16 and 24 Gy Low-voltage X-ray Irradiation With

Ranibizumab 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 efficacy outcomes of 16 or 24 Gy radiation using lowvoltage x-ray irradiation in conjunction with intravitreal
ranibizumab for neovascular age-related macular degeneration (AMD).

DESIGN: Prospective, phase I, open-label, nonrandomized uncontrolled safety study.

METHODS: SETTING: Institutional. STUDY POPULATION:
Neovascular AMD patients. INTERVENTION: One x-ray
irradiation treatment at 16 or 24 Gy was administered
externally through 3 locations in the inferior pars plana.
After 2 initial monthly loading doses of ranibizumab,
subsequent ranibizumab was administered according to
predetermined criteria. MAIN OUTCOME MEASURES: Visual
acuity, number of ranibizumab injections, safety and efficacy metrics at 12 months.

RESULTS: Forty-seven eyes of 47 patients were enrolled
and completed 12 months of follow-up: 16 Gy (n [ 28)
and 24 Gy (n [ 19). There was no evidence of radiation
retinopathy, optic neuropathy, or cataract. The mean
visual acuity improved in both groups: D8.4 11.9
letters and D7.8 12 letters for 16 and 24 Gy, respectively. In both groups, 100% of subjects lost <15 letters,
with 76% and 79% gaining 0 letters in the 16 Gy
and 24 Gy groups, respectively. Patients received
a mean of 1.0 additional injection over 12 months.
The mean change in optical coherence tomography
central subfield thickness from baseline to month 12
was L107 and L87 mm 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.); Department
of Ophthalmology, University of Colorado, Denver, Colorado (H.Q.M.,
R.V.M.); Bascom Palmer Eye Institute, University of Miami Miller
School of Medicine, Department of Ophthalmology, Palm Beach
Gardens, 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 Family
Vitreoretinal Center, Department of Ophthalmology, Stanford
University School of Medicine, Palo Alto, California (S.R.S., D.M.M.).
Inquiries to Darius M. Moshfeghi, Byers Eye Institute, Horngren Family
Vitreoretinal Center, Department of Ophthalmology, Stanford University
School of Medicine, 2452 Watson Ct, Palo Alto, CA 94303; e-mail:
dariusm@stanford.edu

1000

2013 BY

CONCLUSION:

One treatment of 16 or 24 Gy lowvoltage x-ray therapy with as-needed ranibizumab appears

safe in subjects with neovascular AMD at 12 months. An
overall improvement in visual acuity was observed. No
radiation-related adverse effects were reported. (Am J
Ophthalmol 2013;155:10001008. 2013 by Elsevier
Inc. All rights reserved.)

HE IRAY (ORAYA THERAPEUTICS, INC, NEWARK, CALI-

fornia, USA) is an office-based, stereotactic, lowdose 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 clinical
or outpatient suite, to run off commonly available electrical
supply, and to be operated by a retinologist, without additional facility, staff, or patient shielding requirements.1
An active suction apparatus coupled with infrared reflective fiducials allows for the eye to be tracked in the X, Y,
Z planes or rotational angles.1 An accumulated deviation
beyond threshold values for any of these parameters individually or in combination will result in gating of the
device and interruption of the radiation treatment. Additional safety measures include various interlocks designed
to prevent patient interference with system motion, integrated radiation beam-stop and scatter shielding, and
emergency shut-off mechanism.1 Globe axial length, determined via A-scan ultrasound or optical interferometry, is
used as a treatment planning input.1 The radiation is delivered during a single session in 3 consecutive and separate
locations through the inferior pars plana, with the x-ray
beams overlapping on the macula to deliver the total
prescribed dose.1 We have previously demonstrated that
the device delivers the full dose to the plane of the macula
(which is situated exactly 150 mm from the robotically
positioned and tracked x-ray tube aperture) within
a 4-mm-diameter spot size.25 The dosing and targeting
accuracy of the low-voltage stereotactic x-ray irradiation
system has been verified in human cadaver eyes using radiochromic film,6 as well as in animal models.7,8
We recently described the 6-month outcomes of 2 separate low-voltage stereotactic x-ray irradiation system treatment strategies: (1) 16 Gy radiation first with adjunctive,
as-needed (pro re nata; PRN) intravitreal ranibizumab

ELSEVIER INC. ALL

RIGHTS RESERVED.

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

0.5 mg (Lucentis; Genentech, South San Francisco,

California, USA, and Novartis Ophthalmics, Inc, Basel,
Switzerland) based on prospectively defined re-treatment
criteria9; and (2) 16 Gy radiation with 2 loading doses
of intravitreal ranibizumab 0.5 mg injections followed by
ranibizumab 0.5 mg PRN based on prospectively defined
re-treatment criteria.10 Additionally, 12-month safety
data on 16 Gy radiation first with adjunctive PRN ranibizumab was recently published.11 The purpose of the
present study is to assess the feasibility, safety, and preliminary efficacy using the low-voltage, stereotactic x-ray
irradiation system for treatment of neovascular AMD at
either 16 or 24 Gy dose, in conjunction with 2 loading
injections of ranibizumab, followed by as-needed ranibizumab, based on predefined re-treatment criteria, as part of
a safety evaluation.

METHODS
THIS WAS A PROSPECTIVE, NONRANDOMIZED, OPEN-LABEL

safety study of low-voltage radiation therapy and ranibizumab in subjects with neovascular AMD. Approval from the
Institutional Review Board of Associacion Para Evitar La
Ceguera En Mexico, I.A.P. (Mexico City, Mexico) and
the government of Mexico for the use of the low-voltage
stereotactic x-ray irradiation system for this trial of subjects
with neovascular AMD was obtained prior to the start of
the study. After proper informed consent was obtained in
the patients native language, subjects were enrolled into
the trial. The main outcome measure was the development
of ocular and nonocular adverse events. Secondary
outcome metrics included proportion of subjects losing
more than 15 ETDRS (Early Treatment of Diabetic Retinopathy Study) letters of visual acuity at 12 months
compared with baseline, mean change in ETDRS visual
acuity from baseline, mean change in central retinal thickness on optical coherence tomography (OCT), and mean
change in choroidal neovascularization (CNV) lesion size
on fluorescein angiography (FA).

STUDY ENTRY CRITERIA: Eligible subjects included
individuals aged 50 years or older with evidence of subfoveal CNV activity secondary to neovascular AMD. Pertinent exclusion criteria included previous treatment for
AMD and history of diabetes mellitus or elevated fasting
blood glucose. Additionally, previous history of ipsilateral photodynamic therapy was an exclusion criterion.
Details of inclusion and exclusion criteria are shown in
Table 1.

EXAMINATION PROTOCOL: Subjects underwent baseline clinical examination, intraocular pressure determination, best-corrected protocol acuity testing with ETDRS
charts starting at 4 meters, spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec,

VOL. 155, NO. 6

Dublin, California, USA), and fluorescein angiography.

Clinical examination, safety assessment, and OCT testing
were performed monthly; FA testing was performed quarterly, unless there was an unexplained decrease in visual
acuity. The OCT images were evaluated at Stanford
University (Palo Alto, California, USA). Fluorescein
angiograms were read at the University of Wisconsin,
Madison (Madison, Wisconsin, USA).

TREATMENT PROTOCOL: All subjects received 2 mandatory intravitreal ranibizumab 0.5 mg injections at day 0 and
day 30 and a single 16 or 24 Gy x-ray treatment (see below)
between days 1 and 14. Additional ranibizumab injections
were performed on a monthly as-needed basis based on the
_10 ETDRS
following re-treatment criteria: (1) loss of >
letters compared with previous visit, in conjunction with
_100 mm central
persistent fluid on OCT; (2) increase of >
foveal thickness on OCT compared with previous visit;
(3) development of a new subretinal hemorrhage in the
macula; and (4) development of new classic choroidal
neovascularization on FA.

TREATMENT SYSTEM:

The low-voltage stereotactic x-ray

irradiation 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 the
patients eye to the x-ray delivery system; (4) an eye tracking
subsystem that monitors X, Y, Z and rotational movements of
the eye for dose determination and safety gating; (5) graphical user interface; and (6) treatment planning software.
The system is designed to deliver 3 overlapping 4-mm radiation beams to a specified point in space that corresponds to
the patients macula, as determined by a treatment planning
algorithm using globe axial length. Actual dose over the
entire macula is calculated from analysis of the ocular movements during the treatment session. Radiation therapy
consisted of 1 fraction of 16 or 24 Gy delivered in approximately 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 analysis
as he was discovered to have had central retinal vein occlusion rather than CNV attributable to AMD. One subject
died between the month 10 and month 11 follow-up visits,
and another subject missed the month 12 visit; they are
consequently not included in the aggregate 12-month
visual acuity data presented in this paper. (These subjects
injection history is included, however.) Twenty-five
subjects (92.8%) completed 12 months of follow-up and
are included in the visual acuity analyses. Baseline OCT
could not be quantified for 3 of the 27 protocol subjects

LOW-VOLTAGE X-RAYS FOR WET AGE-RELATED MACULAR DEGENERATION

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

Exclusion Criteria

1. Subjects must be aged 50 years or older

_1 year or surgically sterilized

2. Women must be postmenopausal >

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

consent form
4. Subjects must be willing and able to return for scheduled treatment
and follow-up examinations for the 2-year duration of the study
_11
5. Subjects must have choroidal neovascularization lesion size of <
total disc areas (28.26 mm2) and a greatest linear dimension
_6 mm
of <

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
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.
8. Subretinal hemorrhage (if any) must not comprise more than 50%
of total lesion size, and may not involve the subfoveal space
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
nave
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

1. Subjects with prior or concurrent therapies including submacular

surgery, thermal laser photocoagulation (with or without
photographic evidence), photodynamic therapy, and
transpupillary thermotherapy
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 with advanced glaucoma (>0.8 cup-to-disc ratio) or
_30 mm Hg in the study eye
intraocular pressure >
4. Previous glaucoma filtering surgery in the study eye
5. Refractive error in the study eye demonstrating more than 8
_26 mm). For subjects
diopters of myopia (or globe axial length >
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 with any retinal vasculopathies, including diabetic
retinopathy or retinal vein occlusions, in the study eye
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. Current vitreous hemorrhage in the study eye
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
_8 diopters or
rupture, or pathologic myopia (spherical equivalent >
_26 mm)
axial length >
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

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AMERICAN JOURNAL OF OPHTHALMOLOGY

JUNE 2013

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
_99 mg/dL
(recent test) >
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
AMD age-related macular degeneration; CNV choroidal neovascularization; ETDRS Early Treatment Diabetic Retinopathy Study; FA
fluorescein angiography; OCT optical coherence tomography; RPE retinal pigment epithelium; VEGF vascular endothelia growth factor.

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

24 GY: Nineteen subjects were enrolled and treated. All
completed 12 months of follow-up and are included in the
safety, visual acuity, and injection analysis. Twelve-month
OCT data were available for 18 of the 19 subjects (95%).

SAFETY: Safety was good, with no serious ocular or
nonocular adverse events reported related to the study
device. Specifically, there were no arteriothromboembolic
events, endophthalmitis, or evidence of radiation-related
adverse events, including retinopathy, optic neuropathy,
cataract advancement, lid necrosis, or scleral injury. The
only described ocular adverse outcome was an asymptomatic, self-limited superficial punctate keratopathy that
resolved spontaneously, likely attributable to the I-Guide
(Table 2). No treatment-related systemic adverse outcomes
were observed. One subject in the 16 Gy group died

VOL. 155, NO. 6

between the month 10 and month 11 follow-up visits

because of a myocardial infarct. The event is not considered related to study treatment.

VISUAL ACUITY:

16 Gy. The mean baseline ETDRS

score was 46.2 6 21.3 letters (range, 5-80; Snellen equivalent
w20/240). At 12 months, the mean ETDRS score was 55.8
6 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 ETDRS
letters (Figure 2). There were 2 subgroups: treatment-nave
(n 16) and previously treated (n 11). Treatment-nave
subjects demonstrated a mean change from baseline
of 8.6 6 11.8 ETDRS letters, whereas previously treated
subjects demonstrated a mean change of 8.2 6 12.9
ETDRS letters (Figure 1). For treatment-nave subjects, the
responder analysis demonstrated that 100% (16/16) lost
_0 ETDRS
<15 ETDRS letters, 75% (12/16) gained >
_15 ETDRS letters
letters, and 44% (7/16) gained >

LOW-VOLTAGE X-RAYS FOR WET AGE-RELATED MACULAR DEGENERATION

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TABLE 2. Ocular Adverse Events for the 16 or 24 Gy X-ray

Irradiation Trial With Ranibizumab for Neovascular AgeRelated Macular Degeneration
Eye Disorder

16 Gy (n 28)

24 Gy (n 19)

Temporary keratopathy
Conjunctivitis
Blepharitis
Vitreous floaters
Conjunctival hemorrhage
Decreased vision
Eye pain
Increased lacrimation
Photopsia
Asthenopia
Cataract
Keratitis
Ocular hyperemia
Trichisias
Blurred vision
Conjunctivitis, allergic
Corneal infiltrates
Corneal leukoma
Eye irritation
Eye pruritis
Foreign body sensation
Retinal vein occlusion
Conjunctivitis, viral
Herpes zoster
Hordeolum
Intraocular pressure increased

28 (100%)
2 (7%)
4 (14%)
1 (4%)
3 (11%)
3 (11%)
1 (4%)
1 (4%)
0 (0%)
2 (7%)
2 (7%)
0 (0%)
1 (4%)
1 (4%)
2 (7%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
1 (4%)
0 (0%)
3 (11%)
1 (4%)
1 (4%)
2 (7%)

10 (53%)
4 (21%)
2 (11%)
3 (16%)
0 (0%)
1 (5%)
1 (5%)
1 (5%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
1 (5%)
1 (5%)
0 (0%)
1 (5%)
0 (0%)
0 (0%)
1 (5%)
1 (5%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)

(Figure 2). Similarly, in previously treated subjects 100% (9/

_0 ETDRS
9) lost <15 ETDRS letters, 78% (7/9) gained >
_15 ETDRS letters (Figure 2).
letters, and 56% (5/9) gained >
24 Gy. The mean baseline ETDRS score was 38.3 6 19.5
letters (range, 4-68). At 12 months, the mean change in
vision was 7.8 6 12 letters (Figure 1). In the responder
analysis, 100% (19/19) of eyes lost <15 letters, 79% (15/
_0 letters, and 26% (5/19) gained >
_15 letters
19) gained >
(Figure 2). There were 2 subgroups: treatment-nave (n
8) and previously treated (n 11). Treatment-nave
subjects demonstrated a mean change in vision from
baseline of 8.3 6 12.6, whereas previously treated
subjects showed a mean change of 7.5 6 12.2 letters
(Figure 1). For treatment-nave subjects, the responder
analysis demonstrated that 100% (8/8) of eyes lost <15
_0 letters, and 38% gained >
_15
letters, 75% (6/8) gained >
letters (Figure 2). In previously treated subjects, the
responder analysis demonstrated that 100% (11/11) of
_0 letters, and
eyes lost <15 letters, 82% (9/11) gained >
_15 letters (Figure 2).
18% (2/11) gained >

INJECTIONS: 16 Gy. The previously treated group
entered the study having received a mean of 3 anti-VEGF
injections (range, 1-5). On study, each subject received

1004

2 mandatory ranibizumab injections at day 0 and day 30.

An additional 26 PRN injections were performed, for
a total of 80 injections (54 mandatory and 26 PRN) in
27 subjects over 12 months, from a possible maximum
of 351 injections allowed by protocol for all subjects
completing 1 year of follow-up. The mean time to first
PRN ranibizumab injection was 11.5 months (standard
deviation 1.4 months). Fourteen of the 27 subjects
received no PRN injections (52%), 4 received 1 injection
(15%), 5 received 2 injections (19%), 4 received 3
injections (15%), and no subject received 4 or more
injections (Figure 3). The mean number of PRN
injections over 12 months was 1.0, with a standard
deviation of 1.2.
24 Gy. The previously treated group entered the study
having received a mean of 1.6 anti-VEGF injections
(range, 1-4). On study, each subject received 2 mandatory
injections at day 0 and day 30. An additional 19 PRN
injections were performed, for a total of 57 injections in
19 subjects over 12 months, from a possible maximum of
247 allowed by protocol. Eleven of the 19 subjects
received no PRN injections (58%), 2 received 1 injection
(11%), 2 received 2 injections (11%), 3 received 3
injections (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 was
1.0, with a standard deviation of 1.4.

OPTICAL COHERENCE TOMOGRAPHY AND FLUORESCEIN ANGIOGRAPHY ASSESSMENT: 16 Gy. The mean

baseline OCT central subfield thickness measurement

was 386 mm (range, 197 to 1101 mm; n 24). Mean
OCT central subfield thickness was 293 mm (range, 173
to 631 mm; n 24) at month 1, 293 mm (range, 166 to
614 mm; n 24) at month 3, 260 mm (range, 162 to
426 mm; n 23) at month 6, 292 mm (range, 161
to 563 mm; n 24) at month 9, and 267 mm (range, 121
to 574 mm; n 22) at month 12. The mean change in
OCT central subfield thickness from baseline to month 3
was 93 mm (range, 487 to 40 mm); at month
6, 131 mm (range, 720 to 89 mm); and at month
9, 94 mm (range, 538 to 113 mm). The mean change
in OCT central subfield thickness from baseline to
month 12 was 107 mm (range, 609 to 197 mm).
The greatest linear dimension of the CNV lesion measured
a mean of 3.9 6 1.8 mm at baseline and then changed
by 0.3 6 1.2 mm at month 1, 0.7 6 2.2 mm at month
3, 1.0 6 2.5 mm at month 6, 1.3 6 2.4 mm at month 9,
and 1.3 6 2.4 mm at month 12.
24 Gy. The mean baseline OCT central subfield thickness measurement was 376 mm (range, 171 to 662 mm;
n 19). Mean OCT central subfield thickness was
325 mm (range, 186 to 764 mm; n 19) at month 1,
345 mm (range, 183 to 758 mm; n 19) at month 3,

AMERICAN JOURNAL OF OPHTHALMOLOGY

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

FIGURE 2. Visual acuity responder analysis for 16 and 24 Gy low-voltage x-ray irradiation with ranibizumab therapy for neovascular age-related macular degeneration. Percentage of patients losing <15 letters, gaining 0 letters, and gaining 15 letters
at 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 and
treatment-nave subgroups.

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

326 mm (range, 154 to 774 mm; n 19) at month 6, 290 mm

(range, 153 to 613 mm; n 19) at month 9, and 294 mm
(range, 140 to 456 mm; n 18) at month 12. The mean
change in OCT central subfield thickness from baseline to
VOL. 155, NO. 6

month 3 was 31 mm (range, 427 to 272 mm); at month

6, 50 mm (range, 441 to 265 mm); and at month
9, 86 mm (range, 443 to 215 mm). The mean change
in OCT central subfield thickness from baseline to month

LOW-VOLTAGE X-RAYS FOR WET AGE-RELATED MACULAR DEGENERATION

1005

12 was 87 mm (range, 433 to 104 mm). The greatest

linear dimension of the CNV lesion measured a mean of
3.8 6 1.6 mm at baseline and then changed by 0.1 6
0.7 mm (n 15) at month 1, 0.1 6 0.7 mm (n 16)
at month 3, 1.0 6 2.0 mm (n 17) at month 6, 1.3
6 1.9 mm (n 11) at month 9, and 0.2 6 3.7 mm
(n 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 irradiation with 2 loading doses of ranibizumab followed by
adjunctive, as-needed ranibizumab injections demonstrated good safety and a visual acuity improvement in
both treatment-nave and previously treated subjects with
neovascular AMD at 12-month follow-up.
There were no arterial thromboembolic events, endophthalmitis, or radiation-related complications including
radiation retinopathy, optic neuropathy, lid necrosis,
scleral injury, or cataract. Although the safety data are
encouraging, additional follow-up will be required to determine the true incidence of radiation-related complications.
Because 90% of the radiation dose (16 or 24 Gy) is
constrained to a 4-mm-diameter circle targeted on the
macula, resulting in a 3.14-mm3 irradiated volume of tissue,
we believe the long-term risk of vision-threatening radiation
retinopathy or optic neuropathy will be low. In addition, the
x-ray irradiation delivered by the IRay System is precision
controlled and electronically gated for any eye movements
that exceed a preset threshold, ensuring that the dose to
the plane of the macula is reproducible and unvarying.1,36
Thus, radiation delivery to bystander ocular structures is
minimized. Finally, the highly collimated nature of the
x-ray beams, and the beam placement through the inferior
pars plana, should result in a low rate of cataract
progression, as shown in this report.1,36
The visual acuity results were equally encouraging in the
present study, with 100% (44/44) of subjects losing <15
_0 letters, and 39
ETDRS letters, 77% (34/44) gaining >
_15 letters. The approach described herein
(17/44) gaining >
was equally effective in both treatment-nave and previously
treated subjects. Three randomized, double-masked, multicenter clinical trialsMARINA, ANCHOR, and PIER
demonstrated that the main visual benefit of ranibizumab
occurred in the first 3 months following onset of antiVEGF administration,1214 with minimal subsequent
improvement despite monthly injections, or a gradual
decrease in vision with PRN and quarterly dosing. One
therefore would not expect most subjects who have already
undergone multiple anti-VEGF injections to improve their
visual acuity with ongoing therapy. In contrast, 80%

1006

(16/20) of the previously treated subject subgroup in the

present study, who entered having up to 4 prior anti-VEGF
_0 ETDRS letters, with 35%
injections, showed a gain of >
_15 letters. When compared to
(7/20) of the group gaining >
historical radiation studies,1527 the 24 Gy treatment, in
conjunction with ranibizumab therapy, exhibited superior
safety and visual acuity outcomes. Recently, another
targeted radiation delivery using a pars plana vitrectomy
and intraoperative epiretinal Sr-90 24 Gy brachytherapy
technique also had similar results. Beta irradiation alone,28
or combined with 2 off-label bevacizumab (Avastin; Genentech) injections followed by adjunctive, PRN bevacizumab,29 has been described for treatment-nave subjects
with neovascular AMD. This new therapy reported mean
gains at 12 months of 8.9 ETDRS letters when combined
with bevacizumab, and 10.3 letters when given alone.28,29
Low-voltage stereotactic x-ray irradiation therapy at
24 Gy in conjunction with ranibizumab appears to reduce
the number of anti-VEGF injections required to manage
neovascular AMD in both treatment-nave and previously
treated subjects. Nineteen subjects received a total of 57
injections (38 mandatory, 19 as-needed) over a period of
12 months (of a possible 209 maximally allowed by
protocol) to achieve a mean gain of 7.8 6 12.0 letters.
These results compare favorably to the MARINA and
ANCHOR trials with respect to visual acuity, but using
only w25% of the ranibizumab injections.12,14
There are several deficiencies of this clinical study,
including the small sample size, nonrandomized study
design, and, most importantly, short follow-up period
to find radiation-related complications. Nonetheless,
the treatment approach was well tolerated, with no
significant ocular or systemic adverse effects related
to the study device noted during the first 12 months;
and longer-term follow-up is in progress. Additionally,
randomized controlled trials combining anti-VEGF
therapy with precisely targeted irradiation are underway
and will add further information (INTREPID-IRay Plus
Anti-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 ranibizumab
followed by as-needed injections based on prospectively
defined re-treatment criteria appears to be safe, with
no significant device-related serious adverse effects or
radiation-related complications at 12 months in both
previously treated and treatment-nave subjects. Visual
acuity results in both groups were similar to those reported for monthly ranibizumab treatment regimens,
but required only 25% of anti-VEGF injections used
in those protocols. Longer follow-up is necessary to
more fully assess the safety and efficacy profile of this
therapy.

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ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
and 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, intellectual 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 funding
support. 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.); analysis 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.

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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.

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