16 and 24 Gy Low-voltage X-ray Irradiation WithRanibizumab Therapy for Neovascular Age-Related

Macular Degeneration: 12-Month Outcomes

VIRGILIO MORALES-CANTON, HUGO QUIROZ-MERCADO, RAUL VELEZ-MONTOYA,ALICIA ZAVALA-AYALA, ANDREW A. MOSHFEGHI, E. MARK SHUSTERMAN, PETER K. KAISER,

STEVEN R. SANISLO, MICHAEL GERTNER, AND DARIUS M. MOSHFEGHI

� PURPOSE: To describe the 12-month safety and effi-cacy outcomes of 16 or 24 Gy radiation using low-voltage x-ray irradiation in conjunction with intravitrealranibizumab for neovascular age-relatedmacular degener-ation (AMD).� DESIGN: Prospective, phase I, open-label, nonrandom-ized uncontrolled safety study.� METHODS: SETTING: Institutional. STUDY POPULATION:Neovascular AMD patients. INTERVENTION: One x-rayirradiation treatment at 16 or 24 Gy was administeredexternally through 3 locations in the inferior pars plana.After 2 initial monthly loading doses of ranibizumab,subsequent ranibizumab was administered according topredetermined criteria. MAIN OUTCOME MEASURES: Visualacuity, number of ranibizumab injections, safety and effi-cacy metrics at 12 months.� RESULTS: Forty-seven eyes of 47 patients were enrolledand completed 12 months of follow-up: 16 Gy (n [ 28)and 24 Gy (n [ 19). There was no evidence of radiationretinopathy, optic neuropathy, or cataract. The meanvisual acuity improved in both groups: D8.4 ± 11.9letters and D7.8 ± 12 letters for 16 and 24 Gy, respec-tively. In both groups, 100% of subjects lost<15 letters,with 76% and 79% gaining ‡0 letters in the 16 Gyand 24 Gy groups, respectively. Patients receiveda mean of 1.0 additional injection over 12 months.The mean change in optical coherence tomographycentral subfield thickness from baseline to month 12wasL107 andL87mm for the 16 Gy and 24 Gy groups,respectively.

Accepted for publication Jan 8, 2013.From the Associacion Para Evitar La Ceguera En Mexico, I.A.P.,

Mexico City, Mexico (V.M.C., H.Q.M., R.V.M., A.Z.A.); Departmentof Ophthalmology, University of Colorado, Denver, Colorado (H.Q.M.,R.V.M.); Bascom Palmer Eye Institute, University of Miami MillerSchool of Medicine, Department of Ophthalmology, Palm BeachGardens, Florida (A.A.M.); Oraya Therapeutics, Inc, Newark,California (E.M.S., M.G.); Cole Eye Institute, Cleveland Clinic,Cleveland, Ohio (P.K.K.); and Byers Eye Institute, Horngren FamilyVitreoretinal Center, Department of Ophthalmology, StanfordUniversity School of Medicine, Palo Alto, California (S.R.S., D.M.M.).

Inquiries to Darius M. Moshfeghi, Byers Eye Institute, Horngren FamilyVitreoretinal Center, Department of Ophthalmology, Stanford UniversitySchool of Medicine, 2452 Watson Ct, Palo Alto, CA 94303; e-mail:dariusm@stanford.edu

1000 � 2013 BY ELSEVIER INC.

� CONCLUSION: One treatment of 16 or 24 Gy low-voltage x-ray therapy with as-needed ranibizumab appearssafe in subjects with neovascular AMD at 12 months. Anoverall improvement in visual acuity was observed. Noradiation-related adverse effects were reported. (Am JOphthalmol 2013;155:1000–1008. � 2013 by ElsevierInc. All rights reserved.)

THE IRAY (ORAYATHERAPEUTICS, INC,NEWARK,CALI-

fornia, USA) is an office-based, stereotactic, low-dose x-ray irradiation system for the treatment of

neovascular age-related macular degeneration (AMD).1

This device is designed to be placed in a typical clinicalor outpatient suite, to run off commonly available electricalsupply, and to be operated by a retinologist, without addi-tional facility, staff, or patient shielding requirements.1

An active suction apparatus coupled with infrared reflec-tive fiducials allows for the eye to be tracked in the X, Y,Z planes or rotational angles.1 An accumulated deviationbeyond threshold values for any of these parameters indi-vidually or in combination will result in gating of thedevice and interruption of the radiation treatment. Addi-tional safety measures include various interlocks designedto prevent patient interference with system motion, inte-grated radiation beam-stop and scatter shielding, andemergency shut-off mechanism.1 Globe axial length, deter-mined via A-scan ultrasound or optical interferometry, isused as a treatment planning input.1 The radiation is deliv-ered during a single session in 3 consecutive and separatelocations through the inferior pars plana, with the x-raybeams overlapping on the macula to deliver the totalprescribed dose.1 We have previously demonstrated thatthe device delivers the full dose to the plane of the macula(which is situated exactly 150 mm from the roboticallypositioned and tracked x-ray tube aperture) withina 4-mm-diameter spot size.2–5 The dosing and targetingaccuracy of the low-voltage stereotactic x-ray irradiationsystem has been verified in human cadaver eyes using radio-chromic film,6 as well as in animal models.7,8

We recently described the 6-month outcomes of 2 sepa-rate low-voltage stereotactic x-ray irradiation system treat-ment strategies: (1) 16 Gy radiation first with adjunctive,as-needed (pro re nata; PRN) intravitreal ranibizumab

0002-9394/$36.00http://dx.doi.org/10.1016/j.ajo.2013.01.015

ALL RIGHTS RESERVED.

0.5 mg (Lucentis; Genentech, South San Francisco,California, USA, and Novartis Ophthalmics, Inc, Basel,Switzerland) based on prospectively defined re-treatmentcriteria9; and (2) 16 Gy radiation with 2 loading dosesof intravitreal ranibizumab 0.5 mg injections followed byranibizumab 0.5 mg PRN based on prospectively definedre-treatment criteria.10 Additionally, 12-month safetydata on 16 Gy radiation first with adjunctive PRN ranibi-zumab was recently published.11 The purpose of thepresent study is to assess the feasibility, safety, and prelim-inary efficacy using the low-voltage, stereotactic x-rayirradiation system for treatment of neovascular AMD ateither 16 or 24 Gy dose, in conjunction with 2 loadinginjections of ranibizumab, followed by as-needed ranibizu-mab, based on predefined re-treatment criteria, as part ofa safety evaluation.

METHODS

THIS WAS A PROSPECTIVE, NONRANDOMIZED, OPEN-LABEL

safety study of low-voltage radiation therapy and ranibizu-mab in subjects with neovascular AMD. Approval from theInstitutional Review Board of Associacion Para Evitar LaCeguera En Mexico, I.A.P. (Mexico City, Mexico) andthe government of Mexico for the use of the low-voltagestereotactic x-ray irradiation system for this trial of subjectswith neovascular AMD was obtained prior to the start ofthe study. After proper informed consent was obtained inthe patient’s native language, subjects were enrolled intothe trial. The main outcome measure was the developmentof ocular and nonocular adverse events. Secondaryoutcome metrics included proportion of subjects losingmore than 15 ETDRS (Early Treatment of Diabetic Reti-nopathy Study) letters of visual acuity at 12 monthscompared with baseline, mean change in ETDRS visualacuity from baseline, mean change in central retinal thick-ness on optical coherence tomography (OCT), and meanchange in choroidal neovascularization (CNV) lesion sizeon fluorescein angiography (FA).

� STUDY ENTRY CRITERIA: Eligible subjects includedindividuals aged 50 years or older with evidence of subfo-veal CNV activity secondary to neovascular AMD. Perti-nent exclusion criteria included previous treatment forAMD and history of diabetes mellitus or elevated fastingblood glucose. Additionally, previous history of ipsilat-eral photodynamic therapy was an exclusion criterion.Details of inclusion and exclusion criteria are shown inTable 1.

� EXAMINATION PROTOCOL: Subjects underwent base-line clinical examination, intraocular pressure determina-tion, best-corrected protocol acuity testing with ETDRScharts starting at 4 meters, spectral-domain optical coher-ence tomography (Cirrus HD-OCT; Carl Zeiss Meditec,

VOL. 155, NO. 6 LOW-VOLTAGE X-RAYS FOR WET AGE-R

Dublin, California, USA), and fluorescein angiography.Clinical examination, safety assessment, and OCT testingwere performed monthly; FA testing was performed quar-terly, unless there was an unexplained decrease in visualacuity. The OCT images were evaluated at StanfordUniversity (Palo Alto, California, USA). Fluoresceinangiograms were read at the University of Wisconsin,Madison (Madison, Wisconsin, USA).

� TREATMENTPROTOCOL: All subjects received 2manda-tory intravitreal ranibizumab 0.5 mg injections at day 0 andday 30 and a single 16 or 24 Gy x-ray treatment (see below)between days 1 and 14. Additional ranibizumab injectionswere performed on a monthly as-needed basis based on thefollowing re-treatment criteria: (1) loss of >_10 ETDRSletters compared with previous visit, in conjunction withpersistent fluid on OCT; (2) increase of >_100 mm centralfoveal thickness on OCT compared with previous visit;(3) development of a new subretinal hemorrhage in themacula; and (4) development of new classic choroidalneovascularization on FA.

� TREATMENT SYSTEM: The low-voltage stereotactic x-rayirradiation system consists of the following components: (1)a precision-controlled x-ray tube; (2) a patient interface; (3)an eye stabilizing device (I-Guide) that optically couples thepatient’s eye to the x-ray delivery system; (4) an eye trackingsubsystem thatmonitors X, Y, Z and rotationalmovements ofthe eye for dose determination and safety gating; (5) graph-ical user interface; and (6) treatment planning software.The system is designed to deliver 3 overlapping 4-mm radia-tion beams to a specified point in space that corresponds tothe patient’s macula, as determined by a treatment planningalgorithm using globe axial length. Actual dose over theentire macula is calculated from analysis of the ocular move-ments during the treatment session. Radiation therapyconsisted of 1 fraction of 16 or 24 Gy delivered in approxi-mately 15 minutes (about 3-5 minutes of x-ray exposure)over 3 equal spots in the inferior pars plana.

RESULTS

� 16 GY: Twenty-eight subjects were enrolled and treated,but 1 was subsequently excluded from the efficacy analysisas he was discovered to have had central retinal vein occlu-sion rather than CNV attributable to AMD. One subjectdied between the month 10 and month 11 follow-up visits,and another subject missed the month 12 visit; they areconsequently not included in the aggregate 12-monthvisual acuity data presented in this paper. (These subjects’injection history is included, however.) Twenty-fivesubjects (92.8%) completed 12 months of follow-up andare included in the visual acuity analyses. Baseline OCTcould not be quantified for 3 of the 27 protocol subjects

1001ELATED MACULAR DEGENERATION

TABLE 1. Inclusion and Exclusion Criteria for the 16 or 24 Gy X-ray Irradiation Trial With Ranibizumab for Neovascular Age-RelatedMacular Degeneration

Inclusion Criteria Exclusion Criteria

1. Subjects must be aged 50 years or older 1. Subjects with prior or concurrent therapies including submacular

surgery, thermal laser photocoagulation (with or without

photographic evidence), photodynamic therapy, and

transpupillary thermotherapy

2. Women must be postmenopausal >_1 year or surgically sterilized 2. Subjects with concomitant disease in the study eye, including

uveitis, diabetic retinopathy, presence of RPE tears or rips, acute

ocular or periocular infection

3. Subjects must sign (and be given) a copy of the informed

consent form

3. Subjects with advanced glaucoma (>0.8 cup-to-disc ratio) or

intraocular pressure >_30 mm Hg in the study eye

4. Subjects must be willing and able to return for scheduled treatment

and follow-up examinations for the 2-year duration of the study

4. Previous glaucoma filtering surgery in the study eye

5. Subjects must have choroidal neovascularization lesion size of <_11

total disc areas (28.26 mm2) and a greatest linear dimension

of <_6 mm

5. Refractive error in the study eye demonstrating more than �8

diopters of myopia (or globe axial length >_26 mm). For subjects

who had undergone prior refractive or cataract surgery in the

study eye, the preoperative refractive error could not exceed �8

diopters of myopia

6. Subjects must have ETDRS best-corrected visual acuity of 69 to 24

letters (20/40 to 20/320 Snellen equivalent) in the study eye

6. Subjects with any retinal vasculopathies, including diabetic

retinopathy or retinal vein occlusions, in the study eye

7. Only 1 eye will be assessed in the study. If both eyes have active

disease, the one with the worst acuity will be selected. The eye

selected for treatment will receive a single treatment of 11, 16, or

24 Gy to the macula, up to and including 14 days following

intravitreal injection of 0.5 mg ranibizumab.

7. Subjects with inadequate pupillary dilation or significant media

opacities in the study eye, including cataract, which could

interfere with visual acuity or the evaluation of the posterior

segment

8. Subretinal hemorrhage (if any) must not comprise more than 50%

of total lesion size, and may not involve the subfoveal space

8. Current vitreous hemorrhage in the study eye

9. Patient has neovascular AMD characterized by leakage on FA in

conjunction with fluid accumulation on OCT, with a fellow eye that

has characteristics consistent with AMD (drusen,

hyperpigmentation, previous but not active choroidal

neovascularization [eg, disciform scar], and/ or geographic

atrophy) as determined by the treating physician, and is treatment

naı̈ve

OR

Subject has known neovascular AMD as determined by the treating

physician, subject has received anti-VEGF injections during

a continuous sequential treatment course for AMD, and the

physician determines the need for additional treatment with the

following criteria:

Fluorescein leakage on FA from CNV

Increased intraretinal, subretinal, or sub-RPE fluid

Persistent cystoid macular edema on OCT

9. History of rhegmatogenous retina detachment in the study eye

10. Subjects who present with choroidal neovascularization due to

causes other than AMD, including ocular histoplasmosis

syndrome, angioid streaks, multifocal choroiditis, choroidal

rupture, or pathologic myopia (spherical equivalent >_8 diopters or

axial length >_26 mm)

11. Other than cataract surgery, subjects who have undergone any

intraocular surgery of the study eye within 30 days prior to

treatment with the IRay system; in the instance of cataract surgery

within 30 days, the investigator examination must reveal a healed

corneal incision

12. Subjects with known serious allergies to fluorescein dye used in

angiography unless subject has received an anti-allergenic

regimen successfully in the past and agrees to receive the

regimen again

13. Subjects who underwent previous radiation therapy to the eye,

head, or neck

14. Subjects with an intravitreal device or drug in the study eye

15. Subjects with any other condition that, in the judgment of the

investigator, would prevent the subject from completing the study

(eg, dementia, mental illness)

16. History of other disease, metabolic dysfunction, physical

examination finding, or laboratory finding giving reasonable

suspicion of a disease or condition that contraindicates the use of

intravitreal ranibizumab or that might affect interpretation of the

results of the study or render the subject at high risk for treatment

complication

17. Known sensitivity or allergy to ranibizumab

Continued on next page

1002 JUNE 2013AMERICAN JOURNAL OF OPHTHALMOLOGY

TABLE 1. Inclusion and Exclusion Criteria for the 16 or 24 Gy X-ray Irradiation Trial With Ranibizumab for Neovascular Age-Related

Macular Degeneration (Continued )

Inclusion Criteria Exclusion Criteria

18. Subjects with a history of optic neuritis

19. Subjects that have been previously diagnosed or have retinal

findings consistent with type 1 or type 2 diabetes mellitus

20. Subjects with a questionable history of type 1 or type 2 diabetes

mellitus without retinal findings and fasting blood glucose level

(recent test) >_99 mg/dL

21. Current treatment for active systemic infection or history of

significant recurrent/chronic infections

22. Subjects currently receiving chemotherapy, having completed

a course within the 90 days preceding study enrollment, or

expecting to begin chemotherapy while participating in the study

23. Evidence of significant uncontrolled concomitant diseases such

as cardiovascular disease or nervous system, pulmonary, renal,

hepatic, endocrine, or gastrointestinal disorders

24. Current participation in another drug or device clinical trial or

previous enrollment in a trial involving the study in the last year

25. History of use of drugs with known retinal toxicity, including

chloroquine, hydroxychloriquine, phenothiazines,

chlorpromazine, thioridazine, fluphenazine, perphenazine, and

trifluoperazine

26. Concurrent use of systemic anti-VEGF agents

27. History of corneal transplant in the study eye

28. Any additional concurrent intraocular condition in the study eye

that, in the opinion of the investigator, could either require medical

or surgical intervention during the 24-month study period to

prevent or treat visual loss that might result from that condition or

that, if allowed to progress untreated, could likely contribute to

a loss of at least 2 Snellen equivalent lines of BCVA over the

24-month study period

29. Implantable cardioverter defibrillator or pacemaker

AMD¼ age-related macular degeneration; CNV¼ choroidal neovascularization; ETDRS¼ Early Treatment Diabetic Retinopathy Study; FA¼fluorescein angiography; OCT¼ optical coherence tomography; RPE ¼ retinal pigment epithelium; VEGF ¼ vascular endothelia growth factor.

because of technical reasons, and month 12 OCT examina-tions were available for 22 of the 27 protocol subjects.

� 24 GY: Nineteen subjects were enrolled and treated. Allcompleted 12 months of follow-up and are included in thesafety, visual acuity, and injection analysis. Twelve-monthOCT data were available for 18 of the 19 subjects (95%).

� SAFETY: Safety was good, with no serious ocular ornonocular adverse events reported related to the studydevice. Specifically, there were no arteriothromboembolicevents, endophthalmitis, or evidence of radiation-relatedadverse events, including retinopathy, optic neuropathy,cataract advancement, lid necrosis, or scleral injury. Theonly described ocular adverse outcome was an asymptom-atic, self-limited superficial punctate keratopathy thatresolved spontaneously, likely attributable to the I-Guide(Table 2). No treatment-related systemic adverse outcomeswere observed. One subject in the 16 Gy group died

VOL. 155, NO. 6 LOW-VOLTAGE X-RAYS FOR WET AGE-R

between the month 10 and month 11 follow-up visitsbecause of a myocardial infarct. The event is not consid-ered related to study treatment.

� VISUAL ACUITY: 16 Gy. The mean baseline ETDRSscorewas 46.26 21.3 letters (range, 5-80; Snellen equivalentw20/240). At 12 months, the mean ETDRS score was 55.86 20.5 letters (Figure 1). In the responder analysis, 100%(25/25) lost <15 ETDRS letters, 76% (19/25) gained>_0 ETDRS letters, and 48% (12/25) gained >_15 ETDRSletters (Figure 2). There were 2 subgroups: treatment-naı̈ve(n¼ 16) and previously treated (n ¼ 11). Treatment-naı̈vesubjects demonstrated a mean change from baselineof þ8.6 6 11.8 ETDRS letters, whereas previously treatedsubjects demonstrated a mean change of þ8.2 6 12.9ETDRS letters (Figure 1). For treatment-naı̈ve subjects, theresponder analysis demonstrated that 100% (16/16) lost<15 ETDRS letters, 75% (12/16) gained >_0 ETDRSletters, and 44% (7/16) gained >_15 ETDRS letters

1003ELATED MACULAR DEGENERATION

TABLE 2. Ocular Adverse Events for the 16 or 24 Gy X-rayIrradiation Trial With Ranibizumab for Neovascular Age-

Related Macular Degeneration

Eye Disorder 16 Gy (n ¼ 28) 24 Gy (n ¼ 19)

Temporary keratopathy 28 (100%) 10 (53%)

Conjunctivitis 2 (7%) 4 (21%)

Blepharitis 4 (14%) 2 (11%)

Vitreous floaters 1 (4%) 3 (16%)

Conjunctival hemorrhage 3 (11%) 0 (0%)

Decreased vision 3 (11%) 1 (5%)

Eye pain 1 (4%) 1 (5%)

Increased lacrimation 1 (4%) 1 (5%)

Photopsia 0 (0%) 0 (0%)

Asthenopia 2 (7%) 0 (0%)

Cataract 2 (7%) 0 (0%)

Keratitis 0 (0%) 0 (0%)

Ocular hyperemia 1 (4%) 1 (5%)

Trichisias 1 (4%) 1 (5%)

Blurred vision 2 (7%) 0 (0%)

Conjunctivitis, allergic 0 (0%) 1 (5%)

Corneal infiltrates 0 (0%) 0 (0%)

Corneal leukoma 0 (0%) 0 (0%)

Eye irritation 0 (0%) 1 (5%)

Eye pruritis 0 (0%) 1 (5%)

Foreign body sensation 1 (4%) 0 (0%)

Retinal vein occlusion 0 (0%) 0 (0%)

Conjunctivitis, viral 3 (11%) 0 (0%)

Herpes zoster 1 (4%) 0 (0%)

Hordeolum 1 (4%) 0 (0%)

Intraocular pressure increased 2 (7%) 0 (0%)

(Figure 2). Similarly, in previously treated subjects 100% (9/9) lost <15 ETDRS letters, 78% (7/9) gained >_0 ETDRSletters, and 56% (5/9) gained >_15 ETDRS letters (Figure 2).

24Gy. Themean baseline ETDRS scorewas 38.36 19.5letters (range, 4-68). At 12 months, the mean change invision was þ7.8 6 12 letters (Figure 1). In the responderanalysis, 100% (19/19) of eyes lost <15 letters, 79% (15/19) gained >_0 letters, and 26% (5/19) gained >_15 letters(Figure 2). There were 2 subgroups: treatment-naı̈ve (n ¼8) and previously treated (n ¼ 11). Treatment-naı̈vesubjects demonstrated a mean change in vision frombaseline of þ8.3 6 12.6, whereas previously treatedsubjects showed a mean change of þ7.5 6 12.2 letters(Figure 1). For treatment-naı̈ve subjects, the responderanalysis demonstrated that 100% (8/8) of eyes lost <15letters, 75% (6/8) gained >_0 letters, and 38% gained >_15letters (Figure 2). In previously treated subjects, theresponder analysis demonstrated that 100% (11/11) ofeyes lost <15 letters, 82% (9/11) gained >_0 letters, and18% (2/11) gained >_15 letters (Figure 2).

� INJECTIONS: 16 Gy. The previously treated groupentered the study having received a mean of 3 anti-VEGFinjections (range, 1-5). On study, each subject received

1004 AMERICAN JOURNAL OF

2 mandatory ranibizumab injections at day 0 and day 30.An additional 26 PRN injections were performed, fora total of 80 injections (54 mandatory and 26 PRN) in27 subjects over 12 months, from a possible maximumof 351 injections allowed by protocol for all subjectscompleting 1 year of follow-up. The mean time to firstPRN ranibizumab injection was 11.5 months (standarddeviation 1.4 months). Fourteen of the 27 subjectsreceived no PRN injections (52%), 4 received 1 injection(15%), 5 received 2 injections (19%), 4 received 3injections (15%), and no subject received 4 or moreinjections (Figure 3). The mean number of PRNinjections over 12 months was 1.0, with a standarddeviation of 1.2.

24 Gy. The previously treated group entered the studyhaving received a mean of 1.6 anti-VEGF injections(range, 1-4). On study, each subject received 2 mandatoryinjections at day 0 and day 30. An additional 19 PRNinjections were performed, for a total of 57 injections in19 subjects over 12 months, from a possible maximum of247 allowed by protocol. Eleven of the 19 subjectsreceived no PRN injections (58%), 2 received 1 injection(11%), 2 received 2 injections (11%), 3 received 3injections (16%), 1 subject received 4 injections (5%),and no subject received 5 or more injections (Figure 3).The mean number of PRN injections over 12 months was1.0, with a standard deviation of 1.4.

� OPTICAL COHERENCE TOMOGRAPHY AND FLUORES-CEIN ANGIOGRAPHY ASSESSMENT: 16 Gy. The meanbaseline OCT central subfield thickness measurementwas 386 mm (range, 197 to 1101 mm; n ¼ 24). MeanOCT central subfield thickness was 293 mm (range, 173to 631 mm; n ¼ 24) at month 1, 293 mm (range, 166 to614 mm; n ¼ 24) at month 3, 260 mm (range, 162 to426 mm; n ¼ 23) at month 6, 292 mm (range, 161to 563 mm; n ¼ 24) at month 9, and 267 mm (range, 121to 574 mm; n ¼ 22) at month 12. The mean change inOCT central subfield thickness from baseline to month 3was �93 mm (range, �487 to þ40 mm); at month6, �131 mm (range, �720 to þ89 mm); and at month9, �94 mm (range, �538 to þ113 mm). The mean changein OCT central subfield thickness from baseline tomonth 12 was �107 mm (range, �609 to þ197 mm).The greatest linear dimension of the CNV lesion measureda mean of 3.9 6 1.8 mm at baseline and then changedby �0.3 6 1.2 mm at month 1, �0.7 6 2.2 mm at month3,�1.06 2.5 mm at month 6,�1.36 2.4 mm at month 9,and �1.3 6 2.4 mm at month 12.

24 Gy. The mean baseline OCT central subfield thick-ness measurement was 376 mm (range, 171 to 662 mm;n ¼ 19). Mean OCT central subfield thickness was325 mm (range, 186 to 764 mm; n ¼ 19) at month 1,345 mm (range, 183 to 758 mm; n ¼ 19) at month 3,

JUNE 2013OPHTHALMOLOGY

FIGURE 1. Visual acuity outcomes for 16 and 24 Gy low-voltage x-ray irradiation with ranibizumab therapy for neovascular age-related macular degeneration. Mean change in visual acuity at 12 months in the (Left) 16 Gy and (Right) 24 Gy dose for the entiregroup as a whole, as well as previously treated and treatment-naı̈ve subgroups.

FIGURE 2. Visual acuity responder analysis for 16 and 24 Gy low-voltage x-ray irradiation with ranibizumab therapy for neovas-cular age-related macular degeneration. Percentage of patients losing <15 letters, gaining ‡0 letters, and gaining ‡15 lettersat 12 months in the (Left) 16 Gy and (Right) 24 Gy dose for the entire group as a whole, as well as by previously treated andtreatment-naı̈ve subgroups.

FIGURE 3. Number of ranibizumab injections for 16 and 24 Gy low-voltage x-ray irradiation with ranibizumab therapy for neovas-cular age-related macular degeneration. Patients received an initial 2 baseline ranibizumab injections, followed by re-treatment injec-tions according to prespecified criteria. The number of re-treatment ranibizumab injections at 12 months after the 2 baselineinjections in the (Left) 16 Gy and (Right) 24 Gy group is shown for the entire group as a whole, as well as previously treated andtreatment-naı̈ve subgroups.

326mm (range, 154 to 774mm; n¼ 19) at month 6, 290mm(range, 153 to 613 mm; n ¼ 19) at month 9, and 294 mm(range, 140 to 456 mm; n ¼ 18) at month 12. The meanchange in OCT central subfield thickness from baseline to

VOL. 155, NO. 6 LOW-VOLTAGE X-RAYS FOR WET AGE-R

month 3 was�31mm (range,�427 toþ272mm); at month6, �50 mm (range, �441 to þ265 mm); and at month9, �86 mm (range, �443 to þ215 mm). The mean changein OCT central subfield thickness from baseline to month

1005ELATED MACULAR DEGENERATION

12 was �87 mm (range, �433 to þ104 mm). The greatestlinear dimension of the CNV lesion measured a mean of3.8 6 1.6 mm at baseline and then changed by þ0.1 60.7 mm (n ¼ 15) at month 1, þ0.1 6 0.7 mm (n ¼ 16)at month 3, �1.0 6 2.0 mm (n ¼ 17) at month 6, �1.36 1.9 mm (n ¼ 11) at month 9, and �0.2 6 3.7 mm(n ¼ 9) at month 12.

DISCUSSION

IN THIS PHASE I, OPEN-LABEL, SINGLE-CENTER CLINICAL

trial, externally applied 16 or 24 Gy low-voltage x-ray irra-diation with 2 loading doses of ranibizumab followed byadjunctive, as-needed ranibizumab injections demon-strated good safety and a visual acuity improvement inboth treatment-naı̈ve and previously treated subjects withneovascular AMD at 12-month follow-up.

There were no arterial thromboembolic events, endoph-thalmitis, or radiation-related complications includingradiation retinopathy, optic neuropathy, lid necrosis,scleral injury, or cataract. Although the safety data areencouraging, additional follow-up will be required to deter-mine the true incidence of radiation-related complications.Because 90% of the radiation dose (16 or 24 Gy) isconstrained to a 4-mm-diameter circle targeted on themacula, resulting in a 3.14-mm3 irradiated volume of tissue,we believe the long-term risk of vision-threatening radiationretinopathy or optic neuropathy will be low. In addition, thex-ray irradiation delivered by the IRay System is precisioncontrolled and electronically gated for any eye movementsthat exceed a preset threshold, ensuring that the dose tothe plane of the macula is reproducible and unvarying.1,3–6

Thus, radiation delivery to bystander ocular structures isminimized. Finally, the highly collimated nature of thex-ray beams, and the beam placement through the inferiorpars plana, should result in a low rate of cataractprogression, as shown in this report.1,3–6

The visual acuity results were equally encouraging in thepresent study, with 100% (44/44) of subjects losing <15ETDRS letters, 77% (34/44) gaining >_0 letters, and 39(17/44) gaining >_15 letters. The approach described hereinwas equally effective in both treatment-naı̈ve and previouslytreated subjects. Three randomized, double-masked, multi-center clinical trials—MARINA, ANCHOR, and PIER—demonstrated that the main visual benefit of ranibizumaboccurred in the first 3 months following onset of anti-VEGF administration,12–14 with minimal subsequentimprovement despite monthly injections, or a gradualdecrease in vision with PRN and quarterly dosing. Onetherefore would not expect most subjects who have alreadyundergone multiple anti-VEGF injections to improve theirvisual acuity with ongoing therapy. In contrast, 80%

1006 AMERICAN JOURNAL OF

(16/20) of the previously treated subject subgroup in thepresent study, who entered having up to 4 prior anti-VEGFinjections, showed a gain of >_0 ETDRS letters, with 35%(7/20) of the group gaining >_15 letters. When compared tohistorical radiation studies,15–27 the 24 Gy treatment, inconjunction with ranibizumab therapy, exhibited superiorsafety and visual acuity outcomes. Recently, anothertargeted radiation delivery using a pars plana vitrectomyand intraoperative epiretinal Sr-90 24 Gy brachytherapytechnique also had similar results. Beta irradiation alone,28

or combined with 2 off-label bevacizumab (Avastin; Genen-tech) injections followed by adjunctive, PRN bevacizu-mab,29 has been described for treatment-naı̈ve subjectswith neovascular AMD. This new therapy reported meangains at 12 months of 8.9 ETDRS letters when combinedwith bevacizumab, and 10.3 letters when given alone.28,29

Low-voltage stereotactic x-ray irradiation therapy at24 Gy in conjunction with ranibizumab appears to reducethe number of anti-VEGF injections required to manageneovascular AMD in both treatment-naı̈ve and previouslytreated subjects. Nineteen subjects received a total of 57injections (38 mandatory, 19 as-needed) over a period of12 months (of a possible 209 maximally allowed byprotocol) to achieve a mean gain of 7.8 6 12.0 letters.These results compare favorably to the MARINA andANCHOR trials with respect to visual acuity, but usingonly w25% of the ranibizumab injections.12,14

There are several deficiencies of this clinical study,including the small sample size, nonrandomized studydesign, and, most importantly, short follow-up periodto find radiation-related complications. Nonetheless,the treatment approach was well tolerated, with nosignificant ocular or systemic adverse effects relatedto the study device noted during the first 12 months;and longer-term follow-up is in progress. Additionally,randomized controlled trials combining anti-VEGFtherapy with precisely targeted irradiation are underwayand will add further information (INTREPID-IRay PlusAnti-VEGF Treatment for Patients With Wet AMD,http://clinicaltrials.gov/ct2/show/NCT01016873).Low-voltage stereotactic 16 or 24 Gy x-ray irradiation

in conjunction with a loading regimen of ranibizumabfollowed by as-needed injections based on prospectivelydefined re-treatment criteria appears to be safe, withno significant device-related serious adverse effects orradiation-related complications at 12 months in bothpreviously treated and treatment-naı̈ve subjects. Visualacuity results in both groups were similar to those re-ported for monthly ranibizumab treatment regimens,but required only 25% of anti-VEGF injections usedin those protocols. Longer follow-up is necessary tomore fully assess the safety and efficacy profile of thistherapy.

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ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTERESTand the following were reported: D.M.M.: Oraya, Inc, consultant, equity; Genentech, Thrombogenics, Synergetics, consultant; Convene, LLC, OcuBell,Inc, Versavision, LLC, InSitu Therapeutics, LLC, Realm Global LLC, equity; V.C.M., H.Q.M., S.R.S.: Oraya, Inc, consultant; M.G.: Oraya, Inc, intel-lectual property, equity; P.K.K.: Research to Prevent Blindness, research; Bayer, Genentech, Regeneron, Kanghong, Novartis, consultant; Oraya, Inc,consultant, equity; A.A.M.: Genentech, Inc, Allergan, Inc, Bausch & Lomb, Inc, Alcon, Inc, Valeant, Inc, consultant/speaker; Eyetech, Inc, Alimera,Inc, consultant; Thrombogenics, Inc, research funding; Optistent, Inc, equity; E.M.S.: Oraya, Inc, employee, equity. The authors indicate no fundingsupport. Contributions of authors: design and conduct (V.M.C., H.Q.M., R.V.M., A.Z.A., A.A.M., E.M.S., P.K.K., S.R.S., M.G., D.M.M.); collection(V.M.C., H.Q.M., R.V.M., A.Z.A., E.M.S., S.R.S., M.G., D.M.M.); management (V.M.C., H.Q.M., R.V.M., A.Z.A., E.M.S., S.R.S.,M.G., D.M.M.); anal-ysis and interpretation (V.M.C., H.Q.M., R.V.M., A.Z.A., A.A.M., E.M.S., P.K.K., S.R.S., M.G., D.M.M.); preparation (V.M.C., H.Q.M., R.V.M.,A.Z.A., A.A.M., E.M.S., P.K.K., S.R.S., M.G., D.M.M.); review/approval (V.M.C., H.Q.M., R.V.M., A.Z.A., A.A.M., E.M.S., P.K.K., S.R.S., M.G.,D.M.M.). This trial was registered at ClinicalTrials.gov (NCT01217762).

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Biosketch

Virgilio Morales-Canton trained in ophthalmology and vitreoretinal surgery at the Asociacion para Evitar la Ceguera en

Mexico, Mexico City, Mexico, followed by one year at the Eye Research Institute and Retina Associates at Harvard

University. He has published dozens of papers, book chapters, and authored a book on diabetic retinopathy, in addition

to presenting over 300 times at international meetings. In his current capacity as Chief of the Retina Department at

Asociacion para Evitar la Ceguera, he oversaw the Phase I clinical trial for radiation therapy of age-related macular

degeneration, as well as numerous other clinical trials in retina. He has received numerous awards for his surgical videos.

VOL. 155, NO. 6 1008.e1LOW-VOLTAGE X-RAYS FOR WET AGE-RELATED MACULAR DEGENERATION

Biosketch

Darius M. Moshfeghi, MD, is an Associate Professor of Ophthalmology at Stanford University School of Medicine in

Stanford, California. He serves as the Director of the Vitreoretinal Fellowship Program, Director of Pediatric Retinal

Disease & Surgery, and the Director of Telemedicine in the Department of Ophthalmology. Additionally, he is the

Founder and Director of the Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP).

He continues to be actively involved in entrepeneurship and technology development.

1008.e2 JUNE 2013AMERICAN JOURNAL OF OPHTHALMOLOGY