Radiation retinopathy intricacies and advances in management

ABSTRACT

Background

Radiation retinopathy is a chronic, progressive, vision-threatening complication from exposure to various radiation sources. While several treatment modalities are available, proper management for this disease is a continuing challenge with no consensus on the most efficacious.

Objective

The aim of this article is to provide an updated review of the published literature on the course of the disease, available treatments and their efficacies, frequency of regimen, core issues in patient management, and additional newer treatment modalities, including possible prophylactic approaches.

Value

We also highlighted the challenges encountered with managing chronically treated patients through an analysis of a clinical case report on a patient who was treated for several years with different modalities after a diagnosis of radiation retinopathy.

KEYWORDS:

• Radiation retinopathy
• maculopathy
• Intravitreal anti-VEGF
• corticosteroids
• bevacizumab
• aflibercept

Introduction

Radiation retinopathy is a chronic, progressive, vision-threatening complication from exposure to various radiation sources. It is often exhibited in patients undergoing intraocular tumor irradiation (such as for ocular melanoma and retinoblastoma) and orbital, periorbital, facial, nasopharyngeal, and intracranial irradiation. The incidence of radiation-induced retinopathy ranges from 3 to 20% and is largely determined by the source, dose, and type of irradiation used in oncological management, along with tumor and treatment characteristics.¹

In 1933, Stallard first described radiation retinopathy as a delayed yet progressive presentation of degenerative and proliferative retinal vascular changes in a patient who was previously treated with radon seeds for retinoblastoma.² The changes in the retina included microaneurysms, telangiectasias, neovascularization, vitreous hemorrhage, hard exudates, cotton wool spots, and macular edema. Dr Moore corroborated these findings in 1935 in a case of melanotic sarcoma of the choroid treated by sclera implantation of radon seeds. In the following years, numerous authors demonstrate profound alterations in the retinal microvasculature following newer and prevailing types of radiotherapy.^3–12 Since then, the growing prevalence of radiation retinopathy is a result of the increased use of radiotherapy for a multitude of diseases.

Despite the various treatment modalities available, the management of radiation retinopathy remains an ongoing challenge. This review presents a case of radiation retinopathy and discusses the development and course of the disease, a selection of treatment methods available, suggested dosing, and newer treatments. The authors hope to highlight the current core issues surrounding the management of radiation-induced retinopathy and the dire need for advancements in the treatment options for these patients.

Methods of Literature Search

The MEDLINE and PUBMED Library databases were searched for all literature published in English language before April 2021. While it would not be feasible to include a comprehensive list of all the relevant search terms used in the preparation of this article, combinations and derivatives of the following words provided most of the manuscripts that were reviewed for inclusion in the article: radiation retinopathy, cranial irradiation, external beam radiation, proton beam irradiation, plaque radiotherapy, uveal melanoma, retinoblastoma, microaneurysms, telangiectasias, neovascularization, vitreous hemorrhage, hard exudates, cotton wool spots, macular edema, endothelial cell injury, macular ischemia, cystoid macular edema, diabetic macular edema, Fluorescein Angiography (FA), Indocyanine Green Angiography (ICG), Optical Coherence Tomography (OCT), Spectral Domain OCT, Optical Coherence Tomography Angiography (OCT-A), Vascular Endothelial Growth Factor (VEGF), Intravitreal Anti-VEGF agents, pegaptanib sodium, bevacizumab, ranibizumab, aflibercept, brolucizumab, laser photocoagulation, coagulation, protein denaturation, intravitreal corticosteroids, intravitreal triamcinolone acetonide, sub-Tenon’s steroid injections, sustained-release steroid implants, sustained-release dexamethasone implant (Ozurdex), macular thickness, photodynamic therapy, verteporfin, hyperbaric oxygen, and oral pentoxifylline. The abstracts of the resulting articles were carefully reviewed for suitability and inclusion, and the articles that were not relevant were discarded. The bibliographies of all identified literature were reviewed to track additional relevant references, including some that were not published in English language.

Case presentation

A 64-year-old patient presented in 2018 with a chronic decrease in vision of the left eye for several years. The patient had been diagnosed with an intracranial frontal lobe astrocytoma in 1997, for which she underwent a left frontal lobe craniotomy and several aggressive cycles of radiation to the brain. She is otherwise healthy, with no other significant systemic disorders. Given her oncological history, diffuse left eye macular edema, and unilateral microvascular retinopathy without a history of associated comorbidities, the patient was diagnosed with radiation retinopathy of her left eye in November 2016, with a Best-Corrected Visual Acuity (BCVA) of 20/80.

At that time, the patient was initially treated in a pro-re-nata (PRN) regimen according to subretinal fluid (SRF), requiring two intravitreal bevacizumab injections, one adjunct intravitreal Triesence, and one sub-Tenon’s Kenalog (STK) later on within two years with good response. By early 2018, she had recurrent SRF involving the macula and a BCVA of 20/125 for which she was started on a more continuous regimen of monthly intravitreal bevacizumab and STK every 4 months. One treatment with focal laser was added to try to reduce the injection interval. However, interval reduction was not possible as after 6 bevacizumab injections, the macular edema and exudates persisted with a worsening BCVA of CF at 6 ft and a central foveal thickness (CFT) of 352 microns in mid-2018.

Given the recalcitrant state, she was treated with two subsequent monthly trials of intravitreal aflibercept (Eylea), with a BCVA improvement to 20/200 (Pinhole, PH 20/30) and CFT reduction to 318 microns. Due to insurance changes, the patient had to be switched back to monthly bevacizumab by the end of 2018. Around one year later at the end of 2019, her vision was maintained at 20/100 but with a worsening CFT of 376. At that visit, fluorescein angiography showed ischemia on the far inferotemporal periphery with delayed venous filling, for which she was diagnosed with Peripheral Branch Retinal Vein Occlusion (BRVO). Despite our expectation of significant visual acuity improvement and significant reduction in CFT with monthly aflibercept injections, the patient remained relatively unimproved in CFT and BCVA: ranged between 360 and 403 and 20/100 and 20/400, respectively, toward mid-2020. Sectoral panretinal photocoagulation (PRP) was then added to the peripheral inferotemporal ischemic retina, and the anti-VEGF treatment interval was extended to bimonthly injections (every 8 weeks) primarily for patient convenience. The patient maintained a CFT within the above range and a stable BCVA of 20/400 (PH 20/50) with bimonthly intravitreal aflibercept injections.

Pathogenesis

Radiotherapy has been employed for the treatment of oncological diseases for numerous decades. Despite the progress and advances in radiotherapy, its use in head and neck neoplasms remains a definite cause of radiation retinopathy. Retinopathy may follow cranial radiation, external beam radiation for extracranial head and neck tumors, or local therapy for intraocular tumors.^13–15 Amoaku et al. reported that the overall incidence of radiation-induced retinopathy following cranial irradiation is 17%. The proximity of radiation to ocular structures increases the incidence of radiation retinopathy with 85% incidence in eye or orbit, 45.4% for paranasal sinus, and 36.4% for nasopharynx irradiation.¹³

The onset of radiation-induced retinopathy varies according to the type and dose of radiation. Brown reported that the mean latent period until the onset of radiation retinopathy in patients treated with Cobalt60 plaque therapy is 15 months vs. 19 months for external beam radiation.¹⁴ The timeline for a late sequel of radiation, proliferative radiation retinopathy, is also more prevalent as the disease progresses: 5.8% of eyes at five years and 7% at ten years postplaque radiotherapy for uveal melanoma.¹⁵ Several exogenous factors such as young age, diabetes mellitus, hypertension, tumor distance to optic disc, and concurrent chemotherapy augment the onset and development of radiation retinopathy.^14–16

Studies report that the total dose, as well as dose per fraction, has an impact on the development of retinopathy. Parsons reported that radiation retinopathy was more commonly observed at doses larger than 45 Gy.¹⁷ The generally accepted total radiation retinopathy threshold is 3000 rads (30 Gy) delivered in 1/3rd weekly treatments divided into five daily equal fractions of 200 rads.^9,14,16,18 Radiation doses larger than the threshold (either total dose or daily/weekly fraction) will understandably exhibit a greater occurrence and severity of retinopathy. For example, Merriam et al noted an 85% incidence of retinopathy in eyes treated with 7,000–8,000 rads (70–58 Gy).¹⁸

Histopathological and ultrastructural studies report that the fundamental insult is radiation-induced endothelial cell injury of the retinal vasculature, with relative sparing of the pericytes. These pathological alterations resemble that of diabetic retinopathy eyes, in which vascular pericytes are decreased in number and function in addition to endothelial injury.^14,19–22 Archer et al. suggested that the alterations in radiosensitivity of Retinal Vascular Endothelial Cells (RVECs) result from their nuclear chromatin conformation. The heterochromatic nucleus of endothelial cells facilitates less enzymatic repair and differs in cell metabolism with lower antioxidant properties than neighboring cells, thereby increasing their susceptibility and resulting in cell death and epithelial damage.²⁰ Such endothelial cell injury of retinal vasculature exceeds the ability of the RVEC layer to maintain the endothelial lining, which triggers inflammation and clotting cascades, resulting in occlusion of retinal capillary beds. The hemodynamic stress from capillary occlusion results in the formation of capillary collaterals and dilation of the neighboring capillaries, ultimately leading to retinal ischemia.^19–22 The altered hemodynamics of retinal vessels produce large telangiectatic channels with thick adventitia and fenestrated endothelium, ultimately resulting in vascular incompetence and exudation beyond the blood-retina barrier (ie, macular edema).^19,20

Retinal manifestations

The retinal effects and complications of radiotherapy, although highly prevalent, are usually not clinically expressed for 1.5 to 3 years following irradiation.²³ Studies such as the one conducted by Archer et al. suggest that despite modern radiotherapeutic screening techniques, approximately 55% of patients receiving therapy for orbital and periorbital tumors develop radiation retinopathy and 50% of these patients have worsened to sight-threatening vascular complications of irradiation.²⁴

The clinical and histopathological features of radiation retinopathy are similar to the fibrovascular proliferation seen in diabetic retinopathy.²¹ Stallard first observed radiation-induced retinal changes as a circinate type of retinopathy with retinal hemorrhages, exudates, optic disc edema, and sheathing of the central retinal vessels 20 months after irradiation in the case of retinoblastoma that was treated with radon seeds.² Studies have revealed that the posterior pole is more radiosensitive than the peripheral retina, with primary manifestations being microaneurysms, cotton wool spots, retinal hemorrhages, capillary nonperfusion, and nerve fiber layer infarction. These effects may be followed by cystoid macular edema, exudates, telangiectasia, neovascularization, vitreous hemorrhage, and vitreoretinal traction.^14,21,25

Decreased vision secondary to macular edema is the earliest symptom of radiation-induced retinopathy, as stated by Horgan et al. in a study of retinopathy following plaque radiotherapy for uveal melanoma. OCT evidence of macular edema was present in 33% of study subjects in the absence of clinical evidence of radiation retinopathy, asserting that macular edema can be found on OCT approximately five months earlier than clinically evident radiation retinopathy.²⁶

Vascular manifestation of radiation insult involved microvascular infarcts that can expand to large confluent areas of retinal ischemia in severe exposures. The experimental primate model of Irvine et al documented infarcts (eg, cotton wool spots in the posterior pole) that expanded into large areas of ischemia where the level of nonperfusion correlated with the dose of radiation.²² The ischemic retina would trigger a cascade of dilation of feeding vessels, new retinal hemorrhages, and microaneurysm formation. Finger and Kurli devised a classification system of retinal manifestations describing stages I–IV, dependent upon worsening peripheral to macular findings or neovascularization with or without vitreous hemorrhage from radiation-dependent ocular ischemia.²⁷

Ocular manifestations

Ocular structures consist of varying sensitivity to radiation and its effects. In addition to retinal manifestations, radiotherapy affects the anterior segment of the eye. The acute short-term effects to the lids and the anterior segment include lid edema, dermatitis, erythema, epilation, conjunctivitis, dermatitis, keratitis, corneal ulceration, and iritis. The delayed and long-term radiation effects to the ocular structures consist of tissue necrosis, dry eye, telangiectasia, scleral melting, cataract formation, secondary glaucoma, corneal neovascularization, retarded bone growth (of bones within the irradiated field), and radiation-induced cancers.^28–31

Parallel to radiation-induced retina effects, numerous studies have explored the numerical dose effects of radiation therapy on the anterior segment and ocular adnexa, such as the effects of the fraction size of radiotherapy (Table 1). Large fractions with a shorter exposure time using radiation with greater relative biological effectiveness (RBE) tend to be more damaging.³⁷

Table 1. Radiation dose effects on ocular structures

Radiation dose (cGy)	Affected ocular structure	Comments
>50	Lens: Cataract changes (ICRP threshold)^Citation32–34	Six-fold increase in cataract extraction rates after ≥ 500 cGy compared to eyes exposed to ≤ 250 cGy.^Citation35 Lens-sparing techniques upon irradiation can reduce the cataract formation rate from 87.5% to 23.1%.^Citation36
3000–4000 (and large fractions eg, 1000 cGy)	Eyelid erythema, blepharitis, and lash loss^Citation37 Cornea: Keratitis, edema, and small ulcers^Citation37	Alterations prevented with smaller fractions until the threshold exceeds 5000 cGy^Citation37
>5000-6000	Lacrimal gland changes, tear duct atrophy, ocular surface disease→keratoconjunctivitis sicca and permanent loss of secretions→corneal ulceration (late complication)^Citation32,Citation37,Citation38	≤ 4000 cGy could avoid development of dry eyes^Citation32,Citation38

Abbreviations: cGy, centigray; ICRP, International Commission on Radiological Protection

Diagnostic procedures

The techniques utilized for diagnosing radiation retinopathy has progressed over the years from clinical findings and ophthalmoscopic evidence to additional diagnostic procedures such as Fluorescein Angiography (FA), Indocyanine Green Angiography (ICG), Optical Coherence Tomography (OCT) to faster Spectral Domain OCT and swept-source OCT, and newer procedures such as Optical Coherence Tomography Angiography (OCT-A).

Fluorescein Angiography

The first fluorescein angiographic features of radiation retinopathy were described by Chee in 1968 as microvasculopathy with capillary incompetence and closure.⁹ Since then, fluorescein angiography has been greatly utilized to highlight vascular architecture alterations, which demonstrate that vascular decompensation is the primary mechanism of radiation damage in the posterior segment.^39,40

Amoaku and Archer conducted a fluorescein angiography study of patients who received cephalic radiation to document the natural course of the disease. The study demonstrated a wide range of microvasculature alterations graded from I–IV depending on the extent and degree of capillary malformation, incompetence, and closure.⁴¹

While fluorescein angiography remains advantageous showing vascular structures and functional changes including retinal ischemia, it involves an invasive, time-consuming procedure with several side effects of the intravenous infusion of fluorescein such as nausea, vomiting, urticaria, and dizziness. Rare but serious reactions such as chest pain, hypertensive crises, allergic reactions, and myocardial infarctions have been documented.⁴²

Indocyanine Green Angiography

Indocyanine green angiography (ICG-A) is highly utilized in radiation retinopathy to detect associated damage to the choroidal vasculature.⁴³ Choroidal vasculature is greatly affected by radiation with partial or complete loss of choroidal vessels and vascular remodeling. The choroidal changes include sclerosis of choroidal vessels, atrophy of the different layers of the choroid and Bruch’s membrane, and proliferation of the RPE.^44,45 The choroidal contribution to retinal diseases such as radiation retinopathy promotes ICG-A in the diagnostic process.

The ICG-A demonstrated that, morphologically, the features of radiation-induced choroidal vasculopathy resemble the vasculopathy of the neurosensory retina such as beading of vessels, telangiectatic-like dilatations, microaneurysms, and new vessel formation. Amoaku et al. suggested that ICG staining of the choroidal vascular wall in radiation choroidopathy is due to radiation-induced endothelial cell loss.⁴⁵ This highlights the pathogenic association between the choroidal and retinal vasculature in radiation-induced disease to the posterior segment and emphasizes the importance of ICG-A examination of the choroid for radiation-induced retinopathy.

Optical Coherence Tomography

Optical Coherence Tomography (OCT) has been established as an important tool in the diagnosis and management of various retinal diseases as it is a noninvasive and reproducible approach that produces cross-sectional, three-dimensional images of the retina. OCT is commonly utilized to detect, evaluate, and grade cystoid macular edema in radiation retinopathy. Levitz et al. first documented OCT evaluation of radiation maculopathy in 2005 and described intraretinal cystic spaces and photoreceptor loss.⁴⁶ Its high efficiency and accuracy in the detection of edema has been reported in numerous studies.

Horgan et al. evaluated the onset and development of macular edema following plaque radiotherapy for uveal melanoma using OCT in comparison to clinical examination. The incidence of macular edema detected by OCT was 17% at 6 months, 40% at 12 months, 57% at 18 months, and 61% at 24 months (in comparison to incidence of 1%, 12%, 26%, and 29%, respectively, when detected by clinical examination).²⁶ The study demonstrated that OCT-evident macular edema may be identified much earlier than when clinically detectable and before a substantial visual loss occurs. However, poor contrast limits its use for identifying vascular changes and differentiating between static tissue and blood vessels in the retinal layers.⁴⁷

The advent of Spectral Domain (SD-OCT) and Swept-Source OCT (SS-OCT) improves the detection and monitoring of retinal diseases with higher resolution and faster scanning engines that allow for more detailed visualization of retinal architecture and its distinctive layers.^48,49 Shah et al. demonstrated SD-OCT detection of vasculopathy changes and evidence of macular edema in radiation-induced maculopathy as early as 3 months following radiotherapy, suggesting its use for early detection and management of the disease.⁵⁰ Due to its diagnostic value, Horgan et al. proposed a modification in the radiation retinopathy classification by Finger and Kurli that integrated SD-OCT findings of macular edema.^26,27

Optical Coherence Tomography-Angiography

The recent development of OCT-angiography (OCT-A) for retinal imaging, as a noninvasive, dye-free, high-resolution, reproducible imaging tool, detects the flow of streaming blood to visualize retinal microvasculature. It provides a detailed visualization of the inner and outer retinal capillary networks including the deeper vasculature, which corresponds to a more accurate assessment of disease progression and visual prognosis of radiation-induced retinal microvascular retinopathy.^51,52

Ocular pathologies are highlighted by leakage and staining in FA, while OCT-A identifies the abnormal presence of flow in the layers that usually lack blood vessels or the absence of flow in normally vascular layers. With its ability to quantify perfusion and separately visualize retinal and choroidal vasculature, OCT-A is highly utilized in various clinical applications.²³ It enables early detection of choroidal neovascularization before the development of symptoms or detectable changes with FA or structural OCT.⁵³ Since the primordial and earlier retinal complications from radiation seem to be vascular related, OCT-A has a potential in the early diagnosis of the disease. Studies of OCT-A have demonstrated several distinct signs induced by radiation including foveal avascular zone (FAZ) enlargement, superficial and deep capillary plexus dropout, and decreased choriocapillaris vascular density. These detailed features suggest its ability to detect vascular abnormalities and signs earlier than clinically observable through ophthalmoscopy or SD-OCT.^52,54–56 Moreso, correlations between these findings and their role in visual acuity are being studied.^52,55 These OCTA features are being combined with SD-OCT findings of cystoid macular edema and macular thickness to develop grading systems for radiation retinopathy that may guide treatment.^53,57 However, OCT-A visualization of retinal vessels may be limited by the presence of edema, and it may be misinterpreted with the presence of technical artifacts.^47,55

OCT-A may be valuable in distinguishing benign from malignant lesions, in earlier detection of radiation-related complications, in management and duration of therapy with established disease, and in possible treatment interventions to delay the retinopathy. Both SD-OCT and OCT-A analyses may play an important role as biomarkers that predict the anatomical and functional outcomes and efficacy after anti-VEGF treatment.^55,58,59

Management

Various therapeutic regimens have been endeavored to treat radiation-induced retinopathy, ranging from surgical to pharmacological methods. Despite the various treatment methodologies and combinations reported for treating radiation retinopathy, no mainstay treatment currently exists.^60–62 The efficacy of treatment regimens is generally assessed by the improvement (or stabilization) of visual acuity, macular edema resolution, and regression of fundoscopic retinal features, including hemorrhages, exudates, microaneurysms, and neovascularization.

Retinal Laser Photocoagulation

Laser photocoagulation is extensively used in the treatment of diverse retinal diseases. It involves the absorption and conversion of radiant energy into thermal energy by retinal tissues, resulting in protein denaturation and, ultimately, coagulation. A meager increase of 10°C to 20°C is sufficient for coagulation of tissue, but the effect is dominant at 60–70°C.⁶³ Retinal photocoagulation effectivity in vasculopathies has allowed its use to treat radiation retinopathy, although with limited efficacy.

Photocoagulation decreases the leakage from abnormally permeable retinal vessels and proliferation of new retinal vessels and limits the neovascularization stimulus by converting a hypoxic retina into an anoxic state. This effect is observed clinically as complete regression of neovascularization after treatment, decreased radiation-induced retinopathy signs, resolution of macular edema, and temporary preservation of vision following laser treatment.^27,64–66 Visual acuity improvement has been observed as a modest one-line gain in the Snellen chart that is not sustained after 24–39 months of single treatment with focal laser photocoagulation.⁶⁶ Although panretinal photocoagulation (PRP) studies also improved clinical signs of maculopathy, visual acuity did not, with patients having worsening vision despite treatment.^27,66 According to Missotten et al.,⁶⁷ there are above-average levels of antivascular endothelial growth factor (VEGF) in eyes with uveal melanoma that increased after plaque radiotherapy and proton beam irradiation, suggesting a dual tumor and retinal source of VEGF production. As laser photocoagulation obliterates the ischemic retina, it may reduce the intraocular production of VEGF, having potential as a prophylactic tool with better effectivity before there is clinical evidence of retinopathy. A study by Finger et al. explored this concept in a subset of high-risk patients and reported only 3 out of 16 patients who developed retinopathy (only one involving the macula) after receiving prophylactic laser treatment that regressed after sector enlargement. This approach may benefit long-term vision preservation.²⁷ Therefore, laser photocoagulation treatment may be important as a prophylactic intervention but with limited efficacy and unsustained long-term effect as a sole treatment.

Anti-VEGFs

The Vascular Endothelial Growth Factor (VEGF) protein is secreted under hypoxic conditions and acts as a key regulator of angiogenesis. Due to RNA splicing, VEGF exists in 4 different isoforms with similar biological properties, but varying secretory patterns.^68,69 Animal models have displayed the development of ischemic and pathologic alterations following exogenous administration of VEGF.^70–72 It has been known to mediate intraocular neovascularization in numerous ischemic retinal diseases.^73–75

Anti-VEGF agents are selective antibodies that block VEGF to inhibit angiogenesis. These agents have demonstrated to be revolutionary in preventing vision loss in various retinal diseases including diabetic retinopathy, retinal vein occlusions, and age-related macular degeneration.^76,77 Similarly, their positive effect in radiation retinopathy and consistent success has shifted the research focus toward the study of these agents either as sole management or in combination with laser or steroids.

Pegaptanib Sodium

Pegaptanib sodium (Macugen) is a selective RNA aptamer that inhibits VEGF165, which mediates pathological ocular neovascularization and vascular permeability, while it spares VEGF121, the physiological isoform.⁷⁸ This selectivity was observed in rodent models where the anti-VEGF agent drastically reduced the pathological ocular neovascularization while leaving the physiological neovascularization intact.^79,80 Pegaptanib sodium was the first anti-VEGF agent and the first aptamer approved for therapeutic use in the treatment of ocular vasculopathies, including AMD, with good effectivity and excellent safety profile.^78,81,82 Studies show that it was more effective than laser photocoagulation in the regression of neovascularization, decrease in mean CMT, and increase in visual acuity.^82,83 Some of the reported adverse events include visual impairment, nausea, vomiting and drug hypersensitivity, in contrast to the cardiovascular adverse events in bevacizumab and infective ocular reactions in eyes treated with ranibizumab.⁸⁴

The only study found regarding its use for radiation retinopathy was published by Querques et al. regarding a patient who developed pathological capillary alterations, retinal hemorrhages, neovascularization, and retinal exudation 14 months after treatment with 106Ru episcleral plaque for a choroidal melanoma. The retinopathy was nonresponsive to treatment with sector scatter laser photocoagulation. Following intravitreal pegaptanib sodium injections, they reported regression of retinal and macular exudation and disc neovascularization and improvement in the visual acuity that maintained till the 6-month follow-up.⁸⁵ However, no other reports were found, probably due to the release of the modern effective anti-VEGF agents.

Modern anti-VEGF Agents

Bevacizumab (Avastin®) is a humanized monoclonal antibody to the VEGF-A isoform, which is commonly used in various retinal vascular disorders as first-line therapy due to its cost-effectiveness compared to the other anti-VEGF agents.⁸⁶ Its systemic route increases the risk of cardiovascular and thromboembolic events (stroke and myocardial infarction), with its intravitreal counterpart having a better safety profile with less systemic involvement. Correspondingly, several case reports and case series started publishing on the safety and efficacy of bevacizumab for radiation retinopathy. They presented regression of radiation-induced neovascularization as soon as two days after intravitreal injection and marked improvement in macular edema with a decrease in the mean central macular thickness (CMT) measured by OCT. Results were consistent with improvement of radiation retinopathy clinical signs (cotton wool spots, retinal edema, and intraretinal hemorrhages), but visual acuity changes were variable and unpredictable with the majority of reports showing short-term and very minimal improvement or stabilization of vision.^87–94 Larger interventional case series and retrospective studies supported these findings. Finger reported a decrease in vascular leakage (retinal hemorrhages, exudation, and edema) and stabilization or improved vision with only 3 out of 21 (14%) patients regaining ≥ 2 lines of vision when treated with intravitreal bevacizumab (1.25 mg in 0.05 mL) every 6–12 weeks.⁹⁵ Mashayeki et al. treated 36 patients with macular edema after plaque radiotherapy for uveal melanoma with four monthly injections and found 56% of patients with decreased CMT (−174 µm), 31% with stable CMT (−14 µm), 42% with increased BCVA, and 44% with stable BCVA at 4–6 months follow-up.⁹⁶ Therefore, even with a decrease in the retinal thickness, if the macular edema is long-standing or ischemic changes are present, the effects seen in visual acuity after injection will be limited. Gupta et al. concluded that a shorter duration of macular edema and a younger age may correlate with better visual acuity outcomes.⁹⁷

Some patients who initially responded to intravitreal bevacizumab seem to develop a resistance to its effects after several injections. A study by Khan et al. investigated the efficacy of a higher dose of bevacizumab (2.5 mg/0.1 mL) as rescue therapy for persistent CME after previous treatment with approximately ten injections of the standard 1.25 mg/0.05 mL dose. In the studied 15 patients, there was an initial significant reduction in CMT and visual acuity at three months, but by the month nine follow-up, only 5/15 (30%) maintained significance regardless of constant monthly injections, emphasizing a lesser importance in treatment dosage for efficacy.⁹⁸ Therefore, the availability of multiple anti-VEGF alternatives is key in the management of radiation retinopathy.

Ranibizumab (Lucentis ®) is a recombinant, humanized monoclonal antibody Fab fragment, derived from bevacizumab, that neutralizes all VEGF-A isoforms with more affinity. Rosenfeld reported that the maximum tolerated dose of a single intravitreal ranibizumab injection in neovascular AMD patients is 500 µg and that doses above 1000 µg induces intraocular inflammation.⁹⁹ Ranibizumab has been provided as an effective alternative for patients with radiation maculopathy after tachyphylaxis of previous multiple injections of bevacizumab, achieving complete resolution of cystoid macular edema.¹⁰⁰ Sole administration of this agent as primary treatment was studied in the first five patients with radiation retinopathy with macular edema, secondary to treatment with plaque brachytherapy for uveal melanoma, enrolled in a phase 1, open-label clinical trial by Finger & Chin. They demonstrated the safety and tolerability of serial intravitreal 0.5 mg ranibizumab injections for treating radiation vasculopathy with a decrease in macular edema, improvement in BCVA, and a 35% reduction in CFT over an 8-month study interval. The treatment had a good safety profile with no serious adverse events and only side effects of an increase in intraocular pressure and transient facial swelling.¹⁰¹ Ranibizumab has also been effective in treating maculopathy induced by whole brain radiotherapy with a sustained reduction in the central retinal thickness from 445 µm to 250 µm and a mild improvement in BCVA over 13 months after eight injections.¹⁰² Hence, similar results were achieved with ranibizumab in terms of reduction of macular edema with only a slight improvement in visual acuity.¹⁰³

In a prospective randomized controlled trial, Seibel et al. compared 15 patients treated with ranibizumab and 16 treated with focal and peripheral laser photocoagulation for radiation retinopathy after choroidal melanoma and found superiority in the anti-VEGF over the laser treatment. There was a statistically significant BCVA improvement by 0.14 logMAR and rapid regression of macular edema in the ranibizumab-treated group up to 26 weeks, after which visual acuity worsened and macular thickness reverted to baseline levels on cessation of therapy.¹⁰⁴ On the other hand, Finger et al. studied the effects of increasing the intravitreal ranibizumab dosage to a high dose of 2.0 mg on a phase 1/2 nonrandomized prospective clinical trial of 10 eyes with recalcitrant radiation retinopathy who failed to respond to standard dose anti-VEGF therapy. Results showed 70% stabilizing or improved visual acuity and an 80% significant reduction of central foveal thickness (−19.3% from baseline at one year). Mean improvement BCVA was +3.3 ETDRS letters at 6 months and +0.7 letters at 1 year, supporting that anatomical improvements do not necessarily correlate with visual acuity improvements and that the pharmacology and frequency of intravitreal injections may be more essential than the dosage.¹⁰⁵

A relatively newer anti-VEGF with a higher binding affinity to VEGF-A has demonstrated clinically significant results in the treatment of CRVO,^106,107 AMD,¹⁰⁷ and DME,^108,109 due to its prolonged pharmacokinetics and pharmacodynamics that allows a decrease in intravitreal injection frequency. Aflibercept (Eylea ®) is a fully, humanized, recombinant fusion protein that acts as a soluble decoy VEGF receptor, with a high affinity to multiple isoforms of VEGF-A and VEGF-B and can antagonize other growth factors such as the Placental Growth Factor (PGF). Upon binding to the ligand, aflibercept inhibits the downstream signaling cascade that is mediated by these ligand molecules.^110–112 These characteristics underline a marked potential of aflibercept for the treatment of radiation retinopathy.

Aflibercept is an alternative for rescue therapy in patients with recalcitrant macular edema due to radiation after treatment with multiple injections of other anti-VEGFs, effectively reducing microaneurysms, hemorrhages, exudates and central retinal thickness and improving vision.^113,114 Its ability as a primary agent was demonstrated for recurrent meningioma treatment-associated cystoid macular edema who received three injections within one year and for another patient with bilateral retinopathy with unilateral macular edema associated with glioma radiation who was treated successfully with six intravitreal injections of aflibercept in nine months. Both case reports described excellent results with regression of intraretinal fluid and signs of proliferative disease, and visual acuity, and anatomical OCT appearance improvement.^115,116 These findings were supported in a prospective interventional series of nine patients with maculopathy and edema after ruthenium-106 plaque brachytherapy for choroidal melanoma who were treated with approximately four aflibercept injections in 2 years. Mean CFT decreased to a significant 223 µm from a baseline of 546 µm and 0.56 logMAR from 0.9 baseline logMAR. Results were maintained at the 2-year follow-up, with no complications.¹¹⁷ Aflibercept has generally been tolerated well with low rates of adverse events including intraocular inflammation, endophthalmitis, hypertension, wound-healing, and serious complications.¹¹⁸ Its potent biological effects, reduced toxicities, and overall tolerance suggests marked potential for use as the mainstay treatment of radiation retinopathy and associated macular edema.

The most recent anti-VEGF, brolucizumab (Beovu ®), may be an important addition to the treatment alternatives for radiation retinopathy. There is only one case report in the literature by Corradetti et al., which explored its off-label use in a patient with history of multiple tumors as a child including bilateral retinoblastoma radiation maculopathy with recalcitrant cystoid macular edema and worsening vision despite multiple injections of aflibercept every four weeks, trials with ranibizumab, and refusal of steroid therapy. After a trial of intravitreal brolucizumab 6 mg, there was a marked reduction in CME from 426 µm to 240 µm and near resolution after two weeks and BCVA improved from 20/60 to 20/25. At the 2-month follow-up, CME only increased slightly and BCVA was maintained at 20/25 with significant subjective improvement.¹¹⁹

Brolucizumab is the smallest, low molecular weight (26 kDa), humanized monoclonal single-chain variable (scFv) antibody fragment that binds to the three major isoforms of VEGF-A (VEFG₁₁₀, VEGF₁₂₁, and VEGF₁₆₅) to inhibit their action in VEGF receptors 1 and 2, thereby suppressing endothelial cell proliferation, neovascularization, and vascular permeability.¹²⁰ Its small size, high solubility, and stability increase its potential for deeper tissue penetration, greater molar dose delivery, and prolonged durability.¹²¹ It was approved by the FDA to treat neovascular AMD, and it has shown noninferiority to aflibercept in visual function and favorable anatomic outcomes with greater fluid resolution in the brolucizumab group. An injection regimen every 12 weeks has had sustainable outcomes for 96 weeks, as reported in the HAWK and HARRIER phase 3 clinical trials. Therefore, this agent has a high potential in decreasing the total number of injections and extending the interval between them, possibly decreasing costs and treatment burden.^122,123 Larger and long-term studies are needed to draw conclusions on the use of brolucizumab for radiation retinopathy. However, although the HAWK and HARRIER studies reported overall safety similar to aflibercept and no evidence of inflammation, increases in IOP or vascular occlusion were reported in Corradetti’s case and radiation retinopathy studies may be delayed as precaution is advised due to its association with cases of uveitis, severe intraocular inflammation, and retinal vasculitis with variable occlusion of large and small arteries and venules and associated visual acuity loss.^124–126

Finally, anti-VEGF therapy is the most common primary treatment used for radiation retinopathy at this moment. Other radiation-related ocular complications like recurrent vitreous hemorrhages,¹²⁷ exudative retinal detachments,¹²⁸ optic neuropathy,¹²⁹ rubeosis,¹³⁰ and neovascular glaucoma¹²⁸ have also been successfully managed with anti-VEGFs. Numerous short-term studies have reported on functional and anatomical benefits. According to a 10-year study by Finger et al., continuous intravitreal anti-VEGF therapy is able to provide long-term reduction or resolution of radiation-induced vasculopathy including retinal hemorrhages and edema and can achieve long-term vision preservation, as evidenced by 80% of their patients remaining within or better than 2 lines of their initial visual acuity, up to ten years. They also favor continuous treatment with anti-VEGF agents, regardless of side effect concerns including possible retinal pigment epithelium atrophy, due to the progressive nature and rarity of complete resolution of radiation retinopathy even with this therapy.¹³¹

Dosing Regimen

The chronic, progressive characteristic of radiation retinopathy and rare resolution of the disease implicate long-term therapy and follow-up visits, which is key to maintaining the positive treatment outcomes of anti-VEGFSs.¹⁰⁴ However, the uncertainty on treatment frequency creates an increased treatment burden on patients with radiation-induced ocular disease, which warrants studies assessing an optimal dosing regimen for anti-VEGFs (Table 2). There is no current agreement on the preferred long-term dosing regimen for radiation retinopathy. Fixed monthly intervals, pro-re-nata (PRN) or as-needed treatments based on specific findings, and a combined protocol of both termed treat-and-extend that lengthens the interval between injections according to baseline disease activity are the most common regimens used for anti-VEGFs. The latter management tries to balance treatment efficacy with decreased patient cost, allowing fewer follow-up visits and number of injections.¹³⁶

Table 2. Studies on several treatment regimens using intravitreal anti-VEGF injections for radiation retinopathy

Treatment options	Regimen	Results	Follow-up period (months)
Bevacizumab	Fixed monthly^Citation96	VA: 42% increased BCVA, 44% stable BCVA CMT: 56% decreased CMT, 31% stable CMT *Benefits from monthly injections. Extending the interval beyond 4 weeks may worsen edema, caution advised.	4–6
	Loading (3 monthly high-dose injections)^Citation98	VA: Baseline 0.55 logMAR to 0.51 logMAR CMT: Baseline 406 μm to 395 μm *Patients with persistent retinopathy who do not respond to standard-dose bevacizumab have limited benefits from high-dose treatments. Improvement in the VA and macular thickness was only significant in about 30% of patients.	9
	Loading (3 initial monthly) then PRN^Citation132	VA: Baseline 0.7 logMAR to 1.3 logMAR (Loss of ~5 lines) CFT: Baseline 340 μm to 353 μm *Benefits from injections every 90 days or sooner.	19
Bevacizumab or ranibizumab	Fixed bimonthly^Citation133	VA: Baseline 0.44 logMAR to 0.52 logMAR CMT: Baseline 304 μm to 285 μm FAZ area: Baseline 0.62 to 1.02 *Significant reduction in BCVA loss and FAZ enlargement under the 2-month interval.	6
	Every 4–12 weekly^Citation131	VA: Baseline 69% with 20/40 or better to 65% at last treatment examination, baseline 30% with 20/200 or better but worse than 20/40 to 31% at last examination. Probability of remaining within 2 lines of initial VA after anti-VEGF: 69% at 5 yrs and 38% at 8 years. CFT: Baseline 364.9 μm to 288 μm at 2 years to 382.8 μm at 4 years *Constant anti-VEGF administration over 10 years was well tolerated, preserved vision, and suppressed macular edema although edema may re-emerge after several years of treatment.	81
Aflibercept	Monthly then PRN^Citation117	VA: Baseline 0.9 logMAR to 0.55 logMAR at 12 m and 0.56 logMAR at 24 m (mean gain of 17 ETDRS letters) CFT: Baseline 546 μm to 245 μm at 12 m to 223 μm at 24 m Marked improvement in the radiation maculopathy stage *Aflibercept allows both functional and anatomic improvements with a low number of injections.	24
	Fixed, every 6 weeks, vs variable, treat and adjust centering on 6 weeks^Citation134	VA: Baseline 20/63 to 20/62 (42.5% eyes with better than 20/50 BCVA, only 5% with worse than 20/200 BCVA) CMT: Baseline 432 μm to 294 μm *No difference between groups, unable to extend treatments beyond 6 weeks, ongoing treatment required	12
Ranibizumab	Loading (3 initial monthly) then PRN stopped at 6 months^Citation104	VA: Baseline 0.58 logMAR to 0.38 logMAR at 6 m to 0.75 logMAR at 12 m CFT: Baseline 478 μm to 387 μm at 6 m and 509 μm at 12 m *Ranibizumab superior to laser treatment until 6 months, but benefit disappears if treatment is stopped.	6 and 12
	Fixed, every month vs 3 initial monthly then PRN^Citation135	VA: Baseline 56.9 ETDRS letters (gain of 4.0 letters) CMT: Baseline 423.1 μm (mean change of −97.0 μm) Persistent retinal hemorrhage: Baseline 75% of patients to 0% vs VA: Baseline 60.3 ETDRS letters (gain of 0.9 letters) CMT: Baseline 388.2 μm (mean change of −71.0 μm) Persistent retinal hemorrhage: Baseline 87.5% of patients to 12.5% *Increased effectiveness seen in the fixed, monthly regimen than the PRN approach; concomitant laser did not add benefits	12

Abbreviations: BCVA: Best-corrected visual acuity; CFT: Central foveal thickness; CMT: Central macular thickness; FAZ: Foveal avascular zone; PRN: Pro-re-nata; VA: Visual acuity

In the RadiRet study mentioned before by Seibel et al., they tried a PRN ranibizumab treatment after the three initial monthly injections (total of 4–6 injections), with limited efficacy up to 26 weeks, as a cessation of therapy led to decreased visual acuity and an increased central retinal thickness to baseline levels at week 52 after injection in 15 patients.¹⁰⁴ In contrast, Fallico et al. assessed a regimen of monthly intravitreal injections until the 9 patients enrolled reached maximum visual acuity or had no signs of edema on OCT, followed by PRN injections if there was edema recurrence within two years (total average of 4.4 injections). With this regimen, patients achieved decreased mean CFT and improved BCVA that remained for 2 years.¹¹⁷ On the other hand, a retrospective review by Stacey and Demirci of 31 patients treated with intravitreal bevacizumab monthly for the first three months followed by injections as-needed concluded that serial injections of bevacizumab every 90 days or sooner will favorably stabilize visual acuity and prevent vascular leakage.¹³²

Daruich et al.¹³³ compared fixed and variable regimens in 41 patients during a short term of 6 months. He studied 19 patients undergoing strict intravitreal injections with bevacizumab or ranibizumab in a 2-month interval for 6 months (total of 6 injections) versus 11 patients with variable intervals receiving 1–3 injections versus 11 patients who refused treatment. There was a significantly less BCVA loss in the strict treatment group compared to the variable or no-treatment groups. On OCTA, there was also a more significant reduction in foveal avascular zone (FAZ) enlargement in the deep and superficial plexus in the fixed-treatment patients, with moderate correlation between a change in BCVA and a change in FAZ up to 6 months. There was a significant decrease in CMT without significance between specific treatment groups.¹³³ A comparison of the most common regimen approaches with a longer follow-up of 1 year was published by Murray et al. as part of a randomized, prospective clinical trial. They administered aflibercept injections in 20 patients through a fixed 6-week interval and in 20 patients in the treat-and-adjust group who underwent an initial injection, a second one 6 weeks after, and subsequent injections with an interval increase of one week with improvement in maculopathy by SD-OCT or one-week interval decrease if worsening findings. Average BCVA was maintained around 20/62 at baseline and at one year, with 42.5% of eyes having better than 20/50 and 5% worse than 20/200, and the central retinal thickness improved from 423 µm to 294 µm. Although fewer injections were expected in the treat-and-extend group, both treatment arms received a similar total of injections (8.4 vs 9 in the fixed group) with no statistical or clinical significance.¹³⁴

A similar protocol is being investigated in the phase IIb multicenter, randomized clinical trial Ranibizumab for Radiation Retinopathy (RRR) by Schefler et al.¹³⁵ This anti-VEGF was administered in 40 subjects on three cohorts followed for one year. Cohort A received monthly intravitreal injections of ranibizumab for one year; Cohort B had the same fixed monthly regimen, with an addition of targeted retinal photocoagulation (TRP) after the initial injection to areas with peripheral ischemia and additional TRP on two more occasions PRN, according to persistent or new ischemia. Cohort C received three monthly injections as loading dose, followed by PRN monthly injections due to SD-OCT fluid, increased thickness or vision changes, and the addition of TRP after the initial injection and two more PRN. Results demonstrated a larger improvement in BCVA in Cohort A at one year with a gain of 4 ETDRS letters, with statistical significance when compared to the other two groups with a loss of 1.9 letters in B and a gain of 0.9 letters in C, better than historical controls in the Collaborative Ocular Melanoma Study (COMS). Similarly, improvement in the retinal thickness was greater in the fixed groups than in the PRN cohort, with worsening OCT with every skipped injection. Of note, laser treatment in the cohorts did not demonstrate additional benefits at one year, which authors suggest may be due to an inflammatory response with resulting macular edema and vascular damage counteracting visual improvement. After one year, all cohorts underwent a treat-and-extend regimen of intravitreal injections for one more year, with results pending publication, preliminarily showing attenuation of treatment benefits with less frequent injections.¹³⁵ One ongoing randomized prospective study is investigating the efficacy of aflibercept administration in two cohorts using a treat-and-extend approach with four initial monthly loading doses in one group, and two loading doses in the other, to assess the total number of injections required and efficacy in macular edema and visual acuity.¹³⁷

These studies highlight an increased efficacy of anti-VEGFs when administered continuously at fixed frequent intervals over a long period and their importance in control of the macular thickness and visual outcomes, as seen in studies regarding AMD.¹³⁶ Although more flexible protocols like the treat-and-extend regimen would be convenient for patients with fewer injections and follow-ups, clinical implementation of it has proven to be challenging in patients with radiation retinopathy due to short-term effects. It seems that this chronic, progressive disease and its threat to visual acuity warrant more intravitreal injections to avoid undertreatment. Larger studies with long-term observation are warranted to establish a treatment regimen and decide when more injections will not necessarily translate to increased patient benefit. A combination in treatment using steroids or future long-acting implants may be more feasible.

Disease Prophylaxis

In addition to an optimal dosing regimen for anti-VEGF treatment, the optimal time for treatment initiation is also uncertain. Many of the presented studies suggest that starting treatment at the first sign of maculopathy is detected on diagnostic imaging with a preference of SD-OCT, FA, and OCTA.⁵⁰ However, many proponents believe that anti-VEGFs could play a role in preventing the disease if started prophylactically at the time of irradiation. Bevacizumab was effective in preventing iris rubeosis, and anterior segment neovascularization was reported in a retrospective study of 24 eyes treated with proton irradiation for uveal melanoma and associated ischemic retinal detachment until reattachment allowed for laser photocoagulation.¹³⁸ The first study assessing prevention for retinopathy and maculopathy was published by Shah et al.¹³⁹ who retrospectively evaluated the protective efficacy of intravitreal bevacizumab at the time of plaque removal for uveal melanoma, which repeated every 4 months for 2 years (total of 7 injections) in 292 patients, and the results were compared with 126 controls. The treatment group had less evidence of OCT macular edema (26% vs 40% in control), clinical macular edema (16% vs 31%), visual acuity loss (33% vs 57%), and less patients with poor visual acuity (15% vs 28%).¹³⁹ The author group¹⁴⁰ later continued the study adding a larger cohort for four more years with the same regimen of an initial dose at the time of plaque removal followed by 4-month intervals for 2 years, peak time for retinopathy, in 1131 eyes compared to a nonrandomized historical control group of 117 patients without prophylactic or later treatment with bevacizumab and similar follow-up. The bevacizumab group was consistent in the reduction of OCT macular edema at two and three years, of clinical macular edema at all the four years, and of clinical radiation papillopathy at 1.5 years. There was a marked benefit in vision outcomes in the prophylactic group with better acuity in all four years, especially at four years, of 20/70 compared to counting fingers in the controls.¹⁴⁰ On a further study, they reported on the impact of the age on radiation-related complications in these patients managed prophylactically. Younger patients (<50 years) had a shorter onset time of radiation maculopathy and higher 48-month risk of developing radiation retinopathy and maculopathy, and other radiation-related complications on a survival analysis compared to older age groups.¹⁴¹ Similar benefits of bevacizumab were reported by Powell and Finger in a smaller retrospective study of 14 patients with plaque-irradiated choroidal melanoma treated with intravitreal bevacizumab every 4–6 weeks within six months of plaque placement who were case-matched with 14 historical controls. The mean visual acuity on the prophylactically treated group was 20/32 on the last follow-up (from 20/25 at baseline) compared to 20/160 in the control group (from 20/40 at baseline). Improvement or no change in acuity was seen in 64.3% on the anti-VEGF group (vs 28.36%), with a loss of not more than 3 lines of vision compared to 71.4% in the matched group.¹⁴² On the contrary, another retrospective study found no reduction in the radiation retinopathy rate after 5.1 years following stereotactic fractionated radiotherapy for choroidal melanoma managed with prophylactic bevacizumab. Fourteen treated patients had an incidence rate of 57% compared to 54% of the thirteen untreated patients.¹⁴³ However, these treatment groups had a small number of patients and the regimen consisted of a single dose of bevacizumab on the last day of radiotherapy and PRN thereafter, adding evidence to the importance of regularly continuous dosing treatment.

Only one study was found to report on the preventive effects of another anti-VEGF besides bevacizumab. Kim et al. investigated 40 patients treated with proton irradiation for choroidal melanoma and ranibizumab at tumor location followed by two-month interval injections for 24 months. They determined that prophylactic ranibizumab was safe and preserved visual acuity (≥20/40) in 77% of subjects, 97% with ≥ 20/200 of vision, and only 33% had clinical evidence of radiation maculopathy at year two.¹⁴⁴ The initial ranibizumab injection was given around 2 weeks before the first proton irradiation session, which may indicate an increased benefit with earlier therapy.

Therefore, anti-VEGFs used prophylactically for radiation-treated patients may have lasting protective effects on visual acuity and retinopathy onset. VEGF upregulation caused by hypoxia after radiation damage to endothelial cells may be limited by prophylactic use of anti-VEGFs. Further studies regarding the optimal time of anti-VEGF initiation are needed along with the optimal dosing regimen.

Systemic Absorption

Brito et al. reported a case of bilateral cystoid macular edema secondary to radiation retinopathy from external beam radiation for medulloblastoma. Intravitreal bevacizumab treatment of one eye resulted in significant improvement of his fellow eye with resolution of the central macular thickness and improving visual acuity by 2 ETDRS lines, which underlines the role of systemic absorption of intravitreal administration of the anti-VEGF agent and emphasizes the importance of minimizing any potential ocular or systemic adverse event.¹⁴⁵

With the increasing use of anti-VEGF for retinal diseases and the current search for optimal dosing of the drug, it is important to identify the distribution and clearance after intravitreal injection for systemic safety assessment. There is a half-life increase with an increase in a drug’s macromolecular size and a higher vitreous radial size.¹⁴⁶ The vitreous half-life of 1.25 mg of intravitreal bevacizumab was explored in rabbit eye models and found to be 4.32 to 6.61 days. The maximum serum concentration was achieved at 8 days, with levels drastically decreasing after 1 month.^147,148 Bakri et al. documented that aqueous humor and serum half-lives in rabbit eyes are 4.88 days and 6.86 days, respectively.¹⁴⁷ According to Sinapis et al., vitreous, aqueous humor, and serum half-lives in rabbit eye models are 6.61, 6.51, and 5.87 days, respectively.¹⁴⁸ Both studies reported very little drug levels in the serum and noninjected eyes, suggesting a wide distribution range. These studies demonstrate that bevacizumab has a pharmacokinetic profile that is favorable for its monthly dose in VEGF-mediated retinal diseases.

The pharmacokinetics of 1.25 mg of intravitreal bevacizumab was compared with 0.5 mg of intravitreal ranibizumab in similar rabbit eye models. The vitreous half-life of 0.5 mg of intravitreal ranibizumab is 2.88 to 2.9 days. Serum levels and levels in the noninjected eyes were undetected when treated with ranibizumab, while very small amounts were detected when treated with bevacizumab. Ranibizumab is a smaller molecule (48 kilodaltons) in comparison to bevacizumab (149 kilodaltons), which could explain the more rapid retinal penetration and faster clearance from the systemic circulation.^149,150 The half-life of intravitreal ranibizumab administered to monkey eye models was approximately 3 days, with rapid distribution to the retina within 6 to 24 hours. The bioavailability of the drug was 50 to 60%, and in parallel to rabbit eye models, serum concentrations were very low.¹⁵⁰

The vitreous half-life of aflibercept in rabbit eye models is 3.92 days, which is longer than that of ranibizumab and shorter than that of bevacizumab. The aqueous humor and retinal half-lives of aflibercept in the rabbit eyes were 2 days and 2.43 days, respectively.¹⁵¹ The half-lives in aqueous humor in ranibizumab and aflibercept were similar in both vitrectomized and nonvitrectomized eyes. The concentration of VEGF was decreased below the limit of detection by intravitreal ranibizumab for 3 weeks in nonvitrectomized and 1 week in vitrectomized eyes, in contrast to 6 and 4 weeks, respectively, by intravitreal aflibercept.¹⁵² While the half-lives of both drugs are similar, intravitreal aflibercept suppresses VEGF levels for a longer period of time. Avery et al. evaluated the pharmacokinetics of aflibercept, bevacizumab, and ranibizumab. The systemic exposure to the anti-VEGF agents was highest with bevacizumab, followed by aflibercept and then ranibizumab. Among the three drugs, aflibercept treatment resulted in the greatest reduction of plasma free-VEGF levels.¹⁵³

The newer brolucizumab seems to have better ocular penetration but faster systemic clearance and lower systemic exposure due to its smaller size compared to the other anti-VEGFs in animal studies. This may translate to fewer systemic side effects with its use, but further research into this drug is required.¹²¹ However, it is difficult to extrapolate animal pharmacokinetic studies to human eyes or directly study them due to physiologic differences and ethical concerns in human samples.¹⁵⁴ Drug pharmacokinetics, vitrectomy status, and interindividual variation to drug response must be taken into consideration when considering selection of anti-VEGFs in patients and make agreeing on an optimal dosing and frequency regimen a challenging task.

Corticosteroids

Intravitreal Corticosteroid Injections

Corticosteroids have also been used for the treatment of macular edema in numerous retinal diseases such as diabetic retinopathy, central retinal vein occlusion, uveitic CME, and age-related macular degeneration. Intravitreal triamcinolone acetonide injections have been successful in achieving short-term anatomic and functional recovery and visual acuity improvement in these retinal diseases.^155,156

This method of treatment has been increasingly used in radiation-induced retinopathy for resolution of macular edema, as both the mainstay treatment and as a part of combination therapy. Sutter and Gillies reported significant improvement in visual acuity and complete resolution of the macular edema on OCT after two treatments with intravitreal triamcinolone acetonide in a patient with radiation-induced retinopathy resistant to focal laser photocoagulation.¹⁵⁷ A prospective, nonrandomized study by Shields et al. also investigated the effect of intravitreal triamcinolone acetonide on 31 patients with visually symptomatic radiation maculopathy after plaque radiotherapy for choroidal melanoma. The study reported that visual acuity was stable or improved in 91% of study patients by one month and 45% by six months. Furthermore, there was OCT evidence of decrease in the mean central subfield foveal thickness. However, the effect of triamcinolone diminished at 6 months, which translates to a need for multiple sequential steroid injections.¹⁵⁸ This group also reported a rapid response to this intravitreal injection on 9 patients with acute radiation papillopathy, allowing some vision improvement and resolution of optic disc hyperemia and edema as early as 1 week postinjection that was maintained to the 11-month follow-up.¹⁵⁹

Combination therapy studies include a report by Kocak et al. regarding a patient with radiation retinopathy who was treated by a combination of intravitreal triamcinolone acetonide with photodynamic therapy two weeks later and panretinal and focal laser photocoagulation for subsequent iris neovascularization at two months with successful resolution of retinopathy signs.¹⁶⁰ On the other hand, three studies used intravitreal triamcinolone injections for patients who had severe macular edema, who developed resistance to treatment or had no response to multiple bevacizumab injections.^161–163 They administered steroids as rescue therapy or as adjuvant to continued intravitreal bevacizumab. Results showed great benefits with triamcinolone with some variability in patient response. Some patients achieved complete resolution of macular edema and vision improvement with triamcinolone monotherapy after stopping bevacizumab, and others required the combined therapy of anti-VEGF and steroid to achieve anatomical and functional benefits. In the study by Kaplan et al.,¹⁶² patients continued high-dose bevacizumab (3.0 mg) every 4 weeks with the addition of triamcinolone acetonide every 8 to 12 weeks, which stabilized or improved vision in all eight patients by 3 months that maintained in 75% at 12 months and decreased mean CFT from 417 um upon steroid start to 339 in one month and 359 in one year. Shah et al.¹⁶³ had fluid improvement on SD-OCT but only had 36% of patients (9/25) with 20/50 or better vision on the last 30-month follow-up, but their subset population had poor initial BCVA (20/138) with possible chronic damage. Corticosteroids are believed to act upon the tight junction proteins in the inner retinal barrier by increasing their activity and density, thereby reducing capillary permeability. It is also hypothesized that they work in decreasing the osmotic swelling in Muller cells and reducing intraocular cytokines that would otherwise upregulate VEGF expression.^164–166 This mechanism may act in conjunction with the VEGF-binding property of bevacizumab to reduce vascular leakage.

Long-term effects of injection triamcinolone have not yet been determined, but it has been associated with side effects such as glaucoma, intraocular pressure increases, cataract formation (posterior subcapsular), and small but potential risk of retinal detachment and endophthalmitis.¹⁶⁷ Steroid therapy is usually not needed in short monthly intervals, which could translate to fewer injections in patients. However, their efficacy is still short-termed and requires constant follow-up due to the possible side effects, which ultimately limits the use of intravitreal triamcinolone acetonide as monotherapy.

Sub-Tenon’s Steroid Injections

Sub-Tenon’s steroid injection is a safe, effective, and appropriate alternative to intravitreal steroid injection for the treatment of macular edema, with similar short-term effectiveness.^168,169 It may require echographic examination to ensure proper placement in the posterior sub-Tenon region for safety. There are no published studies assessing the efficacy of sub-Tenon triamcinolone (STK) for the treatment of established radiation retinopathy, but there are some that investigated its benefit as a preventative measure for macular edema at the completion of radiation therapy. Horgan et al. reported a prospective study¹⁷⁰ and a subsequent randomized controlled trial¹⁷¹ with a comparison of patients who underwent periocular triamcinolone at the time of radiotherapy plaque application for uveal melanoma (at the sub-Tenon’s region) and at the following 4 and 8 months (retrobulbar injection) with those only treated with plaque radiotherapy without triamcinolone. They consistently found a significant reduction in the risk of developing macular edema over 18 months in the treated group. OCT-evident macular edema was seen in approximately 36% of treated patients in both studies compared to approximately 58% in the control group in the 18-month follow-up. Results at 1 year were 12% in the treated group (vs 42% controls) at 1 year and 50% (vs 61%) at 2 years in the prospective study. There was also a significant reduction in vision loss in the treatment group.^170,171 Materin et al. also reported on a similar preventive strategy used with 29 patients after Iodine₁₂₅ plaque radiotherapy for uveal melanoma. They were given STK upon plaque application and the 4- and 8-month follow-ups, but they also underwent additional sector panretinal photocoagulation laser 4 to 8 months after radiation. This combination was reported as safe and beneficial in the prevention of macular edema, since merely 17% of the eyes developed macular edema at the 1-year follow-up and 24% of eyes at the 2-year follow-up.¹⁷²

The complications of sub-Tenon’s injection include accidental injection directly into the choroidal or retinal circulation, perforation of the ocular bulb, occlusion of the central retinal artery, cataract, orbital fat atrophy, ptosis, strabismus, conjunctival necrosis, and elevations of intraocular pressure.¹⁶⁹

Sustained-release Steroid Implants

The sustained-release dexamethasone implant (Ozurdex ®, Allergan, Inc., California, USA) is an alternative treatment for macular edema secondary to a variety of diseases. Its anti-inflammatory properties can be six times greater than triamcinolone. This implant is utilized in diseases such as DME,¹⁷³ RVO,¹⁷⁴ and noninfectious uveitis¹⁷⁵ with a peak effect between 1 and 4 months evidenced by a reduction in the macular thickness and improvement in visual acuity. The effect can be maintained up to 5 months after administration, which requires repeated injections thereafter.¹⁷⁶ Its anti-inflammatory properties can be six times greater than triamcinolone, and the sustained release maintains concentration longer, which could be important in the management of radiation retinopathy.^176,177 Studies on the treatment of macular edema secondary to other retinal diseases paved the way for the use of sustained-release steroid implants in radiation-induced macular edema.

Several case series have evaluated the efficacy of dexamethasone 0.7 mg intravitreal implant in patients with macular edema. All five treatment-naive patients with history of proton beam therapy for choroidal melanoma reported by Baillif et al. had slightly improved or stable visual acuity and a decrease in the mean central retinal thickness, with two patients requiring a second dose at 5 months after initial implantation.¹⁷⁶ A larger case series of thirteen eyes with maculopathy after Iodine₁₂₅ brachytherapy were evaluated retrospectively by Frizziero et al., able to gain a median of 6.5 letters at day 33 and a reduction of 148 μm of CFT that continued to decrease until stabilizing by month three, a starting recurrence at four months with measurements comparable to baseline by six months. They recommend a retreatment time point at four months to prevent further damage and visual impairment.¹⁷⁷ A comparison between the sustained-released dexamethasone implant and intravitreal ranibizumab was also evaluated in sixteen patients distributed equally to each treatment group. In the eight patients treated with ranibizumab, a mean of 7.8 injections were administered within 33 months versus a mean of 2.1 injections within 22 months in the dexamethasone-treated group. Both groups had an improvement in visual acuity and CFT and similar outcomes, but the steroid implant allowed fewer injections with similar benefits.¹⁷⁸

A greater benefit has been seen with recalcitrant radiation maculopathy unresponsive to other treatments after ruthenium-106 plaque brachytherapy for choroidal melanoma,^179,180 charged-particle radiation, iodine-125 brachytherapy, or gamma-knife radiosurgery for uveal melanoma and carcinoma of the maxillary sinus.^179–181 The first report was published by Russo et al. in a patient previously treated with intravitreal bevacizumab unsuccessfully, who responded with resolution of macular edema, reduced CFT, and improvement in visual acuity one month after dexamethasone implant.¹⁷⁹ Then, two more patients were treated with the steroid implant after a limited response to multiple bevacizumab and alternating intravitreal triamcinolone injections; both patients stabilized anatomically translating to visual improvement in one of them with up to four months of efficacy.¹⁸¹ Similarly, four patients resistant to previous intravitreal bevacizumab, including one with adjunct PRP and intravitreal triamcinolone, had a transient 14- to 17-week decrease in the foveal thickness after salvage treatment with Ozurdex®.¹⁸⁰ A larger series of 12 patients (nine previously treated with anti-VEGF injections and/or laser photocoagulation, and three therapy-naive) treated with plaque brachytherapy for choroidal melanoma had a marked improvement in macular edema and a subsequent reduction in Horgan’s OCT-based macular edema grading, with a significant reduction in CFT of 416 to 254, and hard exudate regression, but a non-significant improvement in visual acuity.¹⁸² Koc et al. also had seven eyes that responded to a mean of 1.7 implant injections every 5 months in a mixed treatment-naive and bevacizumab-resistant group, achieving a mean 7.4 ETDRS letter improvement in acuity and 226.7 mean reduction in CMT after 9.1 months of follow-up.¹⁸³ Therefore, the dexamethasone implant seems to have an effective benefit anatomically but limited function regarding visual acuity gain. A greater benefit is obtained with retreatment at around 4 months for sustained efficacy. Its sustained-release nature may play a significant role in reducing the total number of injections needed or as salvage therapy for patients with limited response or adverse effects to other treatments. However, the literature shows side effects including intraocular pressure elevations, which can respond to pressure-lowering agents and increased cataract formation and progression rates, which may limit its role as a long-term agent, require additional follow-up visits, and limit its prophylactic use to prevent retinopathy induced by radiation.^182–184

Seibel et al. compared 78 patients with radiation maculopathy and optic neuropathy after a history of choroidal or ciliary-body melanoma treated with proton beam therapy who received bevacizumab injections (38/75), intravitreal triamcinolone acetonide (35/75), and dexamethasone implants (5/75). All groups had similar outcomes in visual acuity improvement, CFT reduction, and functional stability, with no statistical difference between treatment groups.¹⁸⁵ Comparison outcomes suggest the need to focus less on the type of treatment for radiation retinopathy and a greater importance of close follow-up on patients treated with radiation to allow for an earlier retinopathy diagnosis with SD-OCT, FA, and OCTA and start treatment specific to patient’s comorbidities, previous response to therapy, and medical history. It also underlines the importance of a close post-treatment observation to manage complications or detect treatment unresponsiveness early, so patients may benefit from an early switch in therapy or adjunct combined treatments. Prospective studies and clinical trials are needed with larger cohorts specifically in the dexamethasone implant group to draw conclusions upon treatment comparison.

Other Treatment Modalities

Photodynamic Therapy

Photodynamic therapy (PDT) is a two-step therapeutic process in which an intravenous infusion of verteporfin is followed by irradiance with a 689 nm laser for usually 83 seconds. During this process, verteporfin binds to low-density lipoproteins in the plasma, which then preferentially binds to choroidal neovascular membranes. The use of laser energy results in the formation of radical oxygen species that induces damage to cellular structures.^1,186 This free radical damage may result in platelet activation and subsequently may thrombose the newly formed abnormal choroidal vessels within the treated area.^187,188

PDT has been proven to be effective in animal models of choroidal neovascularization, and there have been reports of its use in AMD and other vasculopathies.^188,189 Although this may suggest its use as a potential selective therapy in radiation retinopathy patients, published studies are minimal and mostly based on case series, with unclear long-term effectiveness. In a case series of four patients by Bakri and Beer, they acknowledged a marked decrease in hard exudates in all patients and an increase in visual acuity in three of the eyes when they used PDT to treat radiation-induced macular edema.¹⁸⁶ Lee et al. also report a case of visual acuity improvement and regression of subretinal neovascularization after a single treatment of PDT.¹⁹⁰

Hyperbaric Oxygen

The first case of hyperbaric oxygen for the treatment of radiation-induced retinopathy was presented by Stanford et al. in 1984.¹⁹¹ Since then, hyperbaric oxygen has been used to treat various ocular vasculopathies by applying 100% oxygen at high pressures to increase oxygenation and initiation of cellular and vascular repair mechanisms. Hyperbaric oxygen produces a steep oxygen gradient between the irradiated and nonirradiated tissues, which directly enhances the fibroblastic activity, collagen synthesis, and neovascularization in the irradiated tissues.^1,192,193 Case reports of radiation-induced macular ischemia and optic neuropathy show improvement in vision, macular perfusion, and fundoscopic appearance after treatment with hyperbaric oxygen.^194,195 However, further studies are required to evidence its safety and efficacy in a larger number of patients.

Oral Pentoxifylline

Oral pentoxifylline is a methyl-xanthine derivative commonly used for the treatment of peripheral vascular diseases. The drug is speculated to cause vasodilation, decrease blood viscosity, and increase blood flow. A study on its short-term effects on ocular health demonstrated an increase in the blood flow of healthy eyes, suggesting that pentoxifylline could be used therapeutically in vaso-occlusive retinal disorders, including those induced by radiation.¹⁹⁶ There is only one case report of radiation-induced retinopathy treated with oral pentoxifylline by Gupta et al., which resulted in the full reversal of retinopathic effects within 8 months of treatment onset, suggesting its potential to improve capillary reperfusion and visual acuity.¹⁹⁷ Although a positive outcome was observed, conclusions cannot be drawn in terms of safety and efficacy in a larger population.

Future Implications

Understanding of radiation retinopathy disease and its various treatment modalities has progressed over time, along with the development of new advances to modify radiotherapy and decrease the effects of radiation on the surrounding structures of the eye.

Studies have explored the use of vitreous substitutes for attenuation of radiation effects on the retina.^198,199 Ahuja et al. suggested silicone oil to protect the retina from radiation insult when used as an adjunct to Iodine125 brachytherapy, delivering 65% of the original dose of ocular radiation to the posterior pole for the treatment of uveal melanoma.²⁰⁰ However, Morrison et al. concluded that a reduction in total radiation dose by the presence of silicone oil may translate to an undertreatment to the tumor edges, suggesting a patient-specific approach.²⁰¹ Further investigation is needed to evaluate the surgical risks and the precise role of silicone oil in protecting the retina.

With recent advances in nanotechnology, newer studies are exploring modifications to the conventional radiotherapeutic effects. For example, in contrast to commonly used eye plaque brachytherapy, the Monte Carlo dosimetry kv x-ray is a targeted, noninvasive technique for the treatment of intraocular tumors. A poly-capillary lens is used to focus 45 kv x-ray and nanoparticle enhancement to concentrate high dose radiation to the tumor region and margin. The doses are sufficient for optimal tumor coverage with significantly reduced doses to the optic disc and fovea.²⁰² Ngwa et al. explored the integration of gold nanoparticles with I125 with brachytherapy for choroidal melanoma to decrease the delivery of radiation to normal tissues. Additions of gold nanoparticles inside the tumor before treatment supposedly alter the radiation-absorbing sensitivity of the tumor cells and enhance the dose to the tumor, while leaving the normal tissue unaffected.²⁰³

Several emerging technology and treatment modalities are currently under investigation for optimum control and treatment of radiation retinopathy. With further research, there is potential for a more targeted and less damaging radiotherapy method and a more specified therapeutic modality for treating radiation-induced retinopathic effects.

Case Discussion

The case presented represents, to our knowledge, the only long-term report of monthly aflibercept for macular edema secondary to radiation retinopathy and the response of a chronically treated patient. As observed in the literature, her initial treatment with bevacizumab and STK in a PRN regimen led to worsening disease and vision. After optimizing her bevacizumab injections to fixed monthly intervals and quarterly STK, the macular edema and exudates persisted with a worsening vision for the first six months. Her recalcitrant state demonstrated significant response in BCVA improvement and CFT reduction with two trials of aflibercept, highlighting the development of resistance in bevacizumab-treated patients after multiple injections and the usefulness of aflibercept as initial therapy and rescue therapy in radiation retinopathy. The patient had to return to monthly bevacizumab injections due to insurance changes, during which, interestingly, her initial improvement with the two aflibercept trials was maintained with stable visual acuity and CFT for one year. This stage of treatment underlines the importance of continuous treatment in this disease. With an incidental diagnosis of peripheral BRVO, she was started on monthly aflibercept. Despite our expectation of further improvement in visual acuity and reduction in CFT, the improvement was slight and she remained within a similar anatomical and vision range. Radiation retinopathy treatment proves to be challenging as after long-standing macular edema or ischemic changes, the chronic damage to the retina will limit response to treatment. More so, even with improvement in anatomy (decrease in macular edema and regression of retinopathy signs), the patient may not benefit from further improvement in visual acuity. Initial monthly aflibercept produced a reduction of CFT, which translated to improved vision, but it was dependent upon monthly treatments. Still, this effect appeared to decrease over time, potentially signaling a reduction of benefits in monotherapy. It is uncertain if adjunct treatment with laser photocoagulation allows an increase in the anti-VEGF injection interval, contemplated in our patient who could not extend the interval with initial laser while on bevacizumab but was then successful with sectoral PRP while on aflibercept. Adjunct sustained-release steroid implants may be much more effective in decreasing treatment frequency. Therefore, early initial treatment with monthly anti-VEGF combined with other therapies like steroids seems to be feasible to improve initial visual acuity and retinopathy signs. A later objective when disease stabilizes could entail an extension in the treatment interval, as further fixed monthly treatment seems not to yield further benefit for the patient. It is essential to highlight the need for continuous therapy in patients with radiation retinopathy balanced with a reasonable treatment regimen in the long-term in a way that decreases patient burden after the disease is controlled.

Conclusion

Radiation retinopathy is a chronic progressive disease for which continuous treatment is crucial, evidenced by the worsening visual acuity and central edema in untreated historical controls. Management can be complex with no consensus on ideal treatment or prophylaxis and high patient response variability requiring multiple therapeutic strategies. While several treatment modalities for radiation retinopathy exist, better outcomes in macular edema, visual acuity, and resolution of retinal neovascularization have been obtained with the use of intravitreal anti-VEGFs and corticosteroids as monotherapy or in combination regimens. As reported in our case, neither intravitreal bevacizumab, aflibercept, nor corticosteroids definitively treat radiation-induced macular edema. Therefore, in patients with radiation retinopathy, the objective may not be a complete resolution of macular edema but control of disease progression with a stable visual acuity and anatomical findings. Patients with radiation retinopathy initially benefit from continuous monthly injections, but chronically treated patients may not have an added benefit with this regimen. Although anti-VEGFs have a short-lasting effect, requiring multiple injections, we believe that aflibercept’s higher binding affinity and safety profile may allow for an extension in the injection interval for about a month. This extension can lead to fewer total injections and follow-up visits in chronically treated patients with stable anatomical and visual acuity findings and no further improvement for months. Further studies on the prophylactic use of anti-VEGFs to prevent or allow early intervention with possible fewer deleterious effects in vision should be explored. Still, the main challenge will be an adequate prophylactic or interventional therapy regimen that maximizes patient benefits and minimizes their burden.

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Funding

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