Navigating ocular effects of cancer therapy: Insights from breast cancer and head-neck cancers

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The last decades of the previous millennium seemed to be a stepping-off point in medicine when clinicians began to recognize in earnest the association between the eye and systemic disease.¹

The amount of information available to clinicians on the involvement of the eye in systemic disease has been expanding exponentially since, as evidenced by just a quick Internet search that identifies dozens of such studies in every medical specialty.

This article focuses on breast cancer and the ocular effects of systemic therapy to treat breast cancer and the effects of radiation therapy and targeted cancer therapy (TCT) for head and neck cancers.

Breast cancer

Ocular metastasis

The spread of breast cancer to the eye is rare but can occur in men and women.² Freedman and Folk reported that the “breast is the most common site of origin of ocular metastatic tumors, since, in 49% of patients with ocular metastatic disease, the primary tumor origin was the breast."³

The uveal tract in the eye was reported as “the most favored sites where breast cancer metastases develop.”⁴

Ocular toxicity with systemic treatment

Kevin Kalinsky, MD, MS, pointed out the fairly recent recognition of the toxic side effects in the eye caused by the newer systemic breast cancer treatment modalities. He is Professor of Medicine and Director of the Medical Oncology Division, Department of Hematology and Medical Oncology, Emory University School of Medicine, and the Louisa and Rand Glenn Family Chair in Breast Cancer Research, Winship Cancer Institute of Emory University, Atlanta.

Toxicity from systemic treatment of breast cancer is being increasingly evaluated in patients treated with novel therapeutics, according to Kalinsky. “With the antibody-drug conjugants that we administer, we are seeing development of keratitis, for example. Some drugs that provided limited efficacy but caused significant ocular toxicity, did not move forward through the approval process,” he explained.

One such drug was trastuzumab duocarmazine which was evaluated in the phase 3 TULIP Study.⁵

In that study, 291 patients were randomized to the active treatment group with the HER2-directed antibody-drug conjugate trastuzumab duocarmazine and 146 to the control group. The groups were followed respectively for median times of 35.6 and 32.0 months. The authors reported that the median overall survival rate was 21.0 months in the trastuzumab group and 19.5 months in the control group, with respective survival rates of 70% and 68%. The major ocular toxicity that developed with use of trastuzumab was keratitis.

With other drugs in development, patients being treated are instructed to not wear contact lenses, especially around the time of drug infusion to prevent development of keratitis, Kalinsky recounted.

The scenario of ocular toxicity associated with systemic breast cancer treatment is becoming increasingly complicated for clinicians and researchers in relation to drug development, he explained. “We often have ophthalmologists embedded in our trials with whom we can work closely. Many studies are including ophthalmic appointments even to screen patients before they can be included in clinical trials,” he reported.

Another breast cancer drug, docetaxel, has been observed to impact lacrimal duct function with patients experiencing significant epiphora.

In addition, novel endocrine therapies in clinical trials, such as selective estrogen receptor down-regulator like camizestrant, are associated with photopsia.

Kalinsky commented, “Oncology is a multidisciplinary approach. Historically, we have been in close collaboration with surgeons, radiation oncologists, and immunotherapy specialists. With previously used breast cancer therapies, we were collaborating with pulmonologists and endocrinologists.

However, now with development of novel therapeutics, we are seeing ocular toxicity. Our need for collaboration with ophthalmology is only going to increase along with this relatively new phenomenon of ocular toxicities related to cancer therapies.”

In line with this, Kalinsky pointed out the emergence of new subspecialties, such as cardio-oncologists and pulmonary oncologists. The future may see an increasing need for ophto-oncologists to focus on treatment-related toxicities.

The American Academy of Ophthalmology also reports development other ocular toxicities with breast cancer drugs such as dry eye, retinopathy, cataracts, and conjunctivitis.⁶

Local treatment of metastatic eye disease

Local treatment, including radiotherapy, laser, anti-vascular endothelial growth factor (VEGF) therapy, photodynamic therapy (PDT), and enucleation, is another option used in addition to systemic treatment and also can impact eye health.²

Radiotherapy in the form of external beam radiation therapy is the most widely applied local treatment modality to treat ocular metastatic disease.⁷ However, it induces several ocular side effects, the most common of which are skin erythema, conjunctivitis, cataract, exposure keratopathy, iris neovascularization, radiation retinopathy, and papillopathy.⁸ Patients who survive longer than 6 months after undergoing external beam radiation develop side effects.⁹

Proton beam radiotherapy has been tested for localized intraocular irradiation¹⁰ and has fewer effects compared with external bean radiation therapy that include cataract, keratitis, and radiation maculopathy/papillopathy.

Several types of lasers have been used to treat metastatic eye disease and are beneficial for treating uveal metastatic disease.¹¹ Transpupillary thermotherapy delivers heat to the choroid and retinal pigment epithelium through the pupil and causes tumor necrosis.¹² Laser photocoagulation occludes the tumor vessels and tumor necrosis develops.¹² Laser does not cause ocular complications but is applied in small metastatic foci.¹¹

Bevacizumab (Avastin, Genentech), monoclonal antibody that blocks all VEGF-A isoforms, is the first anti-VEGF therapy approved by the FDA for colorectal, breast, and lung cancers.¹³ Recent case series studies have shown that metastatic choroidal disease refractory to systemic therapy responded to the drug with tumor regression.¹⁴ More extensive trials should help determine the exact treatment protocol. Its role in the treatment of uveal metastasis remains to be determined as more reports become available.²

PDT can achieve local regression of choroidal metastatic disease and complete tumor control was reported in 78% of cases.¹⁵

Ilias Georgalas, MD, and colleagues² commented, “Better screening, earlier detection, and better treatment modalities have positively altered the prognosis and survival time of patients suffering from breast cancer. This subsequently leads to an increased variety of ocular manifestations and problems associated with patients’ vision that are likely to require ophthalmological consultation and management. Because early diagnosis and prompt management may positively alter the prognosis for these patients, ophthalmologists should be aware of this entity.”

Head and neck cancers

Nagham Al-Zubidi, MD, is Associate Professor in the Department of Head and Neck Surgery, Division of Surgery, at MD Anderson Cancer Center, Houston. She asserted that ocular changes resulting from radiation therapy may have long-term treatment consequence.

“Eye changes,” she pointed out, “are common in cancer patients who undergo radiation therapy. This is especially true for patients with head and neck cancers, since radiation is delivered close to the eyes. Care teams deliver the most precise dose to destroy cancer cells; however, sometimes radiation can damage different structures in the eye including the retina and optic nerve, and may be serious enough leading to vision loss.”

In addition, these side effects can appear initially, such as blurred vision, tearing, redness, dry eye, and eye pain and discomfort and up to 18 to 20 months or even later after treatment and are often permanent, she emphasized such as cataract and radiation optic neuropathy and retinopathy.

The symptoms related to targeted cancer therapy (TCT) and immunotherapy for head and neck cancers include photosensitivity, loss of eyelashes, uveitis, changes in color perception, conjunctivitis, epiphora, light flashes/floaters, dry eye, glaucoma, and cataract, blurred vision to optic nerve/retina damage and vision loss in one eye or both eyes.

Al-Zubidi is senior author of a recent review¹⁶ of the ocular side effects of TCT agents.

She and her colleagues, in commenting on advances in cancer management, said, “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 2 main categories of TCT are monoclonal antibodies and small molecules. The former are synthetic biomolecules (-mabs) engineered to attack specific cell surface antigens; the latter can be oral agents and target intracellular pathways.¹⁷

The FDA list of side effects enumerates extensive ocular effects of monoclonal antibodies and small molecules.¹⁸

She explained, “TCT has the inherent risk of provoking and unleashing autoimmune mechanisms and disorders in the eye and visual pathways. Different ocular structures respond differently to various TCTs. 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).

She continued, “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.”

In addition, patients with orbital inflammation can present with pain upon eye movement, conjunctival injection, chemosis, proptosis, exposure keratopathy, diplopia, ophthalmoplegia with or with optic neuropathy, and blindness. Orbital inflammation may require emergent assessment and immediate discontinuation of the TCT.

The retina and/or optic nerve also can be impacted. These patients warrant immediate discontinuation of therapy and urgent referral to an ophthalmologist, Dr. Al-Zubidi said.

“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 immune-related adverse events. Ocular immune-related adverse events 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 immune-related adverse event 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,” she concluded.

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