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Systemic vs ocular cancers Cancer and the Eye: • Ocular cancers What you need to know • 2580 new cases each year (primarily melanomas) • 270 deaths Tammy P. Than OD, MS, FAAO • Systemic cancers University of Alabama Birmingham School of Optometry • 1.65 million new cases each year • 589,000 deaths

http://www.cancer.org/cancer/eyecancer/deta iledguide/eye-cancer-key-statistics

What we are going to talk about Definitions

• Cancer basics •Cancer: • How can systemic cancer affect the eyes? • A collection of diseases in which some • What should I be thinking if I see a patient of the body’s cells begin to divide with cancer? without stopping, grow out of control, • What treatments are available for cancer and can become invasive and how can they affect the eyes? • Malignant •Surgery • Can spread into, or invade, nearby •Radiation tissues •Chemotherapy • Differentiated vs undifferentiated

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“Pre-cancerous” changes Categories of cancer

• Carcinoma – • Lymphoma – begins most common; in lymphocytes (B- or T- formed by cell) epithelioid cells • Multiple Myeloma – • Sarcoma – form malignant plasma cells in bone and soft • Melanoma tissue • Neuroendocrine - • Leukemia – begin forms from cells that release in bone marrow; hormones in response to a abnormal WBCs signal from the nervous system

5 6 http://www.cancer.gov/about-cancer/what-is- http://www.cancer.gov/about-cancer/what-is-cancer cancer#differences-cancer-cells-normal-cells

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Most common cancers Metastasis

• Process by which • Increased risk if cancer spreads from tumor cells have the organ of origin aggressive traits on (primary site) to histopathology distant tissues • Poorly differentiated • Disorganized and • Invade beyond normal tissue boundaries invasive-appearing • Spread to regional tumors lymph nodes is one • Cells generally look of the early signs of the same as cells of met potential and/or the original cancer distant spread

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http://seer.cancer.gov/statfacts/html/all.html

Ocular metastases Choroidal metastases

• Rare site due to the absence of a lymphatic • Creamy yellow system within the eye subretinal mass, • Spread is via blood, therefore parts of eye often with with greatest vascular supply most likely to be subretinal fluid affected (73%) • : , esp perimacular choroid • Plateau or dome configuration • But still may be the most common intraocular malignant neoplasm • Unusually large amount of • Based on autopsy data; often not seen subretinal fluid • , , vitreous, , for their size can also be affected, but these are rare

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Choroidal metastases

• Solitary (72%) • Solid, usually • Avg was 1.6; range white/yellow 1-13 • 74% solitary • Posterior to the •42% inferior equator (92%) •Can shed tumor • Tends to grow rapidly cells that form a • May double in size pseudohyopyon or in a few weeks clog TM and cause

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Ciliary body Management

• Yellow dome- “Treatment may help prolong the lives of shaped; usually some people with metastatic cancer. In difficult to general, though, the primary goal of visualize clinically treatments for metastatic cancer is to • Inferior location control the growth of the cancer or to 48% of the time relieve symptoms caused by it. Metastatic tumors can cause severe damage to how • May be associated the body functions, and most people who with extensive RD die of cancer die of metastatic disease” and severe ocular 13 14 http://www.cancer.gov/about-cancer/what-is- cancer#related-diseases

Treatment/management Radiation

•External beam •Plaque “The aim of treatment is to restore radiation radiotherapy visual acuity and therefore improve • Lung and breast are • Can be completed most common in a few days the patients’ quality of life for their primary sites, and remaining life span” are radiosensitive • Specialty centers • Readily available • Must be able to • Time consuming: undergo surgery • 5 days/week Cohen VML (2013) • 30 min • For 2-10 weeks

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Other treatments Cancer of Unknown Primary

• Systemic chemotherapy • Clinical syndrome • Primary site becomes • May respond, especially to treatments • No primary site is identified obvious in only 5-10% of for breast cancer after standard clinical and patients during their pathological evaluation lifetime. • PDT (Photodynamic therapy) • Exact incidence is • At autopsy, primary site unknown, as many of the identified in ~ 75% of • Best for solitary metastases patient are “assigned” patients. other diagnoses • Primary sites in the • Intravitreal anti-VEGF • May account for 5% of all pancreas, lung, • Best for small, well-circumbscribed mets invasive cancers colorectum and liver without exudative RDs • Usually present with account for 60% of advanced cancer. cases. Breast, ovary, or • Especially good for colon cancer prostate are rare.

17 18 Greco FA, Hainsworth JD, 2011

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Paraneoplastic syndromes Paraneoplastic syndromes

• Group of rare disorders • Symptoms may be • Nervous and • Can cause a host of (~10%) that are triggered endocrine, are rare, affecting as few neurologic symptoms: as 0.01% of patients by an abnormal immune neuromuscular, • Difficulty walking, system response to a musculoskeletal, • Occurs when an immune swallowing, or talking cancerous tumor cardiovascular, response is mounted to • Loss of muscle tone or fine cutaneous, hematologic, motor ability • Disorders arise from tumor cancer antigens; these gastrointestinal, or renal cancer-fighting antibodies • Memory loss, dementia, secretion of hormones, seizures • May in part explain & T-cells mistakenly attack peptides, or cytokines OR • In the eye, they disrupt immune cross-reactivity some of the most normal cells in the nervous common symptoms of system - including brain, normal cellular function, between tumor and normal and ultimately cause host tissues cancer, such as fatigue, spinal cord, peripheral anorexia, and weight nerves or muscle – or the visual dysfunction. • Most common in individuals loss. eye with lung, ovarian, lymphatic, or breast cancer 19 20 Rahimey E, Sarraf D (2013) Rahimey E, Sarraf D (2013)

Cancer-associated Cancer-associated retinopathy

• Likely most common of the intraocular PNS • Precedes diagnosis of underlying cancer in • Painless visual loss, developing over weeks to about 50% of patients months • Diagnosis made by labs (anti-retinal antibody • Symptoms: photosensitivity, photopsia, glare, testing) and ERG (severely reduced to poor central and color vision (cones) OR extinguished) nyctalopia, impaired dark , ring • No effective treatment - long-term , or other peripheral field loss (rods) immunosuppresion is the main therapy – but • Fundus findings normal, or optic nerve pallor, visual prognosis is poor; vision loss is often attenuated retinal arterioles, and RPE thinning rapid and relentless. and mottling • Treatment of underlying malignancy does not appear to be effective

21 22 Rahimey E, Sarraf D (2013) Rahimey E, Sarraf D (2013)

Take home points Basic Principles of Therapy

• Systemic cancer is prevalent in the population, and will continue to be increasingly prevalent •Staging guides therapy • Metastases to the eye are most common in the choroid, but can occur anywhere in the eye •TNM • 75% of the time the primary site will be the lung or breast •Multimodality treatment • Patients with cancer and new complaints of blurred vision or eye pain should be evaluated •Cure versus Comfort • Although rare, be aware of the clinical entities of paraneoplastic syndrome and CAR •Risk versus Benefit

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Surgery Radiation Therapy: The Basics

• Localized malignancy • Administration • Surgery alone for • Teletherapy ~25% of patients • Brachytherapy • May be palliative • I-125, Sr-90, Ru-106 • Ocular complications • Targets DNA - impairs division can occur • Dependent upon tissue • free radicals generated excised • Intensity Modulated Radiation Therapy • Spectacle considerations (IMRT)

Radiation Therapy: Radiation Therapy: The Basics Treatment Considerations

• Rad = unit of absorbed energy in •Fraction Size tissue • < 225 cGy / day • Gray (Gy) = 100 Rad • Fractionation Schedule • the “latest” unit • 5 days / week for 2-7 weeks • beam is on for 1-2 minutes • 1 Gy = 100 cGy • Hyperfractionation • Chest X-Ray is < 1 cGy • Cancer treatment may be 6000 cGy • Fraction size is key!

Radiation Therapy: Radiation Therapy: Tumors to Treat Treatment Considerations

Tissue Dose, cGy •High radiosensitivity Brain 6000 • High mitotic activity Spinal Cord 4500 • Highly vascularized Heart 4500 Intestine 4500 Liver 3000 Lung 2000 Kidney 2000 Bone Marrow 250

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Radiation Therapy: Radiation Therapy: Acute Radiation Sickness Long Term Complications

•GI upset • Tend to be progressive •N/v • Diarrhea • Can occur years after •Anemia treatment • Depends on area radiated • Incidence increases with: •Skin rashes • More fractions • Alopecia - localized • Larger fractions •Fatigue • Higher total dose

Radiation Complications: Radiation Complications: Anterior Segment Diagnosis and Management

• Focal radiation • • Head/neck delivery • Conjunctiva • Total body irradiation •Lacrimal • Prior to bone marrow transplantation • 13% (N=397) had posterior segment system complications • • Hemibody irradiation • Decreases diffuse bone pain •Iris • Treats multiple disease sites • • May require treatment of other half •

Radiation Complications:

• Telangiectasia • Causes secondary to radiation: • •KCS • Transient • Permanent (>50 gy) • Pseudo-epiphora •Erythema • • Usually resolves in several weeks • Nasolacrimal duct obstruction • • Management •Ectropion • Prophylaxis with silicone tubes • •Dcr

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Dry Eye Dry Eye: Management

• Aggressive lubrication • Int J Radiation Oncology 30(4) 1994 • 61% had severe decrease in VA due to dry • Medical Management eye • Salagen® (pilocarpine) • Symptomatic in 1 month •Xerostomia post head/neck • Opacification in 9-10 months radiation • More likely if >30 gy • 5-10 mg tid • Off-labeled for severe, recalcitrant dry eye • Evoxac® (Cevimiline) • 30 mg tid (Sjögren’s associated xerostomia)

Dry Eye: Management

• Conjunctival flap •PSC most • Tarsorraphy common • Enucleation • Can get ASC • 12/30 patients • Can develop in infant if mom receives radiation during first trimester

Let’s move to the posterior segment...

Acta Ophthalmol Scand 2007: 85: 240-250

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Radiation Retinopathy: Radiation Retinopathy Signs

• 6-36 months after radiation • Capillary nonperfusion: hallmark • Damage because of occlusive • Intraretinal hemorrhages microangiopathy • Microaneurysms • Increased incidence if: • Retinal NFL infarcts •Chemotherapy •Exudates •DM or HTN • Vessel sheathing • Collagen vascular disease

Radiation Retinopathy: Clinical and Experimental Further Complications Optometry

• 2007; 90(6) • • 44 YOM •NVE • Referred for evaluation of HTN •NVD retinopathy •NVI • more likely in • Gradual reduced vision OS>OD the angle?

Radiation Retinopathy: Management Neovascular Glaucoma

• R/O other causes of •Incidence retinopathy • 14% if >50 G •Laser •7% overall •PRP • May not have •Focal retinopathy! •Intravitreal •Average time of Injections onset •Anti-VEGF • 1.3 – 2.2 years •Steroid post-radiation •Preventive?

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Radiation Radiation Induced Cerebral Necrosis

• Onset: 2 months - 7 years • Visual pathway is • Average: 1 year • Sudden, painless, unilateral loss of vision highly susceptible •(+) Apd •Optometrist may • Possible prodrome reported detect • Acute presentation (two variations) • Onset 3 - 22 years!! • Anterior ischemic optic neuropathy • Usually irreversible • Retrobulbar optic neuropathy • Chronic presentation and progressive • Optic atrophy

Radiation Induced Cerebral Necrosis Orbit

• Often diagnosis of • Bony structures exclusion •Hypoplasia • Rule out: • Soft tissue •Neoplasm • • Abscess • Prosthetic fit is •Cva difficult •MRI • Diagnostic imaging of choice

Biological Response Modifiers Interferon-Induced Retinopathy • Often asymptomatic • Interferons • Prospective study of chronic hepatitis C • Inhibit transcription of a number of patients oncogenes • Up to 57% incident • Alter cytokine secretion from normal • May be subclinical cells • Intraretinal hemorrhages, cotton wool • Results in regulation of tumor growth spots •Adjuvant • Rule out other causes • Cutaneous melanoma • Resolution often after d/c interferon •Leukemia therapy • Lymphoma

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Chemotherapy: The Basics Tamoxifen

• Disseminated • Selective estrogen receptor malignancy modulator •Neoadjuvant • Interferes with binding of estradiol • Combo drugs to its target tissues •Routes: • Indications •Local •Regional •Breast • Systemic: IV., P.O. • Prophylactic through metastic • Conventional •Ovarian • Targeted •Pancreatic • Malignant melanoma

Tamoxifen: Ocular Effects Tamoxifen Retinopathy

• Keratopathy • Bilateral yellow-white crystals in • White-yellow subepithelial opacities ring-like pattern •Retinopathy • 13-35 microns • +/- Macular edema • Location is debatable: NFL, RPE, IPL, • Cataracts OPL • ASC • Superficial to vasculature • Optic neuropathy •Rare •  Macular edema • Macular holes? • Crystals usually do not resolve • International 2005; 26(3) with discontinuation of therapy

Specific Examples with Specific Examples with known OADR known OADR

• Epidermal growth factor •Docetaxel (taxotere®) receptors (EGFR) inhibitors •Epiphora • Dry eye •Trichomegaly •Canalicular stenosis • Trichiasis • Persistent corneal erosions •Cme • Imatinib (gleevec®) • Periorbital edema •Increased IOP • Epiphora • Subconjunctival hemorrhage

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Our Role Role of Optometrist

• Prevention • During Cancer Treatment • Encourage appropriate behavior • Educate yourself! • Encourage screenings • Educate patient • Early Detection • Treat if symptomatic • If in doubt, refer it out • Depending on treatment – consider prophylactic management

Role of Optometrist We have an important role to play on the cancer •After patient’s management team. • Ocular lubricants • Patient WILL have dry eye • Good case history •Radiation? •Fraction •Dose • Chemotherapy agents? • Refer as needed for ocular sequelae

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