Abstract

In the last few years we have witnessed increasing availability of proton therapy in the United States and worldwide. As a result, proton therapy is considered as either a primary or adjunctive approach for numerous indications where conventional radiation therapy shows promise but is accompanied by toxicities. Age-related macular degeneration (AMD) remains the leading cause of adult blindness in industrialized nations, and third worldwide, following cataract and glaucoma. Current standard therapy is intravitreal injection of anti–vascular endothelial growth factor agents. While this treatment shows improvement and stabilization in visual acuity for 40% of patients, 60% still experience disease progression. These injections are costly, necessitate repeated office visits, and carry the risk of endophthalmitis. The pathophysiology underlying neovascular AMD (nAMD) underscores the need to simultaneously target multiple pathways to retain useful vision. Radiation can be antiangiogenic, anti-inflammatory, and antiproliferative. Early photon therapy clinical trials were heterogeneous, and a Cochrane review of data demonstrated usefulness in treatment of nAMD but recommended further studies. Advantages of proton therapy over photon therapy include the ability to deliver a focal dose to the target while minimizing dose to normal structures, which is enhanced by unique treatment planning software that uses fluorescein angiography to verify target location and allows conformation of dose to the irregular shape and thickness characteristic of choroidal neovascular membranes, the pathognomonic finding in nAMD. Preliminary data suggest a potential role for proton therapy in the treatment of nAMD. In this article we review previous treatments for AMD, including those with both photon and proton radiation, and recommend future directions for clinical investigations to evaluate the role of proton therapy as an adjunct to antiangiogenic therapy, the current standard of care in this challenging setting.

Introduction

Age-related macular degeneration (AMD) is the most common cause of adult blindness in developed countries and the third worldwide, following cataract and glaucoma [1]. Age-related macular degeneration involves the macula, a region of the retina responsible for facilitating central vision and high-resolution visual acuity (VA) [2]. The nonexudative variant of the disease is characterized by the presence of drusen, accumulations of extracellular material between Bruch membrane and the retinal pigment epithelium (RPE) [3]. The exudative or neovascular variant of the disease, affecting 10% to 15% of patients, is defined by the presence of choroidal neovascularization (CNV) and abnormal vascular proliferation originating from the choroid, penetrating Bruch membrane and proliferating deep to the retina. Although neovascular AMD (nAMD) comprises a smaller proportion of AMD, it accounts for >80% of the severe visual loss or legal blindness attributable to AMD [4]. In 2010, AMD affected more than 2.07 million individuals in the United States and is expected to increase to 288 million worldwide by 2040, with almost 5.44 million in the United States by 2050 [5, 6].

Increasing availability of proton therapy has led to consideration of its use as either a primary or adjunctive approach in numerous indications, including nAMD, in which conventional external beam photon therapy has shown promise but has been limited by toxicity. Our review will focus on the history of treatment of nAMD with special attention to radiation therapy, and forethought to future trials to assess proton therapy as an adjunct to antiangiogenic therapy, the current standard of care.

Historical Context

Diagnosis

The diagnosis of nAMD is made by using multiple modalities: biomicroscopy, psychophysical testing, optical coherence tomography, indocyanine angiography, and fluorescein angiography (FA). Where biomicroscopy may pick up structural indicators of active neovascularization (eg, exudation, hemorrhage, edema, and fluid), psychophysical testing may reveal functional decline. Optical coherence tomography may be used to detect early edema or fluid too subtle to be observed biomicroscopically. Indocyanine angiography and FA may be used to elucidate the neovascular complexes themselves, as made evident by characteristic angiographic leakage. Fluorescein angiography and optical coherence tomography are the most commonly used imaging modalities for radiation treatment planning (Figures 1 and 2).

Figure 1.

Arteriovenous phase fundus fluorescein angiogram, right eye, demonstrating angiographic leakage suggestive of classic choroidal neovascular membrane in neovascular age-related macular degeneration.

Figure 1.

Arteriovenous phase fundus fluorescein angiogram, right eye, demonstrating angiographic leakage suggestive of classic choroidal neovascular membrane in neovascular age-related macular degeneration.

Figure 2.

Optical coherence tomography of macula, right eye, demonstrating pigment epithelium detachment and subretinal fluid suggestive of active choroidal neovascularization in neovascular age-related macular degeneration.

Figure 2.

Optical coherence tomography of macula, right eye, demonstrating pigment epithelium detachment and subretinal fluid suggestive of active choroidal neovascularization in neovascular age-related macular degeneration.

Treatment Approaches

Dietary supplementation

After epidemiologic evidence showed decreased risk of nAMD with higher serum concentrations of carotenoids and antioxidants [79], the Age-Related Eye Disease Study (AREDS) demonstrated a 25% decrease in conversion from intermediate to advanced nAMD with supplementation of β-carotene, vitamin C, vitamin E, and zinc at 5 years [10]. Although these supplements do not prevent the development of AMD, they are useful once AMD has developed to prevent further visual deterioration in a minority of patients [11, 12]. The AREDS2 study added lutein (10 mg) and zeaxanthin (2 mg) or docosahexaenoic acid (350 mg) plus eicosapentaenoic acid (650 mg) (or both) to the original AREDS formulation. While results were not superior to the original formulation, smokers would benefit more from this formulation, as β-carotene supplements have been linked to increased lung cancer risk in smokers, and the formulation in AREDS2 eliminates β-carotene [13].

Photocoagulation

Early treatment of CNV focused on photocoagulation with or without porphyrins. The Macular Photocoagulation Study compared 2 laser treatments (argon green and krypton red) for CNV in the extrafoveal, juxtafoveal, and subfoveal regions. The argon green laser trial of extrafoveal CNV (200–2500 μm from the center of the foveal avascular zone) showed 25% and 60% severe visual loss in treated and untreated patients, respectively [14]. However, 59% of treated patients developed recurrent neovascularization, often soon after treatment (24% at 6 months, 43% by 1 year) [15]. The krypton red laser study treated juxtafoveal CNV lesions with a posterior border 1 to 199 μm from the center of the foveal avascular zone. At 3 years, 49% and 58% of treated and untreated patients, respectively, lost ≥6 lines of VA (P = .02). Thirty-two percent of treated eyes had persistent neovascularization, and 47% developed recurrent neovascularization [16]. At 5 years, the relative risk of a loss of ≥6 lines between untreated and treated individuals was 1.20 (P = .04) [17]. Four-year outcomes for subfoveal treatment (randomly assigned to argon green or krypton red lasers) showed that 22% of patients with treatment-naïve CNV and 47% with recurrent CNV experienced a loss of ≥6 lines in VA from baseline (P = .002) [18]. The trade-off for this late improvement was early loss of VA (3 lines within 3 months of treatment), making this less than optimal for patients already presenting with visual compromise [19].

Photodynamic therapy

In photodynamic therapy a photosensitizing drug, verteporfin, is injected peripherally. It is then activated by a laser of a wavelength corresponding to peak absorption for verteporfin. This activation causes a destructive photochemical reaction specific to the vascular endothelium of the neovascular lesion. It is postulated that this reaction manifests its effect via a combination of free radical creation, oxidative damage, and vascular thrombosis. In the verteporfin study [20] those treated fared better than the control population, with 47% of treated eyes and 62% of controls losing >15 letters (or 3 lines) of VA (P < 0.001) [21]. Despite eventual VA stabilization, the initial loss of VA is significant and unacceptable to many patients. The use of photodynamic therapy has decreased since the increased use of anti–vascular endothelial growth factor (VEGF) therapy.

Antiangiogenic therapy

Presently, antiangiogenics, therapeutic agents targeting VEGF, predominate in the treatment of CNV. These agents improve vision in up to 40% of cases; note that prior therapeutic modalities were aimed at visual “stability” [20, 22]. The US Food and Drug Administration (FDA) approved pegaptanib sodium, a pegylated anti-VEGF aptamer that binds to the 165 isoform of VEGF, for the treatment of nAMD in 2004 [23]. Ranibizumab, an antibody fragment from the same parent molecule used for synthesizing bevacizumab, was demonstrated both to yield visual improvement [23] and to be superior to photodynamic therapy [20]. Bevacizumab, a full-length humanized monoclonal antibody to VEGF-A, originally FDA-approved for treatment of metastatic colorectal cancer in 2004 [24], was initially given off-label approval for nAMD [25], showing improvement of CNV with concurrent reduced retinal thickening and improved VA. These results, originally observed with intravenous administration, were reproduced with intravitreal administration [26, 27]. The US Comparisons of AMD Treatments (CATT) [28, 29] and the UK Inhibition of VEGF in Age-Related CNV (IVAN) trials [30, 31] were head-to-head comparisons of intravitreal bevacizumab and ranibizumab that showed noninferiority of bevacizumab and have supported off-label use of bevacizumab for AMD as a cost-effective alternative to ranibizumab. Most recently, aflibercept, a recombinant fusion protein that competes for binding of circulating VEGF, was approved by the FDA and has subsequently been found to be equivalent to ranibizumab, but it has not been tested head-to-head with bevacizumab in clinical trials [32, 33]. Randomized trials with long-term data are available for intravitreal ranibizumab [34] and comparing intravitreal bevacizumab with ranibizumab [30, 35]. Pegaptanib is less effective than bevacizumab or ranibizumab and is therefore infrequently used [36].

Polymorphisms in the complement factor H gene predispose individuals to developing AMD through increased inflammation resulting from abnormal regulation of the alternative complement pathway [3742]. Histopathologic analysis of patients treated with anti-VEGF agents reveals that the bulk of residual tissue is avascular subretinal fibrosis, which can grow and impede vision. Further, antiangiogenic therapy necessitates monthly intraocular injections that are costly, burdensome to the patient, and expose the patient to risk, repeatedly. Given the societal cost of this disease, along with wider understanding of its pathogenesis, multiple biochemical pathways must simultaneously be targeted to improve outcomes.

Rationale for Radiation Therapy

Ionizing radiation is known to have dramatic effects on blood vessels through creation of reactive oxygen species and DNA single- and double-strand breaks, especially in endothelial cells, and also acts to inhibit hyperproliferative processes such as keloids, and hypertrophic osteoarthropathy [43, 44]. Rabbit eyes focally irradiated with 60Co ophthalmic plaques show delayed and attenuated inflammatory and repair responses and decreased granulation tissue [45]. In addition, eyes treated with low-dose radiation for CNV show decreased proliferative fibrosis and scarring, compared with untreated eyes, as well as better maintenance of VA [46]. These effects would be expected to halt the progression of nAMD [47, 48], but for appropriate clinical efficacy, retention of VA is a necessity. The ability of highly focal ionizing radiation to retard the growth of new blood vessels and at the same time spare vision suggests a possible therapeutic role in treatment of CNV.

Early Experience with External-Beam Radiation Therapy

A pilot study of 19 patients with CNV treated with external-beam radiation therapy (EBRT) to a dose of 10 to 15 Gy showed maintenance of central acuity and regression of CNV [49]. Visual acuity was maintained or improved in 63% and 73% of patients at 12 and 18 months, respectively. Visual acuity decreased in 6 of 7 untreated patients. Fluorescein angiography showed significant or complete CNV regression in 83% and 91% of patients at 12 and 18 months, respectively, after treatment. All controls (n = 7) showed progression by 12 months.

These results prompted several phase I/II studies evaluating external-beam photon therapy for CNV [5065]. Trial designs were heterogeneous, limiting comparisons and conclusions. In addition, follow-up periods in most of these reports were quite short, with most reporting results 6 to 12 months after treatment; further, only 2 studies included control populations [60, 61]. Pooled analyses of these phase I/II trials (n = 409) showed that 22.5% and 14.9% of EBRT-treated eyes developed moderate and severe loss of vision, respectively––an ∼50% reduction in the anticipated natural progression of the disease [66].

Eleven prospective phase III randomized controlled trials followed [6777]. Findings from these trials were inconsistent with regard to VA and CNV membrane size. Two of the 11 trials [71, 72] showed significant stabilization/improvement in both VA and CNV size, whereas significant stabilization/improvement in VA alone was found in 3 of the trials [68, 69, 77] and CNV size regression or contrast sensitivity alone was preserved in 2 trials [75, 76]. Six of the 11 randomized trials [67, 70, 7376] failed to identify any benefit. Two studies [68, 69] showed hypofractionation (given in 6 and 7.5 Gy per fraction) to be superior to conventional fractionation schema. A 2010 review [78], including 13 randomized trials (1 brachytherapy trial) and 1154 patients, showed a statistically significant reduction in risk of VA loss in the treatment group. Because of the relatively small magnitude of benefit, the authors recommended further trials with masked control groups to better characterize the role and value of EBRT for nAMD. In the trials reviewed, higher total doses of radiation, as well as hypofractionation schedules using higher dose per fraction, showed greater magnitudes of benefit.

Brachytherapy Trials

Traditional EBRT can deliver as much as 30% to 50% of the prescribed dose to the crystalline lens [49, 68]. To prevent unwanted complications, ophthalmic plaque brachytherapy was developed, based primarily on previous experience in the management of choroidal melanoma [7981]. Various radioisotopes, including 103Pd (γ emitter) and 90Sr (β emitter), have been used. Finger et al [54] first evaluated 103Pd in 1996 with 2 prospective phase I clinical trials, the first of which treated at a retinal dose rate of 35 to 56 cGy/h for a treatment duration of 18 to 48 hours, with maximum doses to the overlying retina ranging from 12.5 to 23.62 Gy prescribed at 2-mm depth. At a mean follow-up of 19 months, 70% of patients had stable or improved VA [82]. The second phase I clinical trial treated 31 eyes (30 patients) to a mean dose of 17.62 Gy with a 103Pd source. Visual acuity at mean follow-up of 33 months was stabilized in 45% of patients, and FA demonstrated regression or stabilization of CNV in 69% [83].

Jaakkola et al [84] used 90Sr brachytherapy plaques in 20 patients (with 12 additional untreated control patients) treated with 32.4 Gy. Visual acuity at 12 months was stable or improved in 45% of treated patients and only 25% of controls. Choroidal neovascular membrane was partially or totally occluded in 74% of those treated, whereas only 25% of controls remained CNV-progression free [84]. The follow-up study of 86 participants (88 eyes), treated either with 32.4 Gy or 12.6 Gy at a depth of 1.75 mm, showed that 20% of treated patients and 42% of controls experienced visual loss (P = .031) at 6 months. At 36 months the benefit was no longer favorable, with visual loss present in 80% of treated patients and 84% of controls [85].

Advances in brachytherapy delivery led to the development of epimacular brachytherapy (EMB), in which radiation is delivered via a pars plana vitrectomy that allows placement of the 90Sr source at the fovea [86]. In 1 study, 50% and 76% of patients treated with 24 (n = 26) or 15 (n = 8) Gy, respectively, experienced stable or improved VA at 12 months [87].

The combination of brachytherapy and anti-VEGF therapy was tested in 34 patients treated with 24 Gy and 2 injections of bevacizumab (first injection just before or on the day of the brachytherapy procedure and the second injection 1 month post procedure). At 12-month follow-up, stable or improved vision was observed in 68%, with 38% gaining >3 lines. Cataracts occurred in 42% of eyes with phakic intraocular lens [86]. At 36-month follow-up, 10% lost >15 letters and 21% gained ≥15 letters, a result dramatically superior to those reported in most monotherapy series [88]. The MERITAGE trial treated CNV in nAMD patients (n = 53) requiring persistent anti-VEGF therapy with 90Sr (24 Gy) followed by ranibizumab injections, as needed, determined at monthly follow-up visits according to predefined criteria. At 12 months, with an average of 3.49 injections of ranibizumab after treatment, 81% of participants had stable VA, compared to only 12.4% before treatment, providing presumptive support for the hypothesis that combined therapy with the addition of radiation, specifically for those already receiving anti-VEGF therapy, might be superior for visual preservation [89]. At 24 months, with a mean of 8.7 ranibizumab treatments, fewer than one third of patients (31.9 %) had lost >15 letters [90]. Conjuctival hemorrhage (71.7%), a self-limited and not vision-threatening finding, and cataract (30.2%), easily treatable, were the most common adverse events.

After these encouraging results, 2 prospective randomized clinical trials were performed, 1 for treatment-naïve individuals (the CNV Secondary AMD Treated with Beta Radiation Epiretinal Therapy [CABERNET] trial) and 1 for patients previously treated with anti-VEGF therapy (Macular Epiretinal Brachytherapy versus Lucentis-Only Treatment [MERLOT] trial). Both studies used a novel EMB system in which a probe was inserted into the posterior segment after vitrectomy to deliver 90Sr brachytherapy directly over the CNV.

The CABERNET trial randomly assigned 494 patients to 90Sr brachytherapy (24 Gy) and monthly intravitreal injections of ranibizumab (0.5 mg) for 2 months (experimental group) or monthly ranibizumab (0.5 mg) loading injections for 3 months, followed by quarterly injections (control group). The protocol was designed to demonstrate the noninferiority of the control arm at 24 months, with a 10% noninferiority margin, an endpoint that was not achieved, therefore ruling out substantial superiority of the experimental arm [91]. Possible explanations for failure to demonstrate efficacy in the experimental arm of the CABERNET trial include vertical dose instability with EMB during the 3 to 5 minutes of administration, a phenomenon that could result in significant underdosing of the target; the use of only treatment-naïve patients, who might have a longer time to visual deterioration, thereby reducing the statistically measurable event rate for the study; and possible altered pharmacokinetics of ranibizumab after the pars plana vitrectomy [92].

The MERLOT trial enrolled 363 patients, with final data collection for primary outcomes analysis completed in January 2015. Patients were randomly assigned to receive a single dose of 24 Gy 90Sr, using the same device as that in the CABERNET trial, followed by ranibizumab (0.5 mg) monthly as needed versus ranibizumab (0.5 mg) monthly as needed per retreatment criteria. Results are not yet available.

SalutarisMD (Salutaris Medical Devices, Inc, Tucson, Arizona) is a new device that uses a minimally invasive retrobulbar episcleral brachytherapy application aimed at treating the nAMD. This requires surgical placement. A prospective phase I industry-sponsored clinical trial has finished recruiting patients, and results are pending.

Stereotactic Radiation Therapy

The advantage of stereotactic radiation therapy over hypofractionated EBRT lies in the ability to conform dose to the target volume while minimizing dose to surrounding normal tissue [93]. A pilot study of 94 patients [94], using dose escalation ranging from 20 to 40 Gy in 2-Gy fractions, demonstrated VA within ±3 lines with no dose dependence at 12 months. Choroidal neovascular membrane size progressed at all dose levels, and no statistically significant difference based on higher dose was observed. Vitreous hemorrhage occurred in 1 patient receiving 20 Gy. At 10-year follow-up 49% of patients had developed central geographic atrophy, and mean VA was 20/300 (compared with a baseline mean of 20/120) [95]. Complications included radiation retinopathy, confirmed in 15% of patients and suspected in 18%, with a mean onset at 5.4 years after treatment. Radiation retinopathy manifested as neovascular glaucoma in 2 patients and macular ischemia in another 2.

The IRay system (Oraya Therapeutics, Inc, Newark, California) is a stereotactic robotic radiation therapy platform designed to deliver focused, low-energy photon radiation to the central macula through the pars plana, thereby avoiding the crystalline lens. Radiation is delivered noninvasively by using 3 circular fields. Canton et al [96, 97] performed 2 prospective phase I nonrandomized, uncontrolled clinical trials, using 16- and 24-Gy stereotactic radiation therapy. In both studies, patients received ranibizumab 1 month before and 1 month after stereotactic radiation therapy, then as needed. Visual acuity was measured according to the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, developed by the National Eye Institute to standardize testing by using the same number of letters per row with equal spacing of rows and letters on a log scale. This approach helps to eliminate inaccuracies seen in other testing methods. Six-month results in the 16-Gy group (n = 26) showed that most (96%) had lost <15 ETDRS letters of vision (an excellent outcome) and 50% had actually gained ≥15 EDTRS letters. An average of 0.5 injection of ranibizumab per patient was given in the 6 months after radiation. Toxicity included self-limited superficial punctate keratopathy in 3.85% of subjects [96]. Six-month results from the 24-Gy group (n = 19) were similar, with 100% losing <15, 79% gaining ≥0 (stabilized or improved VA), and 16% gaining ≥15 ETDRS letters, with an average of 0.4 additional injections 6 months after treatment. No adverse reactions were noted at 6 months [97]. Encouraging 12-month data for this cohort showed that all lost ≤15 letters, and 76% and 79% gained ≥0 letters (stable/improved VA) in the 16- (n = 28) and 24-Gy (n = 19) groups, respectively [98], suggesting the 16-Gy outcomes were equivalent to 24-Gy outcomes with less dose. A mean of 1.0 additional ranibizumab injection was given during a 12-month period with no radiation retinopathy, optic neuropathy, or cataracts.

Moshfeghi et al [99] used a “radiation first” approach and gave 16 Gy in 1 fraction followed by as-needed ranibizumab (n = 13). Eighty-five percent of participants lost <15, 54% gained ≥0, and 0% gained ≥15 ETDRS letters at 12 months. These promising results were translated into a phase III, randomized, double-masked, sham-controlled, multicenter, clinical trial (IRay Plus Anti-VEGF Treatment for Patients with Wet AMD [INTREPID] trial) [100102], with a primary outcome of number of as-needed 0.5-mg ranibizumab injections and secondary outcomes of ETDRS VA and CNV size. Inclusion in the study (n = 230) required detection of CNV within 3 years, ≥3 injections of an anti-VEGF agent in the past year, and an ongoing need for additional anti-VEGF therapy. Patients were randomly assigned to 16- (n = 75), 24- (n = 75), or 0-Gy (sham) radiation therapy (n = 80), with a baseline injection of ranibizumab followed by as-needed ranibizumab according to predefined treatment criteria. At 2 years, patients receiving 16 and 24 Gy had a statistically significant decrease in ranibizumab injections with a mean of 4.5 (P = .008) and 5.4 (P = .09) ranibizumab injections, respectively, compared to a mean of 6.6 ranibizumab injections for sham radiation [102]. Although mean VA was stable in both treatment groups at 12 months, VA gains seen in the early weeks of the study returned to or near baseline over the same period [100]. Results were as follows at 24 months in the 16-Gy, 24-Gy, and sham groups: 68%, 75%, and 79% lost <15 ETDRS letters; 32%, 43%, and 38% gained ≥0 ETDRS letters; and 3%, 1%, and 3% gained ≥15 ETDRS letters. Mean CNV size was estimated to decrease by 0.1 mm2 in all groups. Although VA and CNV size results did not differ significantly in the treated and control groups, the study was not designed to demonstrate superiority or noninferiority.

Overall, the stereotactic radiation therapy outcomes to date demonstrate stabilization of VA with reduced need for anti-VEGF treatment. These results could decrease financial and social burden to the patient by reducing the number of intravitreal injections and clinic visits as well as by reducing complications from repeated intravitreal injections, including endophthalmitis, ocular hypertension, geographic atrophy, and arteriothrombotic events. Anticipated 3-year safety analysis data will help guide future recommendations regarding combination therapy using stereotactic radiation therapy and anti-VEGF agents.

Proton Therapy

Yonemoto et al [103] published their proton therapy experience with 21 patients with CNV treated with 7.27 Gy in 1 fraction (100 MeV protons) between March and August 1994. Fifty-three percent of patients showed regression or stabilization with FA. At a mean follow-up of 11.6 months, visual acuity showed that 58% of patients had improved or had stable vision. Another phase I/II dose-escalation study enrolled 27 patients between September 1994 and January 1996. These patients were treated with a single 12.73 Gy fraction using 100-MeV protons, and they were compared with patients who received 7.27 Gy in 1 fraction [104]. Actuarial lesion control at 21 months was 36% for patients who received 7.27 Gy and 89% for patients who received 12.73 Gy. Of patients with stable lesions, 77% achieved improved/stable VA, compared with 44% of patients with active lesions. The actuarial mean visual loss of proton-treated patients was 0% at 24 months. Increased morbidity (not vision limiting) was associated with higher dose (0% for 7.27 Gy and 26% for 12.73 Gy), which is likely a consequence of giving this total dose in 1 fraction. Flaxel et al [105] reported a mean 22.1-month follow-up for this same cohort. Twelve-month VA was stable in 44% and 75% of patients receiving 7.27 and 12.73 Gy, respectively. Fluorescein angiography showed greater and more continued regression of nAMD at the higher dose. Between October 1995 and February 2000, a total of 166 patients from Harvard (Cambridge, Massachusetts) were randomly assigned to 14.55 and 21.82 Gy proton therapy. Twelve months after completion of treatment, 42% and 35% lost ≥3 lines of vision from baseline. At 24 months, loss of ≥3 lines of vision increased to 62% and 53% in the 14.55-Gy and 21.82-Gy groups, respectively (P = .40) [106]. No significant difference was found in radiation complications between the 2 groups (15.7% and 14.8% for 14.55 and 21.82 Gy, respectively). Ciulla et al [107] treated 37 patients with 14.55 Gy protons in 2 fractions and compared results with those from sham treatments. They observed a nonstatistically significant trend toward stabilization of VA. Accrual was halted because of ethical concerns over those assigned to sham treatment given the anticipated near-term FDA approval of verteporfin. A study from Nice, France, used 9.09 Gy in 58 patients [108]. At 18-month follow-up, VA was stable in 61%, and FA showed stable CNV in 66.6%. Three patients had progressive CNV, and 4 had submacular hemorrhage. A recent pilot study with 3-year follow-up [109] found that ranibizumab administered at 4 monthly injections and combined with 21.82 Gy (in 2 fractions, 24 hours apart) of proton beam radiation for nAMD in 6 patients (4 of whom were treatment-naïve) demonstrated no complications of treatment; furthermore, 3 of the 4 treatment-naïve patients required no further treatment. These early findings lend additional credence to radiation therapy as a useful adjunct to antiangiogenic agents.

The ongoing Prospective Randomized Trial of Proton Beam Combined with Anti-VEGF Therapy for Exudative AMD (PBAMD2 trial) is expected to finish accrual in December 2016. The trial randomly assigns patients to 21.82 Gy proton therapy plus anti-VEGF, 14.55 Gy proton therapy plus anti-VEGF, or sham irradiation plus anti-VEGF.

Stem Cell Transplant in AMD

Stem cell therapy is in its infancy for nAMD and many challenges exist regarding safety and prevention of rejection of transplanted stem cells. Examples of ongoing trials in dry AMD are using bone marrow CD34+ stem cells (NCT01736059 and NCT01920867), human embryonic stem cells (hESCs) (NCT01344993), and human CNS stem cells (NCT01632527). These cells differentiate into RPE and are surgically placed subretinally to replace the damaged RPE. An open-label phase I/II trial (NCT01344993) using hESCs for dry AMD showed that at 12 months (in eyes that did not develop cataract or require ocular surgery during follow-up) VA increased by 8 EDTRS letters (range, 4–23) for dose group 1 (50 000 cells; n = 3), 8 EDTRS letters (range, 2–14) for dose group 2 (100 000 cells; n = 2), and 15 EDTRS letters (range, 13–44) for dose group 3 (150 000 cells; n = 3), and this was statistically significant (P = .0117) [110]. The first nAMD stem cell trial is a phase I trial from Japan at the research institution RIKEN. RIKEN is using human-induced pluripotent stem cells (hiPSCs), which have been shown to differentiate into hiPSC-RPE and are used as a graft for tissue replacement therapy in AMD [111]. Results from these trials are pending and accrual is ongoing.

Discussion

The societal burden of AMD cannot be overstated, and this devastating disease will continue to have a significant impact worldwide, especially in developed countries. Current standard therapy is anti-VEGF treatment. Antiangiogenic therapy has proven effective for some patients, with 40% of individuals experiencing improvement in vision at 12 months, whereas 60% continue to have progressive decline in vision [20, 22]. Antiangiogenic injections, although well tolerated, are costly, necessitate repeated office visits, and carry the risk of endophthalmitis [20, 22]. A cost-of-treatment review of Medicare Part B for bevacizumab and ranibizumab found that 218 000 people were treated with bevacizumab (off-label) and ranibizumab (FDA approved) in 2009 [112]. Estimated reimbursement for covered drugs furnished incident to physician services totaled $40 million for 936 382 bevacizumab treatments and $1.1 billion for 696 927 ranibizumab treatments. Moja et al [113] showed bevacizumab and ranibizumab to be equivalent in numbers of serious systemic adverse events in the first 2 years of treatment, except for gastrointestinal disorders. Therefore, bevacizumab, although off-label, may be the more appropriate choice for treatment of nAMD from a cost perspective [112]. This also makes a strong case for combination therapy that would decrease the frequency of injections while maintaining or improving vision.

Rationale for Combining Antiangiogenic Agents with Radiation Therapy

Unlike anti-VEGF agents, radiation affects both the vascular and avascular fibrous components of nAMD. Radiation can be antiangiogenic, anti-inflammatory, and antifibrotic [114]. Although radiation retinopathy is a potential adverse effect of radiation, multiple studies have shown that bevacizumab is beneficial in treating this condition [115118]. The ongoing Treatment of Radiation Retinopathy trial has yet to accrue a sufficient patient number to study ranibizumab or triamcinolone acetonide versus observation in prevention of radiation retinopathy following irradiation for choroidal melanoma [119].

Previous trials in human umbilical vein endothelial cells and radiation-resistant p53-dysfunctional tumor xenografts derived from SW480 colon adenocarcinoma cells that received combination novel anti-VEGF (PTK787/ZK222584) and ionizing radiation (5 or 10 Gy) demonstrated promising results. Even in the absence of anti-VEGF therapy, radiation-induced arrest of cell proliferation and combined antiangiogenic and radiation therapy showed additive antiproliferative effect without supra-additive cytotoxic effects [120].

Case for Proton Therapy over Photon Therapy

The previously mentioned modalities and devices for photon radiation delivery have several disadvantages. NeoVista (Newark, CA) and Salutaris require surgery; one is actually an intraocular approach and the other requires mobilization of the globe to reach the posterior portion to place the radioactive probe over the lesion. In both cases, because the radioactive probes have a finite size, the CNV has a varying size, and of the difficulty in determining the confines, the lesions could be overtreated or undertreated, and technical challenges in positioning could lead to “geographic” misses. Moreover, surgery in this patient group is associated not only with discomfort but also with significant complications.

Using external-beam photon therapy, x-rays are directed at a target from outside the eye. Unlike photons, protons have the potential to deliver a focal dose to the target while minimizing radiation to adjacent normal tissues. With photons, radiation is delivered not only to the posterior retina but also to the bilateral orbits, contralateral eye, and surrounding soft tissues. The proton beam can be configured to allow no radiation to the contralateral orbit, little if any to the soft tissues, and a minimal dose to the normal retina. In addition, proton treatment planning software allows importing of the FA-identified CNV into the eye model to verify location in relation to other ocular structures. This allows for a customized proton radiation portal and an appropriate gaze for delivery of optimum treatment. Additionally, this allows for targeting the therapy based on irregular shape and thickness––which cannot be achieved as precisely and effectively with photon therapy. A high dose rate is needed to limit the amount of time a patient is required to maintain eccentric gaze during delivery of a large fractional dose. This can be accomplished by using a proton eyeline, which ensures a high dose rate (>30 Gy/min) while avoiding critical structures by using sharp dose gradients and limiting patient gazing time. The patient is positioned in the line of a fixed proton beam. Before starting the treatment, the patient's head is immobilized and position of the eye is set. Treatment then begins after confirmation of adequate positioning and head fixation. Using this therapy is preferred over treatments with proton therapy not designed to deliver stereotactic radiation [121].

Case for Proton Therapy with Anti-VEGF for nAMD

We expect that the increasing availability of proton treatment in the United States will result in more studies for nAMD. Given the current need, further investigation should focus on proton beam radiation in tandem with antiangiogenic therapy. Findings to date suggest that protons could have a role as an effective noninvasive treatment for nAMD.

Given preliminary evidence supporting the use of stereotactic radiation therapy [100102] and proton therapy [109], it is reasonable to consider a randomized, double-masked, prospective phase III clinical trial to determine which combination of therapeutic modalities has the best outcomes and safety profiles. A potential trial design might be 3 armed and include the following: (1) stereotactic radiation therapy given with a dedicated stereotactic radiation delivery system combined with antiangiogenic therapy; (2) proton therapy delivered via a dedicated proton eyeline combined with antiangiogenic therapy; and (3) antiangiogenic therapy alone. Such a study could provide valuable data to support clinical implementation of proton therapy as an adjunct approach in this difficult and debilitating disease setting.

ADDITIONAL INFORMATION AND DECLARATIONS

Conflicts of Interest: MPM has served as a consultant for Cavion, Novocure, and Novartis; has clinical trial research funding from Cellectar and Novocure; and previously served on the Board of Directors of Pharmacyclics. SRR and MSJK have no conflicts of interest to disclose.

References

References
1.
World Health Organization
.
Prevention of blindness and visual impairment: priority eye diseases.
2015
.
2.
Fine
SL,
Berger
JW,
Maguire
MG,
Ho
AC.
Age-related macular degeneration
.
N Engl J Med
.
2000
;
342
:
483
92
.
3.
Bressler
NM,
Silva
JC,
Bressler
SB,
Fine
SL,
Green
WR.
Clinicopathologic correlation of drusen and retinal pigment epithelial abnormalities in age-related macular degeneration
.
Retina
.
1994
;
14
:
130
42
.
4.
Jager
RD,
Mieler
WF,
Miller
JW.
Age-related macular degeneration
.
N Engl J Med
.
2008
;
358
:
2606
17
.
5.
National Eye Institute
.
Age-related macular degeneration (AMD).
2015
.
6.
Wong
WL,
Su
X,
Li
X,
Cheung
CM,
Klein
R,
Cheng
CY,
Wong
TY.
Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis
.
Lancet Glob Health
.
2014
;
2
:
e106
16
.
7.
Seddon
JM,
Ajani
UA,
Sperduto
RD,
Hiller
R,
Blair
N,
Burton
TC,
Farber
MD,
Gragoudas
ES,
Haller
J,
Miller
DT,
et al.
Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration: Eye Disease Case-Control Study Group
.
JAMA
.
1994
;
272
:
1413
20
.
8.
Antioxidant status and neovascular age-related macular degeneration: Eye Disease Case-Control Study Group.
Arch Ophthalmol
.
1993
;
111
:
104
9
.
9.
Goldberg
J,
Flowerdew
G,
Smith
E,
Brody
JA,
Tso
MO.
Factors associated with age-related macular degeneration: an analysis of data from the first National Health and Nutrition Examination Survey
.
Am J Epidemiol
.
1988
;
128
:
700
10
.
10.
A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no
.
8
.
Arch Ophthalmol
.
2001
;
119
:
1417
36
.
11.
Evans
JR,
Lawrenson
JG.
A review of the evidence for dietary interventions in preventing or slowing the progression of age-related macular degeneration
.
Ophthalmic Physiol Opt
.
2014
;
34
:
390
6
.
12.
Evans
JR,
Lawrenson
JG.
Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration.
Cochrane Database Syst Rev
.
2012
;
6:CD000253.
13.
Age-Related Eye Disease Study 2 Research Group
.
Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial
.
JAMA
.
2013
;
309
:
2005
15
.
14.
Argon laser photocoagulation for senile macular degeneration: results of a randomized clinical trial.
Arch Ophthalmol
.
1982
;
100
:
912
8
.
15.
Recurrent choroidal neovascularization after argon laser photocoagulation for neovascular maculopathy: Macular Photocoagulation Study Group.
Arch Ophthalmol
.
1986
;
104
:
503
12
.
16.
Krypton laser photocoagulation for neovascular lesions of age-related macular degeneration: results of a randomized clinical trial: Macular Photocoagulation Study Group.
Arch Ophthalmol
.
1990
;
108
:
816
24
.
17.
Laser photocoagulation for juxtafoveal choroidal neovascularization: five-year results from randomized clinical trials: Macular Photocoagulation Study Group.
Arch Ophthalmol
.
1994
;
112
:
500
9
.
18.
Laser photocoagulation of subfoveal neovascular lesions of age-related macular degeneration: updated findings from two clinical trials: Macular Photocoagulation Study Group.
Arch Ophthalmol
.
1993
;
111
:
1200
9
.
19.
Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration: results of a randomized clinical trial: Macular Photocoagulation Study Group.
Arch Ophthalmol
.
1991
;
109
:
1220
31
.
20.
Brown
DM,
Kaiser
PK,
Michels
M,
Soubrane
G,
Heier
JS,
Kim
RY,
Sy
JP,
Schneider
S.
Ranibizumab versus verteporfin for neovascular age-related macular degeneration
.
N Engl J Med
.
2006
;
355
:
1432
44
.
21.
Bressler
NM.
Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials-tap report 2
.
Arch Ophthalmol
.
2001
;
119
:
198
207
.
22.
Rosenfeld
PJ,
Brown
DM,
Heier
JS,
Boyer
DS,
Kaiser
PK,
Chung
CY,
Kim
RY.
Ranibizumab for neovascular age-related macular degeneration
.
N Engl J Med
.
2006
;
355
:
1419
31
.
23.
Gragoudas
ES,
Adamis
AP,
Cunningham
ET
Jr,
Feinsod
M,
Guyer
DR.
Pegaptanib for neovascular age-related macular degeneration
.
N Engl J Med
.
2004
;
351
:
2805
16
.
24.
Hurwitz
H,
Fehrenbacher
L,
Novotny
W,
Cartwright
T,
Hainsworth
J,
Heim
W,
Berlin
J,
Baron
A,
Griffing
S,
Holmgren
E,
Ferrara
N,
Fyfe
G,
Rogers
B,
Ross
R,
Kabbinavar
F.
Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer
.
N Engl J Med
.
2004
;
350
:
2335
42
.
25.
Michels
S,
Rosenfeld
PJ,
Puliafito
CA,
Marcus
EN,
Venkatraman
AS.
Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration twelve-week results of an uncontrolled open-label clinical study
.
Ophthalmology
.
2005
;
112
:
1035
47
.
26.
Avery
RL,
Pieramici
DJ,
Rabena
MD,
Castellarin
AA,
Nasir
MA,
Giust
MJ.
Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration
.
Ophthalmology
.
2006
;
113
:
363
72.e5
.
27.
Bom Aggio F, Eid Farah M, Melo GB
.
Intravitreal bevacizumab for occult choroidal neovascularization with pigment epithelium detachment in age-related macular degeneration
.
Acta Ophthalmol Scand
.
2006
;
84
:
713
4
.
28.
Martin
DF,
Maguire
MG,
Fine
SL,
Ying
GS,
Jaffe
GJ,
Grunwald
JE,
Toth
C,
Redford
M,
Ferris
FL
III.
Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results
.
Ophthalmology
.
2012
;
119
:
1388
98
.
29.
Martin
DF,
Maguire
MG,
Ying
GS,
Grunwald
JE,
Fine
SL,
Jaffe
GJ.
Ranibizumab and bevacizumab for neovascular age-related macular degeneration
.
N Engl J Med
.
2011
;
364
:
1897
908
.
30.
Chakravarthy
U,
Harding
SP,
Rogers
CA,
Downes
SM,
Lotery
AJ,
Culliford
LA,
Reeves
BC.
Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial
.
Lancet
.
2013
;
382
:
1258
67
.
31.
Chakravarthy
U,
Harding
SP,
Rogers
CA,
Downes
SM,
Lotery
AJ,
Wordsworth
S,
Reeves
BC.
Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial
.
Ophthalmology
.
2012
;
119
:
1399
411
.
32.
Heier
JS,
Brown
DM,
Chong
V,
Korobelnik
JF,
Kaiser
PK,
Nguyen
QD,
Kirchhof
B,
Ho
A,
Ogura
Y,
Yancopoulos
GD,
Stahl
N,
Vitti
R,
Berliner
AJ,
Soo
Y,
Anderesi
M,
Groetzbach
G,
Sommerauer
B,
Sandbrink
R,
Simader
C,
Schmidt-Erfurth
U.
Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration
.
Ophthalmology
.
2012
;
119
:
2537
48
.
33.
Schmidt-Erfurth
U,
Kaiser
PK,
Korobelnik
JF,
Brown
DM,
Chong
V,
Nguyen
QD,
Ho
AC,
Ogura
Y,
Simader
C,
Jaffe
GJ,
Slakter
JS,
Yancopoulos
GD,
Stahl
N,
Vitti
R,
Berliner
AJ,
Soo
Y,
Anderesi
M,
Sowade
O,
Zeitz
O,
Norenberg
C,
Sandbrink
R,
Heier
JS.
Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies
.
Ophthalmology
.
2014
;
121
:
193
201
.
34.
Rofagha
S,
Bhisitkul
RB,
Boyer
DS,
Sadda
SR,
Zhang
K.
Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP)
.
Ophthalmology
.
2013
;
120
:
2292
9
.
35.
Kodjikian
L,
Decullier
E,
Souied
EH,
Girmens
JF,
Durand
EE,
Chapuis
FR,
Huot
L.
Bevacizumab and ranibizumab for neovascular age-related macular degeneration: an updated meta-analysis of randomised clinical trials
.
Graefes Arch Clin Exp Ophthalmol
.
2014
;
252
:
1529
37
.
36.
Solomon
SD,
Lindsley
K,
Vedula
SS,
Krzystolik
MG,
Hawkins
BS.
Anti-vascular endothelial growth factor for neovascular age-related macular degeneration.
Cochrane Database Syst Rev
.
2014
;
8:CD005139.
37.
Schaumberg
DA,
Hankinson
SE,
Guo
Q,
Rimm
E,
Hunter
DJ.
A prospective study of 2 major age-related macular degeneration susceptibility alleles and interactions with modifiable risk factors
.
Arch Ophthalmol
.
2007
;
125
:
55
62
.
38.
Klein
RJ,
Zeiss
C,
Chew
EY,
Tsai
JY,
Sackler
RS,
Haynes
C,
Henning
AK,
SanGiovanni
JP,
Mane
SM,
Mayne
ST,
Bracken
MB,
Ferris
FL,
Ott
J,
Barnstable
C,
Hoh
J.
Complement factor H polymorphism in age-related macular degeneration
.
Science
.
2005
;
308
:
385
9
.
39.
Edwards
AO,
Ritter
R
III,
Abel
KJ,
Manning
A,
Panhuysen
C,
Farrer
LA.
Complement factor H polymorphism and age-related macular degeneration
.
Science
.
2005
;
308
:
421
4
.
40.
Haines
JL,
Hauser
MA,
Schmidt
S,
Scott
WK,
Olson
LM,
Gallins
P,
Spencer
KL,
Kwan
SY,
Noureddine
M,
Gilbert
JR,
Schnetz-Boutaud
N,
Agarwal
A,
Postel
EA,
Pericak-Vance
MA.
Complement factor H variant increases the risk of age-related macular degeneration
.
Science
.
2005
;
308
:
419
21
.
41.
Kondo
N,
Bessho
H,
Honda
S,
Negi
A.
Complement factor H Y402H variant and risk of age-related macular degeneration in Asians: a systematic review and meta-analysis
.
Ophthalmology
.
2011
;
118
:
339
44
.
42.
Raychaudhuri
S,
Iartchouk
O,
Chin
K,
Tan
PL,
Tai
AK,
Ripke
S,
Gowrisankar
S,
Vemuri
S,
Montgomery
K,
Yu
Y,
Reynolds
R,
Zack
DJ,
Campochiaro
B,
Campochiaro
P,
Katsanis
N,
Daly
MJ,
Seddon
JM.
A rare penetrant mutation in CFH confers high risk of age-related macular degeneration
.
Nat Genet
.
2011
;
43
:
1232
6
.
43.
Jonathan
EC,
Bernhard
EJ,
McKenna
WG.
How does radiation kill cells?
Curr Opin Chem Biol
.
1999
;
3
:
77
83
.
44.
Robbins
ME,
Zhao
W.
Chronic oxidative stress and radiation-induced late normal tissue injury: a review
.
Int J Radiat Biol
.
2004
;
80
:
251
9
.
45.
Chakravarthy
U,
Gardiner
TA,
Archer
DB,
Maguire
CJ.
A light microscopic and autoradiographic study of non-irradiated and irradiated ocular wounds
.
Curr Eye Res
.
1989
;
8
:
337
48
.
46.
Hart
PM,
Archer
DB,
Chakravarthy
U.
Asymmetry of disciform scarring in bilateral disease when one eye is treated with radiotherapy
.
Br J Ophthalmol
.
1995
;
79
:
562
8
.
47.
Order
SE,
Donaldson
SS,
Brady
LW,
Heilmann
H-P.
Chapter: Macular Degeneration
.
In: Brady LW, Heilmann HP, Molls M, eds. Radiation Therapy of Benign Diseases: A Clinical Guide. 2nd ed
.
New York, NY
:
Springer;
2003
:
195.
48.
Bert
C,
Engenhart-Cabillic
R,
Durante
M.
Particle therapy for noncancer diseases
.
Med Phys
.
2012
;
39
:
1716
27
.
49.
Chakravarthy
U,
Houston
RF,
Archer
DB.
Treatment of age-related subfoveal neovascular membranes by teletherapy: a pilot study
.
Br J Ophthalmol
.
1993
;
77
:
265
73
.
50.
Berson
AM,
Finger
PT,
Sherr
DL,
Emery
R,
Alfieri
AA,
Bosworth
JL.
Radiotherapy for age-related macular degeneration: preliminary results of a potentially new treatment
.
Int J Radiat Oncol Biol Phys
.
1996
;
36
:
861
5
.
51.
Bergink
GJ,
Deutman
AF,
van den Broek
JE,
van Daal
WA,
van der Maazen
RM.
Radiation therapy for age-related subfoveal choroidal neovascular membranes: a pilot study
.
Doc Ophthalmol
.
1995
;
90
:
67
74
.
52.
Freire
J,
Longton
WA,
Miyamoto
CT,
Brady
LW,
Augsburger
J,
Brown
G,
Micaily
B,
Unda
R.
External radiotherapy in macular degeneration: technique and preliminary subjective response
.
Front Radiat Ther Oncol
.
1997
;
30
:
247
52
.
53.
Churei
H,
Ohkubo
K,
Nakajo
M,
Hokotate
H,
Baba
Y,
Ideue
J,
Miyagawa
K,
Nakayama
H,
Hiraki
Y,
Kitasato
T,
Yabe
N.
External-beam radiation therapy for age-related macular degeneration: two years' follow-up results at a total dose of 20 Gy in 10 fractions
.
Radiat Med
.
2004
;
22
:
398
404
.
54.
Finger
PT,
Berson
A,
Sherr
D,
Riley
R,
Balkin
RA,
Bosworth
JL.
Radiation therapy for subretinal neovascularization
.
Ophthalmology
.
1996
;
103
:
878
89
.
55.
Hart
PM,
Chakravarthy
U,
MacKenzie
G,
Archer
DB,
Houston
RF.
Teletherapy for subfoveal choroidal neovascularisation of age-related macular degeneration: results of follow up in a non-randomised study
.
Br J Ophthalmol
.
1996
;
80
:
1046
50
.
56.
Hollick
EJ,
Goble
RR,
Knowles
PJ,
Ramsey
MC,
Deutsch
G,
Casswell
AG.
Radiotherapy treatment of age-related subfoveal neovascular membranes in patients with good vision
.
Eye (Lond)
.
1996
;
10
(
pt 5
):
609
16
.
57.
Postgens
H,
Bodanowitz
S,
Kroll
P.
Low-dose radiation therapy for age-related macular degeneration
.
Graefes Arch Clin Exp Ophthalmol
.
1997
;
235
:
656
61
.
58.
Prettenhofer
U,
Haas
A,
Mayer
R,
Stranzl
H,
Oechs
A,
Hackl
A.
Long-term results after external radiotherapy in age-related macular degeneration: a prospective study
.
Strahlenther Onkol
.
2004
;
180
:
91
5
.
59.
Sasai
K,
Murata
R,
Mandai
M,
Takahashi
M,
Ogura
Y,
Ngata
Y,
Nishimura
Y,
Hiraoka
M.
Radiation therapy for ocular choroidal neovascularization (phase I/II study): preliminary report
.
Int J Radiat Oncol Biol Phys
.
1997
;
39
:
173
8
.
60.
Spaide
RF,
Guyer
DR,
McCormick
B,
Yannuzzi
LA,
Burke
K,
Mendelsohn
M,
Haas
A,
Slakter
JS,
Sorenson
JA,
Fisher
YL,
Abramson
D.
External beam radiation therapy for choroidal neovascularization
.
Ophthalmology
.
1998
;
105
:
24
30
.
61.
Stalmans
P,
Leys
A,
Van Limbergen
E.
External beam radiotherapy (20 Gy, 2 Gy fractions) fails to control the growth of choroidal neovascularization in age-related macular degeneration: a review of 111 cases
.
Retina
.
1997
;
17
:
481
92
.
62.
Valmaggia
C,
Ries
G,
Ballinari
P. A
5-year follow-up study for distance visual acuity after low dose radiation on subfoveal choroidal neovascularization in age-related macular degeneration
.
Doc Ophthalmol
.
2001
;
103
:
201
9
.
63.
Mauget-Faysse
M,
Chiquet
C,
Milea
D,
Romestaing
P,
Gerard
JP,
Martin
P,
Koenig
F.
Long term results of radiotherapy for subfoveal choroidal neovascularisation in age related macular degeneration
.
Br J Ophthalmol
.
1999
;
83
:
923
8
.
64.
Hoeller
U,
Fuisting
B,
Schwartz
R,
Roeper
B,
Richard
G,
Alberti
W.
Results of radiotherapy of subfoveal neovascularization with 16 and 20 Gy
.
Eye (Lond)
.
2005
;
19
:
1151
6
.
65.
Munshi
A,
Sarin
R,
Dudhani
A,
Dinshaw
KA.
Age related macular degeneration: a study of patients managed with radiotherapy
.
J Cancer Res Ther
.
2007
;
3
:
12
6
.
66.
Chakravarthy
U,
MacKenzie
G.
External beam radiotherapy in exudative age-related macular degeneration: a pooled analysis of phase I data
.
Br J Radiol
.
2000
;
73
:
305
13
.
67.
Anders
N,
Stahl
H,
Dorn
A,
Walkow
T,
Hosten
N,
Wust
P,
Hartmann
C,
Wollensak
J.
Radiotherapy of exudative senile macular degeneration: a prospective controlled study [in German]
.
Ophthalmologe
.
1998
;
95
:
760
4
.
68.
Bergink
GJ,
Hoyng
CB,
van der Maazen
RW,
Vingerling
JR,
van Daal
WA,
Deutman
AF.
A randomized controlled clinical trial on the efficacy of radiation therapy in the control of subfoveal choroidal neovascularization in age-related macular degeneration: radiation versus observation
.
Graefes Arch Clin Exp Ophthalmol
.
1998
;
236
:
321
5
.
69.
Char
DH,
Irvine
AI,
Posner
MD,
Quivey
J,
Phillips
TL,
Kroll
S.
Randomized trial of radiation for age-related macular degeneration
.
Am J Ophthalmol
.
1999
;
127
:
574
8
.
70.
A prospective, randomized, double-masked trial on radiation therapy for neovascular age-related macular degeneration (RAD Study): Radiation Therapy for Age-related Macular Degeneration.
Ophthalmology
.
1999
;
106
:
2239
47
.
71.
The results of randomized controlled trial of low-dose radiation for wet-type age-related macular degeneration on a 1 year term basis [in Japanese].
Nippon Ganka Gakkai Zasshi
.
2003
;
107
:
326
30
.
72.
Kobayashi
H,
Kobayashi
K.
Age-related macular degeneration: long-term results of radiotherapy for subfoveal neovascular membranes
.
Am J Ophthalmol
.
2000
;
130
:
617
35
.
73.
Marcus
DM,
Sheils
W,
Johnson
MH,
McIntosh
SB,
Leibach
DB,
Maguire
A,
Alexander
J,
Samy
CN.
External beam irradiation of subfoveal choroidal neovascularization complicating age-related macular degeneration: one-year results of a prospective, double-masked, randomized clinical trial
.
Arch Ophthalmol
.
2001
;
119
:
171
80
.
74.
Marcus
DM,
Peskin
E,
Maguire
M,
Weissgold
D,
Alexander
J,
Fine
S,
Followill
D.
The age-related macular degeneration radiotherapy trial (AMDRT): one year results from a pilot study
.
Am J Ophthalmol
.
2004
;
138
:
818
28
.
75.
Eter
N,
Schuller
H,
Spitznas
M.
Radiotherapy for age-related macular degeneration: is there a benefit for classic CNV?
Int Ophthalmol
.
2001
;
24
:
13
9
.
76.
Hart
PM,
Chakravarthy
U,
Mackenzie
G,
Chisholm
IH,
Bird
AC,
Stevenson
MR,
Owens
SL,
Hall
V,
Houston
RF,
McCulloch
DW,
Plowman
N.
Visual outcomes in the subfoveal radiotherapy study: a randomized controlled trial of teletherapy for age-related macular degeneration
.
Arch Ophthalmol
.
2002
;
120
:
1029
38
.
77.
Valmaggia
C,
Ries
G,
Ballinari
P.
Radiotherapy for subfoveal choroidal neovascularization in age-related macular degeneration: a randomized clinical trial
.
Am J Ophthalmol
.
2002
;
133
:
521
9
.
78.
Evans
JR,
Sivagnanavel
V,
Chong
V.
Radiotherapy for neovascular age-related macular degeneration.
Cochrane Database Syst Rev
.
2010
;
5:CD004004.
79.
Lommatzsch
P.
Treatment of choroidal melanomas with 106Ru/106Rh beta-ray applicators
.
Surv Ophthalmol
.
1974
;
19
:
85
100
.
80.
Finger
PT,
Lu
D,
Buffa
A,
DeBlasio
DS,
Bosworth
JL.
Palladium-103 versus iodine-125 for ophthalmic plaque radiotherapy
.
Int J Radiat Oncol Biol Phys
.
1993
;
27
:
849
54
.
81.
Finger
PT.
Radiation therapy for choroidal melanoma
.
Surv Ophthalmol
.
1997
;
42
:
215
32
.
82.
Finger
PT,
Berson
A,
Ng
T,
Szechter
A.
Ophthalmic plaque radiotherapy for age-related macular degeneration associated with subretinal neovascularization
.
Am J Ophthalmol
.
1999
;
127
:
170
7
.
83.
Finger
PT,
Gelman
YP,
Berson
AM,
Szechter
A.
Palladium-103 plaque radiation therapy for macular degeneration: results of a 7 year study
.
Br J Ophthalmol
.
2003
;
87
:
1497
503
.
84.
Jaakkola
A,
Heikkonen
J,
Tommila
P,
Laatikainen
L,
Immonen
I.
Strontium plaque irradiation of subfoveal neovascular membranes in age-related macular degeneration
.
Graefes Arch Clin Exp Ophthalmol
.
1998
;
236
:
24
30
.
85.
Jaakkola
A,
Heikkonen
J,
Tommila
P,
Laatikainen
L,
Immonen
I.
Strontium plaque brachytherapy for exudative age-related macular degeneration: three-year results of a randomized study
.
Ophthalmology
.
2005
;
112
:
567
73
.
86.
Avila
MP,
Farah
ME,
Santos
A,
Duprat
JP,
Woodward
BW,
Nau
J.
Twelve-month short-term safety and visual-acuity results from a multicentre prospective study of epiretinal strontium-90 brachytherapy with bevacizumab for the treatment of subfoveal choroidal neovascularisation secondary to age-related macular degeneration
.
Br J Ophthalmol
.
2009
;
93
:
305
9
.
87.
Avila
MP,
Farah
ME,
Santos
A,
Kapran
Z,
Duprat
JP,
Woodward
BW,
Nau
J.
Twelve-month safety and visual acuity results from a feasibility study of intraocular, epiretinal radiation therapy for the treatment of subfoveal CNV secondary to AMD
.
Retina
.
2009
;
29
:
157
69
.
88.
Avila
MP,
Farah
ME,
Santos
A,
Carla
L,
Fuji
G,
Rossi
J,
Nau
J.
Three-year safety and visual acuity results of epimacular 90 strontium/90 yttrium brachytherapy with bevacizumab for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration
.
Retina
.
2012
;
32
:
10
8
.
89.
Dugel
PU,
Petrarca
R,
Bennett
M,
Barak
A,
Weinberger
D,
Nau
J,
Jackson
TL.
Macular epiretinal brachytherapy in treated age-related macular degeneration: MERITAGE study: twelve-month safety and efficacy results
.
Ophthalmology
.
2012
;
119
:
1425
31
.
90.
Petrarca
R,
Dugel
PU,
Bennett
M,
Barak
A,
Weinberger
D,
Nau
J,
Jackson
TL.
Macular epiretinal brachytherapy in treated age-related macular degeneration (MERITAGE): month 24 safety and efficacy results
.
Retina
.
2014
;
34
:
874
9
.
91.
Dugel
PU,
Bebchuk
JD,
Nau
J,
Reichel
E,
Singer
M,
Barak
A,
Binder
S,
Jackson
TL.
Epimacular brachytherapy for neovascular age-related macular degeneration: a randomized, controlled trial (CABERNET)
.
Ophthalmology
.
2013
;
120
:
317
27
.
92.
Moshfeghi
AA.
Radiation therapy for neovascular age-related macular degeneration.
2013
.
2015
.
93.
Finger
PT.
Radiation therapy for orbital tumors: concepts, current use, and ophthalmic radiation side effects
.
Surv Ophthalmol
.
2009
;
54
:
545
68
.
94.
Barak
A,
Hauser
D,
Yipp
P,
Morse
L,
Leigh
B,
Kubo
D,
Goldberg
Z,
Earle
J,
Handa
JT.
A phase I trial of stereotactic external beam radiation for subfoveal choroidal neovascular membranes in age-related macular degeneration
.
Br J Radiol
.
2005
;
78
:
827
31
.
95.
Trikha
R,
Morse
LS,
Zawadzki
RJ,
Werner
JS,
Park
SS.
Ten-year follow-up of eyes treated with stereotactic fractionated external beam radiation for neovascular age-related macular degeneration
.
Retina
.
2011
;
31
:
1303
15
.
96.
Canton
VM,
Quiroz-Mercado
H,
Velez-Montoya
R,
Lopez-Miranda
MJ,
Moshfeghi
AA,
Shusterman
EM,
Kaiser
PK,
Sanislo
SR,
Gertner
M,
Moshfeghi
DM.
16-Gy low-voltage x-ray irradiation with ranibizumab therapy for AMD: 6-month safety and functional outcomes
.
Ophthalmic Surg Lasers Imaging
.
2011
;
42
:
468
73
.
97.
Canton
VM,
Quiroz-Mercado
H,
Velez-Montoya
R,
Lopez-Miranda
MJ,
Moshfeghi
AA,
Shusterman
EM,
Kaiser
PK,
Sanislo
SR,
Gertner
M,
Moshfeghi
DM.
24-Gy low-voltage x-ray irradiation with ranibizumab therapy for neovascular AMD: 6-month safety and functional outcomes
.
Ophthalmic Surg Lasers Imaging
.
2012
;
43
:
20
4
.
98.
Morales-Canton
V,
Quiroz-Mercado
H,
Velez-Montoya
R,
Zavala-Ayala
A,
Moshfeghi
AA,
Shusterman
EM,
Kaiser
PK,
Sanislo
SR,
Gertner
M,
Moshfeghi
DM.
16 and 24 Gy low-voltage X-ray irradiation with ranibizumab therapy for neovascular age-related macular degeneration: 12-month outcomes
.
Am J Ophthalmol
.
2013
;
155
:
1000
8.e2
.
99.
Moshfeghi
AA,
Morales-Canton
V,
Quiroz-Mercado
H,
Velez-Montoya
R,
Zavala-Ayala
A,
Shusterman
EM,
Kaiser
PK,
Sanislo
SR,
Gertner
M,
Moshfeghi
DM.
16 Gy low-voltage x-ray irradiation followed by as needed ranibizumab therapy for age-related macular degeneration: 12 month outcomes of a ‘radiation-first' strategy
.
Br J Ophthalmol
.
2012
;
96
:
1320
4
.
100.
Jackson
TL,
Shusterman
EM,
Arnoldussen
M,
Chell
E,
Wang
K,
Moshfeghi
DM.
Stereotactic radiotherapy for wet age-related macular degeneration (INTREPID): influence of baseline characteristics on clinical response
.
Retina
.
2015
;
35
:
194
204
.
101.
Jackson
TL,
Chakravarthy
U,
Kaiser
PK,
Slakter
JS,
Jan
E,
Bandello
F,
O'Shaughnessy
D,
Gertner
ME,
Danielson
L,
Moshfeghi
DM.
Stereotactic radiotherapy for neovascular age-related macular degeneration: 52-week safety and efficacy results of the INTREPID study
.
Ophthalmology
.
2013
;
120
:
1893
900
.
102.
Jackson
TL,
Chakravarthy
U,
Slakter
JS,
Muldrew
A,
Shusterman
EM,
O'Shaughnessy
D,
Arnoldussen
M,
Gertner
ME,
Danielson
L,
Moshfeghi
DM.
Stereotactic radiotherapy for neovascular age-related macular degeneration: year 2 results of the INTREPID study
.
Ophthalmology
.
2015
;
122
:
138
45
.
103.
Yonemoto
LT,
Slater
JD,
Friedrichsen
EJ,
Loredo
LN,
Ing
J,
Archambeau
JO,
Teichman
S,
Moyers
MF,
Blacharski
PA,
Slater
JM.
Phase I/II study of proton beam irradiation for the treatment of subfoveal choroidal neovascularization in age-related macular degeneration: treatment techniques and preliminary results
.
Int J Radiat Oncol Biol Phys
.
1996
;
36
:
867
71
.
104.
Yonemoto
LT,
Slater
JD,
Blacharski
P,
Archambeau
JO,
Loredo
LN,
Oeinck
SC,
Teichman
S,
Moyers
M,
Slater
JM.
Dose response in the treatment of subfoveal choroidal neovascularization in age-related macular degeneration: results of a phase I/II dose-escalation study using proton radiotherapy
.
J Radiosurg
.
2000
;
3
:
47
54
.
105.
Flaxel
CJ,
Friedrichsen
EJ,
Smith
JO,
Oeinck
SC,
Blacharski
PA,
Garcia
CA,
Chu
HH.
Proton beam irradiation of subfoveal choroidal neovascularisation in age-related macular degeneration
.
Eye (Lond)
.
2000
;
14
(
pt 2
):
155
64
.
106.
Zambarakji
HJ,
Lane
AM,
Ezra
E,
Gauthier
D,
Goitein
M,
Adams
JA,
Munzenrider
JE,
Miller
JW,
Gragoudas
ES.
Proton beam irradiation for neovascular age-related macular degeneration
.
Ophthalmology
.
2006
;
113
:
2012
9
.
107.
Ciulla
TA,
Danis
RP,
Klein
SB,
Malinovsky
VE,
Soni
PS,
Pratt
LM,
Pugh
NO,
Morphis
JG,
Bloch
C,
Cameron
J.
Proton therapy for exudative age-related macular degeneration: a randomized, sham-controlled clinical trial
.
Am J Ophthalmol
.
2002
;
134
:
905
6
.
108.
Zur
C,
Caujolle
JP,
Chauvel
P,
Darmon
J,
Iborra-Brassart
N,
Gastaud
P.
Proton therapy of occult neovessels in age-related macular degeneration [in French]
.
J Fr Ophtalmol
.
2001
;
24
:
949
54
.
109.
Park
SS,
Daftari
I,
Phillips
T,
Morse
LS.
Three-year follow-up of a pilot study of ranibizumab combined with proton beam irradiation as treatment for exudative age-related macular degeneration
.
Retina
.
2012
;
32
:
956
66
.
110.
Schwartz
SD,
Regillo
CD,
Lam
BL,
Eliott
D,
Rosenfeld
PJ,
Gregori
NZ,
Hubschman
JP,
Davis
JL,
Heilwell
G,
Spirn
M,
Maguire
J,
Gay
R,
Bateman
J,
Ostrick
RM,
Morris
D,
Vincent
M,
Anglade
E,
Del Priore
LV,
Lanza
R.
Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies
.
Lancet
.
2015
;
385
:
509
16
.
111.
Kamao
H,
Mandai
M,
Okamoto
S,
Sakai
N,
Suga
A,
Sugita
S,
Kiryu
J,
Takahashi
M.
Characterization of human induced pluripotent stem cell-derived retinal pigment epithelium cell sheets aiming for clinical application
.
Stem Cell Reports
.
2014
;
2
:
205
18
.
112.
Office of the Inspector General, US Department of Health and Human Services
.
Review of Medicare Part B Avastin and Lucentis treatments for age-related macular degeneration.
2011
.
2015
.
113.
Moja
L,
Lucenteforte
E,
Kwag
KH,
Bertele
V,
Campomori
A,
Chakravarthy
U,
D'Amico
R,
Dickersin
K,
Kodjikian
L,
Lindsley
K,
Loke
Y,
Maguire
M,
Martin
DF,
Mugelli
A,
Muhlbauer
B,
Puntmann
I,
Reeves
B,
Rogers
C,
Schmucker
C,
Subramanian
ML,
Virgili
G.
Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration.
Cochrane Database Syst Rev
.
2014
;
9:CD011230.
114.
Silva
RA,
Moshfeghi
AA,
Kaiser
PK,
Singh
RP,
Moshfeghi
DM.
Radiation treatment for age-related macular degeneration
.
Semin Ophthalmol
.
2011
;
26
:
121
30
.
115.
Mason
JO
III,
Albert
MA
Jr,
Persaud
TO,
Vail
RS.
Intravitreal bevacizumab treatment for radiation macular edema after plaque radiotherapy for choroidal melanoma
.
Retina
.
2007
;
27
:
903
7
.
116.
Finger
PT.
Radiation retinopathy is treatable with anti-vascular endothelial growth factor bevacizumab (Avastin)
.
Int J Radiat Oncol Biol Phys
.
2008
;
70
:
974
7
.
117.
Finger
PT,
Chin
K.
Anti-vascular endothelial growth factor bevacizumab (avastin) for radiation retinopathy
.
Arch Ophthalmol
.
2007
;
125
:
751
6
.
118.
Gupta
A,
Muecke
JS.
Treatment of radiation maculopathy with intravitreal injection of bevacizumab (Avastin)
.
Retina
.
2008
;
28
:
964
8
.
119.
Leiden University Medical Center
.
Treatment of Radiation Retinopathy Trial (TORR)
.
2015
.
120.
Hess
C,
Vuong
V,
Hegyi
I,
Riesterer
O,
Wood
J,
Fabbro
D,
Glanzmann
C,
Bodis
S,
Pruschy
M.
Effect of VEGF receptor inhibitor PTK787/ZK222584 [correction of ZK222548] combined with ionizing radiation on endothelial cells and tumour growth
.
Br J Cancer
.
2001
;
85
:
2010
6
.
121.
Slopsema
RL,
Mamalui
M,
Zhao
T,
Yeung
D,
Malyapa
R,
Li
Z.
Dosimetric properties of a proton beamline dedicated to the treatment of ocular disease
.
Med Phys
.
2014
;
41
:
011707
.