. Milder complications are treated symptomatically; however, more severe ocular involvement or vision threatening side effects would warrant a need for urgent referral and withholding of the targeted cancer therapy.

Orbital inflammation can present as pain with eye movement, conjunctival injection, chemosis, proptosis, exposure keratopathy, diplopia, ophthalmoplegia with or with optic neuropathy, and blindness. In contrast to the effects mentioned above, orbital inflammation may require emergent assessment and immediate discontinuation of the targeted cancer therapy.

Other structures that can be affected include the retina and/or optic nerve. These patients warrant immediate discontinuation of therapy and urgent referral to an ophthalmologist.

The immune checkpoint inhibitor (ICI) proteins include the cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) and the programmed death–1 (PD-1) receptors expressed on cytotoxic T cells^[16] (Figure 1). The physiological role of immune checkpoints is to avoid attack against self-antigens during an immune response by negative regulation of effector immune cells.^[17] Cancer cells evade these immunoregulatory mechanisms by expressing ligands, which bind to PD-1 and CTLA-4, called PDL-1 and CD 80/86, favoring the balance to tip off toward the immune escape phase of immune editing. Inhibition of these proteins using checkpoint inhibitors, can unleash the immune system to attack the tumor cells^[18] (Figure 1).

Current FDA-approved ICIs include the following: (1) PD-L1 inhibitors (eg, durvalumab, atezolizumab, avelumab, cemiplimab); (2) PD-1 inhibitors (eg, nivolumab, pembrolizumab); and (3) CTLA4 inhibitors (eg, ipilimumab). The most commonly reported adverse events with ICIs are dry eyes and uveitis.^[18–20] Other reported side effects include macular serous detachment,^[20] uveal effusion,^[21] and immune retinopathy.^[22]

The toxicities of ICIs are collectively termed - IRAEs and mainly involve the gut, skin, endocrine glands, liver, and lungs.^[23] The self-antigen recognition, which was held in check by the CTLA-4 is unleashed by the ICI, leading to a variety of autoimmune conditions. Although the incidence of ocular IRAEs has been reported as less than 1%,^[24] the number of cases is anticipated to rise with increasing use of ICI. In a disproportionality analysis by Fang et al,^[25] using the FDA adverse events reporting system database, a total of 113 ocular IRAE occurred with these agents including uveitis, dry eye, ocular myasthenia, and eye inflammation. Nivolumab had the highest number of IRAE (n = 68). Comparing all ICIs the authors reported, atezolizumab had the highest association with eye inflammation, with a reported odds ratio (OR) of 18.89, and ipilimumab had the highest association with uveitis (OR = 10.54). For ocular myasthenia gravis, nivolumab had an OR of 22.82 followed by pembrolizumab with an OR of 20.17.

The National Cancer Institute uses a descriptive terminology called “Common Terminology Criteria for Adverse Events” (CTCAE) for adverse event reporting. A grading (severity) scale is provided for each adverse event term. Ocular side effects were graded based on the CTCAE criteria for eye disorders (version 4) from grades 1 to 4 (Table 3).^[26]

Pembrolizumab is a highly selective humanized monoclonal antibody against PD-1 receptors and is used in the management of melanomas and nonsmall-cell lung cancers.^[27] Several ocular side effects have been reported. Telfah et al^[28] described two cases of vision loss, one from choroidal effusions and bilateral exudative retinal detachments and the other with bilateral posterior uveitis. The symptoms and signs resolved with drug cessation with recurrence of symptoms upon rechallenge in one patient.

Nguyen et al^[29] described bilateral sequential vision loss secondary to ocular hypotony, which was not responsive to steroid therapy. Interestingly, “pale” ciliary processes were noted intraoperatively. The patient was left with a final vision of 20/125 bilaterally. A recent prospective cohort study (n = 745) reported five cases of IRAEs with intraocular inflammation (two with ocular surface disease and one with orbital myopathy).^[29]

Extraocular muscle involvement in IRAE can be due to inflammatory myopathies^[30,31] that sometimes mimic thyroid orbitopathy^[32] or may present as autoimmune antibody-mediated ocular myasthenia gravis.^[33] Reported IRAE autoimmune antibodies related to myasthenia gravis include antiacetylcholine receptor and antititin receptor antibodies.^[33] Discontinuation of the TCT along with steroids and intravenous immunoglobulin may be considered.^[34]

Other reported IRAE include uveitis related ocular hypotony with secondary steroid-induced cataracts,^[35] uveitis and papillitis,^[36] bilateral bird shot chorioretinopathy,^[37] paraneoplastic retinopathy,^[38] enophthalmos,^[39] Miller Fisher syndrome.^[40]

Nivolumab, is a fully humanized monoclonal antibody against PD-1 effective for treating nonsmall-cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), and other cancers.^[41] Combination therapy with ipilimumab has also been approved for BRAF V600 wild-type melanoma with studies reporting greater than 50% 5-year survival.^[42]

The most common IRAEs is uveitis, including recurrent panuveitis,^[43] macular edema with anterior uveitis,^[20] and chorioretinal scarring and choroidal neovascular membrane.^[44] Specific uveitic entities, including Vogt-Koynanagi-Harada disease manifesting with poliosis, vitiligo, and uveitis have been reported.^[45] Nivolumab also reported to affect the optic nerve and cases of optic neuritis,^[46] photopsia,^[47] and giant cell arteritis^[48] have been reported with its use.

Ipilimumab is a human CTLA-4–blocking antibody approved for management of late-stage melanoma.^[49] Numerous neuro-ophthalmic side effects have been reported. Optic nerve edema,^[50] neuroretinitis (bilateral optic disc edema along with macular edema),^[51] orbital inflammation,^[24] myasthenia gravis,^[52–54] Guillain-Barré syndrome (GBS),^[55] the Miller Fisher variant of GBS ^[56,57] and multiple sclerosis.^[58] Some authors have recommended avoiding ipilimumab in patients with preexisting autoimmune diseases, such as myasthenia gravis,^[53] but the risk remains ill defined.

In a large retrospective chart review of 1474 patients treated with nivolumab with or without ipilimumab, Kim et al^[59] found that 15 patients (1.0%) developed an ocular IRAEs. All patients, except one had bilateral IRAEs. Ophthalmic toxicities included ocular surface related toxicities such as punctate epithelial erosions of the cornea, subconjunctival hemorrhage and corneal perforation, uveal, and retinal involvement, including uveitis, hypotony maculopathy, cystoid macular edema, serous retinal detachment, choroiditis, and Vogt-Koyanagi-Harada–like syndrome, myasthenia gravis, and the first case reposts of nivolumab-related optic neuritis, and nivolumab-ipilimumab–related melanoma-associated retinopathy.^[59]

Carrera reported a case of drug-induced mysositis in a patient with nonsmall-cell carcinoma treated with tremelimumab (anti-CTLA4) and durvalumab (anti-PD-L1).^[60] Electromyography and muscle biopsy were suggestive of an “inflammatory myopathy.” Diplopia and ptosis improved upon drug cessation and oral steroid therapy.

A baseline eye examination before treatment followed by prompt referral to the ophthalmologist in the event of new potential IRAE symptoms is recommended.^[61] Oncologists should have a high index of suspicion for diagnosing and promptly referring these patients to see an ophthalmologist to determine if an IRAE is present and to discuss whether or not treatment should be reduced, tapered, or discontinued. The current American Society for Clinical Oncology guidelines for managing IRAEs have been previously detailed.^[16]

Tyrosine kinases play a central role in cell growth and differentiation.^[62] By means of protein phosphorylation, these enzymes mediate key processes of cell division, differentiation, migration, metabolism, and antiapoptotic signaling.^[63] Tyrosine kinases can further subdivided between receptor tyrosine kinases (RTK) and cellular tyrosine kinases (CTK).^[64]

RTKs have an extracellular ligand binding domain, a transmembrane domain and an intracellular domain. Dimerization of RTKs upon ligand binding leads to autophosphorylation of the tyrosine residues of the intracellular catalytic domains, which in turn activates the signal transduction cascade to involve the CTKs.^[64] Examples of RTKs include epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor, fibroblast growth factor receptor (FGFR), and nonreceptor CTK, such as the SRC, ABL, FAK, and Janus kinase pathways. Tyrosine kinases are implicated in multiple steps of cancer development. These pathways are often genetically or epigenetically altered in cancer cells providing them with a survival advantage.^[62]

EGFR is present in ocular surface layers including the lids, conjunctiva, and cornea. EGFR inhibition affects epithelial cell proliferation and stratification during corneal epithelial wound healing.^[65] Most of the side effects include corneal erosions, blepharitis, conjunctivitis, trichomegaly,^[66] dry eyes, and trichiasis.^[67] There are also reports of uveitis.^[68] Rao et al^[69] reported a case of bilateral retinochoroiditis due to toxoplasmosis in the setting of erlotinib.

A baseline exam before treatment initiation is recommended. Development of ocular symptoms should be considered an indication for ophthalmology referral, which may include administration of topical steroids and lubricants. Grade 3 toxicity or higher may necessitate drug discontinuation.^[16]

Ras-Raf-mitogen-activated protein kinase (MAPK)/extracellular signal related kinase (ERK) is a signaling pathway that is aberrantly activated in various neoplasms^[6] (Figure 2).

MEK inhibitors administered independently or in combination with BRAF inhibitors are approved for use in various cancers, including cutaneous melanomas. MEK inhibitors are associated with subretinal and intraretinal fluid accumulation.^[70] In a study involving 50 eyes, up to 92% developed fluid foci, 77% were multifocal, with at least one involving the fovea (83%). All foci were observed to be between the interdigitation zone and an intact retinal pigment epithelium (RPE).^[70] Schlessinger^[63] found that the MEK/ERK pathway was involved in RPE toxicity and a breakdown of the blood–retinal barrier. A collective term “MEK retinopathy” has been proposed to identify this clinical entity.^[71,72] The clinical presentation is generally bilateral and symmetrical presenting within 1 week of treatment initiation.^[65] The most common symptoms include blurred vision, altered color perception, shadows, light sensitivity, metamorphopsia, and glare.^[65] A preexisting thin choroid was proposed as a possible predisposing factor based on ocular coherence tomography observations.^[65] Tyagi and Santiago^[73] described two new features in patients with MEK retinopathy, including thickening of the ellipsoid zone and a “starry sky” pattern of subretinal granular deposits, both pointing to RPE toxicity and dysfunction.

Retinal vein occlusion has been mentioned as one of the side effects in the package insert for trametinib and has been observed in rabbit models.^[74] The full spectrum of MEK inhibitor side effects are beyond the scope of this review, but there is a reported incidence of 5%–38% in these patients.^[75]

Close communication between the oncologist and the ophthalmologist is essential when considering the possibility of an MEK-related IRAE and assessing whether to continue therapy. Grade 1 to 2 CTCAE reactions are often monitored, Grade 3 to 4 may require a pause, with a rechallenge at a lower dose, or cessation of therapy.^[72] Visual function is usually restored with no permanent visual loss in the majority of those affected.^[76]

BRAF inhibitors also act along the MAP kinase pathway and are used in advanced melanomas. Examples include dabrafenib and vemurafenib. BRAF/MEK inhibitor combinations dabrafenib/trametinib and vemurafenib/cobimetinib are also approved in this setting. Reported IRAE include uveitis and central serous chorioretinopathy.^[77] In a large retrospective review by Choe et al^[78] among 568 patients treated with vemurafenib, 22% developed ocular adverse events. The most common was uveitis followed by conjunctivitis and dry eye. These IRAE did not warrant treatment discontinuation.^[71]

Shailesh et al^[79] reported a case of bilateral lower motor neuron facial palsy in a patient treated with vemurafenib for metastatic melanoma. Examination was otherwise unrevealing, and he had normal neuroimaging with no evidence of cerebral metastases. Hematologic and biochemical tests, including CSF studies were normal. Within 72 hours of drug discontinuation, the patient showed improvement. Oral prednisolone, 50-mg daily, was initiated with gradual taper and complete resolution of symptoms was observed after 4 weeks. Dabrafenib is commonly used along with trametinib in the management of metastatic melanomas and there have been reports of bilateral panuveitis, chorioretinal folds, serous retinal detachments,^[80] and myasthenia gravis^[81] with these agents.

Imatinib was the first TKI developed more than a decade ago for chronic myeloid leukemia (CML). CML is caused by clonal expansion of hematopoietic cells by reciprocal translocation of chromosomes 9 and 22, resulting in a fusion protein, the breakpoint cluster region—Abelson (BCR/ABL) protein. BCR/ABL has intrinsic tyrosine kinase activity^[82]; inhibition leads to improved control of its downstream effects, achieving high 5-year survival rates up to 89%.^[73]

Periorbital edema is the most common side effect seen in up to 70% of cases and occurs because of inhibition of PDGF.^[67] Rare cases of severe periorbital edema have been reported with one patient needing surgical intervention.^[83,84] More severe fluid retention is managed with diuretics. Epiphora and subconjunctival hemorrhages have been reported even in the absence of cytopenia.^[85] Optic disc edema (both unilateral^[86,87] and bilateral^[88]) can occur and is unrelated to raised intracranial pressure. Optic neuritis has been reported,^[89,90] and may require treatment discontinuation and concomitant administration of systemic steroids.^[81]

Second generation TKIs include dasatinib and nilotinib. Monge reported a case of optic neuropathy in a patient receiving dasatinib that manifested as vision loss and bilateral visual field involvement. After suspension and treatment with oral corticosteroid treatment, a complete recovery to baseline was established.^[91]

Mild periorbital edema can be managed conservatively. Ophthalmology referral should be considered in all TKI IRAE with consideration of drug cessation in severe cases.^[16]

Oncogenic fusion genes consisting of anaplastic lymphoma kinase (ALK) are present in a subgroup of nonsmall-cell lung cancers, representing 2%–7% of such tumors.^[92] Crizotinib is an inhibitor of ALK (ALKI) and FDA approved. Visual disturbances in ALKI are rare but include trailing lights and palinopsia, especially with transitions from dark to light.^[93] Chun et al^[94] reported a 69-year-old woman treated with crizotinib who developed no light perception vision in the left eye and a visual field defect in the right eye. There was no mention of the appearance of the optic nerve on clinical examination but magnetic resonance imaging of brain and the orbit demonstrated bilateral optic nerve enhancement.

Visual loss related symptoms may warrant discontinuation of the TCT. Milder symptoms, such as visual disturbances, can be followed.^[16]

The naming of monocolonal antibodies (mAbs) follows the International Nonproprietary Names Working Group guidelines.^[95] The elements that make up an antibody name are “a prefix + target/disease class infix +source infix + mab.” Working our way backward, the names of mAbs always end with a mAb. The source infix preceding this, could be one of the following based on the source of the mAb: zu for humanized, o for mouse, u for fully human, or xi for chimeric. The disease class infixes could include tu or t for tumors, li or l for immunomodulatory, and ba or b for bacterial. The prefix does not have any meaning. In general, mAbs have a safer ocular toxicity profile compared to the above two classes of drugs^[96] (Table 4).

IFN-α is approved for use in hairy cell leukemia, malignant melanoma, and follicular lymphomas.^[111] Ocular side effects include trichomegaly and retinopathy with cotton wool spot formation and splinter hemorrhages. ^[112] Although retinopathy is mostly self-limiting,^[113] more severe complications including retinal vascular occlusion have been described.^[102]

The spectrum of TCT agents continues to expand in terms of both their clinical indications as well as potential toxicities. Although the TCTs have revolutionized cancer care, their ability to interfere with critical cell signaling pathways can cause a broad spectrum of side effects, including IRAEs. Ocular IRAEs are reported with increased frequently and it is imperative for the medical and ocular oncologist to be cognizant of the spectrum of these side effects to effectively manage these complications. Medical oncologists should consider referring patients before administering TCT for baseline ocular assessment and whenever an ocular IRAE is suspected. Ophthalmologists should be aware of the various TCTs and their potential to produce ocular toxicities. Close communicate between both specialists is essential in contemporary management of the patient with cancer.