Critical Review Radiation Therapy for Neovascular Age-related Macular Degeneration Amar U. Kishan, MD,* Bobeck S. Modjtahedi, MD, y Lawrence S. Morse, MD, PhD, y and Percy Lee, MD z *Harvard Medical School, Boston, Massachusetts; y Department of Ophthalmology and Vision Sciences, University of California, Davis, Sacramento, California; and z Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California Received Jun 13, 2012. Accepted for publication Jul 15, 2012 In the enormity of the public health burden imposed by age-related macular degeneration (ARMD), much effort has been directed toward identifying effective and efficient treatments. Currently, anti-vascular endothelial growth factor (VEGF) injections have demonstrated considerably efficacy in treating neovascular ARMD, but patients require frequent treatment to fully benefit. Here, we review the rationale and evidence for radiation therapy of ARMD. The results of early photon external beam radiation therapy are included to provide a framework for the sequential discussion of evidence for the usage of stereotactic radiation therapy, proton therapy, and brachytherapy. The evidence suggests that these 3 modern modalities can provide a dose-dependent benefit in the treat- ment of ARMD. Most importantly, preliminary data suggest that all 3 can be used in conjunction with anti-VEGF therapeutics, thereby reducing the frequency of anti-VEGF injections required to maintain visual acuity. Ó 2013 Elsevier Inc. Introduction Age-related macular degeneration (ARMD) is the leading cause of severe visual impairment in the developed world among individuals aged 65 years or older (1). Advanced ARMD is characterized by progressive lipidization and degenerative changes in the retinal pigment epithelium, Bruch’s membrane, and choriocapillaris. Vision loss is common and may be caused by severe atrophy of the retinal pigment epithelium involving the fovea, referred to as central geographic atrophy, or by the formation of choroidal neovascularization (CNV), referred to as exudative or “wet” ARMD (Fig.) (2). In the United States, cases of advanced ARMD are projected to increase to 3 million by 2020, further increasing an already immense public health burden (1, 3). Intravitreal injections of anti-vascular endothelial growth factor (VEGF) have revolutionized the treatment of neovascular ARMD (4), and although efficacious. they require frequent use to achieve full efficacy, which can place a strain on health care providers, patients, and the health care system as a whole (5). Approximately 95% of individuals receiving ranibizumab (an anti- VEGF therapeutic) lost fewer than 15 letters of visual acuity (VA) after 12 monthly injections compared with 62.2% of those receiving sham injections (P< .001) (6). However, although expression of VEGF represents an important component of exudative ARMD, other pathways responsible for neovascular changes, scar formation, and inflammation exist that remain unaddressed by anti-VEGF therapy. Treatments that work inde- pendently of or synergistically with anti-VEGF are required to fully tackle the burden placed by this disease and to provide alternative therapy to patients who do not respond to standard anti- VEGF treatment. Here we review the evidence for the utility of radiation therapy in the treatment of patients with neovascular ARMD. We begin CME NotedAn online CME test for this article can be taken at http:// astro.org/MOC. Reprint requests to: Percy Lee, MD, David Geffen School of Medicine at UCLA, Department of Radiation Oncology, 200 UCLA Medical Plaza, B265, Los Angeles, CA 90095. Tel: (310) 825-9771; Fax: (310) 794- 9795; E-mail: [email protected]Conflict of interest: none. Int J Radiation Oncol Biol Phys, Vol. 85, No. 3, pp. 583e597, 2013 0360-3016/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2012.07.2352 Radiation Oncology International Journal of biology physics www.redjournal.org
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Reprint requests to:
UCLA, Department o
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0360-3016/$ - see fro
http://dx.doi.org/10.10
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Critical Review
Radiation Therapy for Neovascular Age-related MacularDegenerationAmar U. Kishan, MD,* Bobeck S. Modjtahedi, MD,y Lawrence S. Morse, MD, PhD,y
and Percy Lee, MDz
*Harvard Medical School, Boston, Massachusetts; yDepartment of Ophthalmology and Vision Sciences, University ofCalifornia, Davis, Sacramento, California; and zDepartment of Radiation Oncology, David Geffen School of Medicineat UCLA, Los Angeles, California
Received Jun 13, 2012. Accepted for publication Jul 15, 2012
In the enormity of the public health burden imposed by age-related macular degeneration (ARMD), much effort has been directedtoward identifying effective and efficient treatments. Currently, anti-vascular endothelial growth factor (VEGF) injections havedemonstrated considerably efficacy in treating neovascular ARMD, but patients require frequent treatment to fully benefit. Here,we review the rationale and evidence for radiation therapy of ARMD. The results of early photon external beam radiation therapyare included to provide a framework for the sequential discussion of evidence for the usage of stereotactic radiation therapy, protontherapy, and brachytherapy. The evidence suggests that these 3 modern modalities can provide a dose-dependent benefit in the treat-ment of ARMD. Most importantly, preliminary data suggest that all 3 can be used in conjunction with anti-VEGF therapeutics,thereby reducing the frequency of anti-VEGF injections required to maintain visual acuity. � 2013 Elsevier Inc.
Introduction
Age-related macular degeneration (ARMD) is the leading causeof severe visual impairment in the developed world amongindividuals aged 65 years or older (1). Advanced ARMD ischaracterized by progressive lipidization and degenerativechanges in the retinal pigment epithelium, Bruch’s membrane,and choriocapillaris. Vision loss is common and may be causedby severe atrophy of the retinal pigment epithelium involvingthe fovea, referred to as central geographic atrophy, or by theformation of choroidal neovascularization (CNV), referred to asexudative or “wet” ARMD (Fig.) (2). In the United States, casesof advanced ARMD are projected to increase to 3 million by2020, further increasing an already immense public healthburden (1, 3).
Intravitreal injections of anti-vascular endothelial growthfactor (VEGF) have revolutionized the treatment of neovascular
CME test for this article can be taken at http://
Percy Lee, MD, David Geffen School of Medicine at
f Radiation Oncology, 200 UCLA Medical Plaza,
Biol Phys, Vol. 85, No. 3, pp. 583e597, 2013
nt matter � 2013 Elsevier Inc. All rights reserved.
16/j.ijrobp.2012.07.2352
ARMD (4), and although efficacious. they require frequent use toachieve full efficacy, which can place a strain on health careproviders, patients, and the health care system as a whole (5).Approximately 95% of individuals receiving ranibizumab (an anti-VEGF therapeutic) lost fewer than 15 letters of visual acuity (VA)after 12 monthly injections compared with 62.2% of thosereceiving sham injections (P<.001) (6). However, althoughexpression of VEGF represents an important component ofexudative ARMD, other pathways responsible for neovascularchanges, scar formation, and inflammation exist that remainunaddressed by anti-VEGF therapy. Treatments that work inde-pendently of or synergistically with anti-VEGF are required tofully tackle the burden placed by this disease and to providealternative therapy to patients who do not respond to standard anti-VEGF treatment.
Here we review the evidence for the utility of radiation therapyin the treatment of patients with neovascular ARMD. We begin
B265, Los Angeles, CA 90095. Tel: (310) 825-9771; Fax: (310) 794-
Kishan et al. International Journal of Radiation Oncology � Biology � Physics584
with a discussion of the radiobiology and risks of retinal radiation,and then discuss sequentially the efficacy of standard photonexternal beam radiation therapy (EBRT), stereotactic radiationtherapy (SRT), proton therapy (PT), and brachytherapy.
Radiation and the Retina
Radiobiological basis for radiation in ARMD
Ionizing radiation exerts its lethal effect by directly causingsingle- or double-stranded breaks in DNA molecules and byionizing oxygen atoms and thereby generating reactive oxygenspecies; both effects ultimately lead to cell death (7, 8). Althoughoften harnessed to destroy proliferating cancer cells, ionizingradiation can similarly be used in benign proliferative diseases(9, 10). The aberrant proliferation of choroidal endothelial vesselsleads to the pathologic neovascularization seen in exudativeARMD, and endothelial cells are highly radiosensitive (11-14).Specifically, focally delivered fractions of 16 Gy impaired thevascularity of granulation tissue at the site of ocular woundswithout affecting adjacent tissue in animal models (15, 16),whereas a single 5-Gy fraction arrested division in 99% of irra-diated retinal endothelial cells (12), and 8 cobalt Gray equivalents(CGE) of proton irradiation was lethal against simian choroidalendothelial cells (17). Histopathologic studies suggest that endo-thelial cell loss occurs up to 1 year after irradiation (18).Furthermore, 1 fraction of 10 Gy radiation decreased vascularpermeability, increased blood flow velocity, and improved stasis inan animal model of neovascularization, suggesting additionalfunctional effects (19). Radiation also exerts antiangiogeniceffects by reducing the macrophage-mediated retinal inflammationthat accompanies ARMD (16, 20). Finally, radiation directly leadsto capillary closure, which may underlie its efficacy in reducingvarious types of oncogenic bleeding (11). Pathologically, radiationcan induce retinal atrophy in the irradiated volume, but it isunclear whether this affects VA (21).
Radiation retinopathy
Adverse effects of ocular radiation include keratitis sicca, cata-racts, radiation optic neuropathy, and radiation retinopathy (RR)(22). Improved precision and accuracy in targeting and dosedelivery has limited doses to nearby critical structures. Indeed,
Fig. (a) Geographic atrophy from nonexudative ARMD, with visibdemonstrates hyperfluorescence in the area of a choroidal neovasculari
typical EBRT and PT protocols involve doses in fractions of 2-7.5Gy and 8-12 CGE, respectively, whereas SRT and brachytherapydeliver larger fractions (up to 34.2 Gy) to limited retinal volumes;as a result, doses to critical adjacent structures are far below theirtolerance thresholds, but the dose to the retina still remains animportant consideration.
The threshold dose for developing clinically detectable RR isconsidered 35 Gy, although cases have been reported with doses aslow as 11 Gy (23-25). Visually significant RR is rare below 45 Gy(22). Presumably, endothelial cell death secondary to radiationleads to the migration of new endothelial cells to repair damagedvessels. This incites neovascularization, leading to the formationof microaneurysms, vitreous hemorrhages, macular edema, andeven retinal detachment (13, 26). The gold standard treatmentis photocoagulation, although anti-VEGF therapeutics and corti-costeroids show promise (26-28). The ongoing Treatment ofRadiation Retinopathy Trial is investigating the use of eitherranibizumab or triamcinolone acetonide, compared withobservation, in patients treated with radiation for uveal mela-nomas. Intriguingly, the strategy of using anti-VEGF therapy inconjunction with radiation may not only improve efficacy andreduce the frequency of anti-VEGF injections but also decreasethe risk of RR.
External Beam Radiation Therapy
Although radiation therapywas used to treatARMDas early as 1948and possibly as early as 1919 (29), the results of the first phase 1 trialfor EBRT for ARMDwere reported in 1993. Nineteen patients weretreated with 6 megavoltage (MV) photons to doses of either 10 Gy(based on the aforementioned animal studies) or 15 Gy (to expeditetreatment response) in 5 fractions (Table 1) (30). Overall, VA wasmaintained or improved in 63% of treated patients at 1 year, and77% of treated patients showed CNV membrane regression,whereas all 6 control individuals showed VA decline and CNVprogression. Radiation was well tolerated, with cataract developingby 12 months in 1 patient treated with 15 Gy.
This landmark paper engendered several additional phase 1/phase2 studies (Table 1) (31-47). Several drawbacks limit the conclu-siveness and generalizability of these early studies. Few had follow-up times longer than 2 years, and only 2 used controls, albeitretrospective ones (42, 43). Additionally, many included highnumbers of patients with occult CNV, which has less risk of severevisual loss than classic CNV. A pooled analysis of 409 patients from
le choroid underlying thinned retina. (b) Fluorescein angiogramzation in exudative ARMD.
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a collection of these studies found that overall, 62.6% of eyes showedeither no change or improvement inVA over an average of 13months(48). In that analysis, 22.5% of patients had moderate visual loss,whereas 14.9% had severe visual loss. By comparison, 47.0% and31.0% of patients had severe visual loss with no intervention orphotocoagulation, respectively, in other series (49, 50). The lack ofa coherent control group precluded firm conclusions of statisticalsignificance.
These promising results led to 11 phase 3, randomizedcontrolled trials (Table 2) (51-61). Several studies found statisti-cally significant benefits in patients treated with EBRT (52, 53, 55,56, 61), whereas others found no lasting benefit (51, 54, 57-60).Notably, some studies found significant improvements only for VAand not in terms of CNV membrane size (52, 53, 61), whereasothers did not find improvements in VA overall but did findsignificant benefits in classic CNV regression or contrast sensi-tivity preservation (59, 60). Interestingly, hypofractionatedtherapy with 6 and 7.5 Gy (52, 53) may be more beneficial thanconventional 2 Gy fractionation (Table 2). A pooled analysis of14 randomized trials in 1242 patients found that, assumingmedium-risk ARMD in control individuals, the average relativerisk for severe visual loss at 12 months was 0.62 (95% confidenceinterval, 0.44-0.87) (62). Of note, 2 trials included in the pooledanalysis were not EBRT studies (63, 64).
These results suggest that monotherapy with EBRT can bebeneficial, particularly in reducing the risk of severe visual loss,though the heterogeneity between studies curtails furtherconclusions. The benefit appears to be dose-dependent, withhigher total doses and higher doses per fraction producing morepromising results. However, EBRT may not eliminate progressionof CNV, as membranes progressed universally. As recent trialshave demonstrated a robust benefit to anti-VEGF therapeutics inARMD, an attractive concept would be to combine EBRT withanti-VEGF therapeutics for a synergistic effect. In this model,radiation eliminates pathologic endothelial cells and productionof chemical mediators of pathologic non-VEGF pathways whileanti-VEGF therapeutics antagonize further attempts at angio-genesis. This form of combination therapy has been proposed fora variety of neoplasms (65-68).
However, several advances in radiation therapy allow moreprecise delivery of high dose radiation than standard EBRT, and itwould be more rational to combine these advanced modalitieswith anti-VEGF therapeutics. Preliminary studies with these newmodalities alone have already been reported, and in some cases,early results of combination therapy are already available.
Stereotactic Radiation Therapy
As discussed above, it appears that the effectiveness of EBRT canbe increased with dose escalation; however, the benefits will beabrogated by the accompanying off-target effects. SRT allows foraccurate and precise dose delivery to the target with steep dosedrop-offs for adjacent tissues (69). In a pilot study, Varian 600Clinear accelerator was used to deliver incremental doses of radi-ation (20-40 Gy) to 94 eyes with ARMD (Table 3) (70). Mean VAwas 0.82 before treatment and 0.89 at 12 months, and nosignificant benefits in either improving VA or in reduction ofmembrane size were derived from increasing the dose. Onepatient who was treated with 20 Gy did develop massivehemorrhage at 14 months, plausibly because of radiation-inducedCNV. In a 10-year follow-up study, the progression of ARMDwas
prominent, with 49% of patients developing central geographicatrophy and 9% developing extensive CNV (71). Fourier-domainoptical coherence tomography, which provides high resolutionretinal images, in 3 patients confirmed that that photoreceptorlayer loss was restricted to the areas of atrophy only. RR wasconfirmed in 15% of patients, and suspected in up to 18%; themean time to develop RR was 5.4 years. The episodes of signif-icant retinopathy involved neovascular glaucoma and macularischemia, and 4 of the 6 eyes with retinopathy received 40 Gytreatment. Notably, the rate of RR seen here is much higher thanthat observed in prior radiation therapy studies, likely becausemost studies had follow-up periods of �2 years. Similar rateswere found with single fractions of 14 CGE of protons (72),possibly because of lateral spread of dose (see below) (73).
The commercially developed IRay system (Oraya Therapeu-tics, Inc, Newark, CA) may limit the risk of RR delivering 100kilovoltage (kV) photons, which scatter less than MV photons.The IRay delivers 24 Gy to the macula over 5 minutes via theinferior pars plana (74). During the procedure, the eye is immo-bilized with a suction-enabled contact lens, with the macula 150mm from the source (75). As a result, the average accuracy andprecision of the IRay system are 0.6 mm and 0.4 mm, respectively(76). In models, the tissues at risk received tissue-averaged dosesfar below the thresholds for complication (eg, doses to the lensand optic nerve were 176 mGy and 1291 mGy, respectively) (77).Furthermore, for a variety of plausible setup errors and intra-fraction eye motions, the delivered and prescribed doses to themacula were within 6% of each other, and doses to other normalstructures were below the thresholds for complication (78). InYucatan miniswine, doses �24 Gy were not associated with anycomplications, whereas doses �42 Gy were associated with focalchoroidal and retinal damage (73). Again, the avoidance of radi-ation retinopathy at 24 Gy with the IRay, despite its developing insingle fractions of 14 CGE with proton beams (72), suggests thatthe development of radiation retinopathy could be related to thevolume of the retina irradiated by virtue of less scatter of kVphotons. For the IRay, the 90th percentile isodose curves corre-spond to an approximate volume of 3.14 mm3, whereas with theproton beam, there is more low-dose spillage, so over time theentire retina receives 10% of the dose (77, 79).
Clinical data with the IRay are preliminary (Table 3). In1 study, 19 patients were treated with 2 mandatory ranibizumabinjections flanking a single 24-Gy fraction (Table 3) (80-82). At6 months, 100% of treated eyes lost �15 ETDRS letters, and 16%gained �15 letters. An additional 7 injections were performed.A companion study using a 16-Gy fraction found similar results(81), whereas a “radiation-first” strategy using a 16-Gy fractionand salvage ranibizumab was not as promising (82). The onlyadverse effect in either study was self-limited superficial punctatekeratopathy, although the follow-up has been too short to enabledetection of all cases of RR. Overall, these studies demonstrate thepotential of SRT to treat VA while limiting the number of injec-tions expected with anti-VEGF monotherapy (6, 83, 84). Thepreliminary results of the randomized, sham-controlledINTREPID study comparing IRay combination therapy withanti-VEGF therapy alone are forthcoming.
Proton Therapy
Proton beams can also deliver high doses of radiation to preciselocations because their depth-dose curve includes a Bragg peak,
Table 1 Phase 1/2 trials of photon radiation therapy for ARMD
Sham radiation in subset of controls (nZ22 patients)
88
(62) Pooled analysis of 14 trials. 1242
Abbreviations: CNV Z choroidal neovascular membrane; Fx Z fraction; SE Z side effect; VA Z visual acuity.
Kishan et al. International Journal of Radiation Oncology � Biology � Physics588
allowing for low dose at tissue entry, a maximum dose at thetarget, and an essentially nonexistent exit dose. Along with beamshaping, this allows a 2- to 5-fold reduction in dose to adjacentstructures (85). In ophthalmology, PT has been widely used to
provide therapeutic doses of up to 79 Gy to uveal melanomaswhile sparing adjacent tissue (86).
Yonemoto et al published the first report on PT for ARMD(Table 4) (87). At a mean follow-up time of 11.6 months, 58% of
Reference Outcome Significant SE
(51) VA:
No significant difference in visual acuity after 12 mo
Subretinal bleeding: 7.9% in each arm
(52) VA:
12 mo: 52.2% of untreated and 32.0% of treated patients lost �3 lines of
VA (P<.05)
CNV membrane size:
12 mo: No significant difference, increasing in both arms by w22.5%
(53) VA:
17 mo: Mean loss of VA (in lines) was 5.5 in untreated and 1.9 in treated
patients (P<.05)
CNV membrane size:
17 mo: No significant difference
None
(54) VA
12 mo: Mean loss of VA (lines) of 3.7 in sham-irradiated and 3.5 in treated
patients (P>.05)
Cataract: 16% of controls and 10.3% of treated
patients
Dry eye: 45.2% of controls and 40% of treated
patients
(56) VA:
24 mo: Mean change in VA (logMAR) of 0.226 and 0.563 in treated and
control patients, respectively (P<.0001)
CNV membrane size:
24 mo: Mean change in area of 53.1% and 190.3% in treated and control
patients, respectively (P<.001)
Cataract: 1.9% of treated patients, at 3 mo
Conjunctival injection: 3.9% of treated patients
(57) VA:
12 mo: 19% of treated and 33% of untreated patients lost �1 line (P>.05).
None reported
(59) VA:
6 mo: Average decrease of 27% in treated and of 31% in untreated
controls; among patients with classic CNV, this was a significant
difference
CNV membrane size:
6 mo: Increased by 56% in treated patients and 28% in untreated controls
None reported
(60) VA:
24 mo: No significant differences in preservation of distance VA or near
VA; however, treated patients had a relative improvement in contrast
sensitivity, compared with controls, of 17.4% (P<.05).
Decrease in tear production: 2.02%
(61) VA:
18 mo: Mean VA loss (in lines) was 3.23 (controls), 1.73 (8 Gy), and 1.93
(16 Gy); both patients treated with 8 Gy and those treated with 16 Gy
had significantly greater VA at 18 mo
CNV membrane size:
18 mo: No difference between groups
None reported
(55) VA:
12 mo: Significantly greater in treated patients
None reported
(58) VA:
6 mo: 49% of untreated eyes and 26% of treated eyes lost �3 lines (P<.05)
12 mo: 49% of untreated eyes and 42% of treated eyes lost �3 lines
(P>.05)
CNV membrane size:
12 mo: Significantly smaller in treated patients
Radiation retinopathy: 1.1%
(possible case only)
(62) VA:
Loss of �3 lines
12 mo: RR 0.90 (0.74-1.1) nZ759
24 mo: RR 0.81 (0.63-1.03) nZ428
Loss of �6 lines
12 mo: RR 0.62 (0.44-0.87) nZ576
24 mo: RR 0.81 (0.64-1.03) nZ428
Mean difference in visual acuity:
12 mo: 0.08 lower (0.14-0.01 lower), nZ799
Table 2 (continued )
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19 patients treated with 8 CGE had improved or stable VA. Notably,no patients experienced radiation-related morbidity. A subsequentdose escalation study examined single fractions of 8 and 14 CGE in48 eyes (72). At 1 year, 44%of the eyes in the 8CGE group and 75%
of the eyes in the 14 CGE group had improved or stable VA. CNVmembranes decreased steadily in the 14 CGE group but not in the8 CGE group. However, 48% of the eyes in the 14 CGE group fol-lowed up for at least 30 months experienced RR, with onset as early
Table 3 Trials of stereotactic radiation therapy for ARMD
Dose: 24 CGEFx: 12 CGEOther: 4 ranibizumab injections over 4 mo, and then as
needed
6
Abbreviations: CNV Z choroidal neovascular membrane; Fx Z fraction; SE Z side effect; VA Z visual acuity.
Kishan et al. International Journal of Radiation Oncology � Biology � Physics590
Reference Outcome Significant SE
(70) VA:12 mo: 82% were within �3 lines; no dose dependenceCNV membrane size:12 mo: Increased with all doses; no dose dependence
None reported
(71) VA:Mean at 7 y: 20/300, from baseline mean of 20/120Macular findings:(average of 7 y):Central geographic atrophy (49%), disciform scar (30%), and active choroidal
neovascular membrane (9%)
Radiation retinopathy: Suspected in18% and confirmed in 15%; onset atmean of 5.4 y after treatment
(81) VA:6 mo: 96% lost �15, 81% gained �0, and 50% gained �15 ETDRS lettersInjections:Average of 0.5 additional injections over the 6 mo after radiation
(82) VA:6 mo: 100% lost �15, 53.8% gained �0, and 0% gained �15 ETDRS
lettersInjections:Total of 15 injections: none (nZ2), 1 (nZ7), 2 (nZ5)
None reported
(80) VA:6 mo: Mean change in VA was 6.4 � 9.8 ETDRS lettersInjections:Average of 0.4 additional injections over the 6 mo after radiation
None reported
Reference Outcome Significant SE
(87) VA:11.6 mo: 58% had improved or stable VACNV membrane size:6 mo: No progression in 53%
Visual loss of unknown cause: 5.3%
(72) VA:12 mo: 44% of the eyes in the 8 CGE group and 75% of theeyes in the 14 CGE group had stable or improved VA
CNV membrane size:22.1 mo: Decreased slowly and stabilized in the 8 CGEgroup; steadily decreased in the 14 CGE group
Radiation retinopathy: 78.6% of eyes followed to30 mo in the 14 CGE group. One eye (7.1%)experienced severe visual loss at 15 mo
(88) VA:12 mo: VA was stable or improved in 80%18 mo: VA was stable or improved in 61%CNV membrane size:18 mo: No progression in 66.6%
None reported
(63) VA:24 mo: Nonsignificant trend toward stabilization of VACNV membrane size:24 mo: No difference between treated patients and controls
None reported
(89) VA:12 mo: 42% and 35% of eyes lost �3 lines16 CGE and 24 CGE groups, respectively24 mo: 62% and 53% of eyes lost �3 lines16 CGE and 24 CGE groups, respectively
Complications in 15.7% and 14.8% of patientsreceiving 16 CGE and 24 CGE, respectively
Radiation retinopathy: 80% of eyes with complications,most commonly as cotton wool spots (66.67%) andhemorrhage (47.6%)
(90) VA:12 mo: Mean gain of 9.2 letters24 mo: No gain overall, but mean gain of 4.3 letters for 3patients with new diagnosis of ARMD
None. Reported
Table 4 (continued )
Table 3 (continued )
Volume 85 � Number 3 � 2013 Radiation therapy for neovascular age-related macular degeneration 591
Table 5 Trials of brachytherapy for ARMD
Reference CNV morphology Dose, isotope, and time n
Dose: 24 GyIsotope: 90SrTime: 5 minOther: bevacuzimab during and after radiation, then as
needed
34
(91) Not reported Dose: 24 GyIsotope: 90SrTime: 3-5 minOther: rabinizumab at procedure and afterward, as needed
53
Abbreviations: CNV Z choroidal neovascular membrane; Fx Z fraction; SE Z side effect; VA Z visual acuity.
Kishan et al. International Journal of Radiation Oncology � Biology � Physics592
as 3 months. One case arose at 15 months and led to severe visualloss. A phase 2 feasibility trial in France found similar results (88).Thus, 14 CGE may be more efficacious than 8 CGE but carries anunacceptably high rate of RR.
In the first randomized controlled trial of PT for ARMD,37 patients were randomized to receive either sham irradiation or16 Gy of proton irradiation in 2 fractions (63). Inasmuch as thetrial was halted early because of US Food and Drug
Administration approval of verteporpfin for photodynamictherapy, the results merely showed a trend toward stabilization ofVA in treated patients, with no RR. A subsequent trial randomized166 patients to receive 16 or 24 CGE PT in 2 fractions (89). At 24months, 62% and 53% of eyes in the 16 and 24 CGE groups,respectively, had moderate visual loss (P>.05). In that trial, 12.7%of patients experienced RR, and none experienced significantvisual loss. These studies suggest that fractionation limits RR.
Reference Outcome Significant SE
(103) VA:12 mo: Stable or improved in 45% and 25% of treated patients and
controls, respectivelyCNV membrane size:12 mo: 74% of those treated had CNV membranes that were partially or
totally occluded; 75% of controls experienced progression
None reported
(98) VA:12 mo: 31% lost �3 lines24 mo: 22% lost �3 linesOver mean of 19 mo, 70% had improved or stable VA
Diplopia: 8.7%, 1 with strabismusMacular hole: 4.38%, developed in 6 mo
(99) VA:Mean of 33.3 mo: 55% lost �3 lines of vision, 16% improved �3 linesCNV membrane size:After 6 mo: 62% had no progression
Macular scars: 16.1%
(64) VA:12 mo: Control group lost an average of 3.95 lines, and treated group lost
0.82; significant only for 32.4 Gy group24 mo: Control group lost an average of 4.90 lines, and treated group lost
2.41; not significantCNV membrane size:12 mo: Decreased in 71.4% of controls and 76.9% of treated subjects;
not significant24 mo: Decreased in 75.0% of controls and 78.4% of treated subjects;
not significant.
Radiation retinopathy-like changes: 1.1%of patients, no significant change in VA
(101) VA:12 mo: Stable or improved in 50% and 76% of patients treated with 15
Gy and 24 Gy, respectively
Cataract: 42% of phakic eyesRetinal tear: 2.9%
(100) VA: (Intent-to-treat analysis on 24 patients)12 mo: In terms of best corrected VA, 68% were stable or improved, and
(92) VA:24 mo: 90% lost �15 letters from baseline, 35% had gained �1 letter,
and 15% gained �15 letters36 mo: 90% lost �15 letters from baseline, 53% had gained �1 letter,
and 21% �15 lettersAdditional injections: Through 36 mo, 11 eyes (of 19 patients) received
a mean of 3.0 injections
Cataract: 50% of phakic eyesNonproliferative radiation retinopathy: 2.9%Retinal fibrosis: 6%
(91) VA:12 mo: Mean change of �4.0 � 15.1 ETDRS lettersCentral retinal thickness:12 mo: 50 � 179 mmAdditional injections: 81% maintained stable vision, with a mean of 3.49
anti-VEGF injections in 12 mo; previously, required 12.5 injections in12 mo
Volume 85 � Number 3 � 2013 Radiation therapy for neovascular age-related macular degeneration 593
Park et al recently published the results of the first studyexamining combination treatment with PT and anti-VEGF therapy(90). Six patients were treated with 24 CGE PT in 2 fractions 24hours apart in addition to 4 monthly treatments with ranibizumab,followed by retreatment as needed. Overall, there was no gain inVA at 24 months; however, among patients with newly diagnosedcases (nZ3), there was a mean gain of 4.3 letters at 24 months. By24 months, patients had received a mean of 10 injections of
ranibizumab, less than the 24 monthly injections in most anti-VEGF monotherapy protocols. No cases of RR were identifiedby 3 years of follow-up. Two patients experienced severe visionloss, but this was likely subsequent to disease progression. In alleyes treated, �10% of the retina received �90% of the prescribeddose of radiation. The reduction in anti-VEGF therapy noted hereparallels that noted in 2 studies of brachytherapy-based combi-nation therapy (91, 92).
Kishan et al. International Journal of Radiation Oncology � Biology � Physics594
Overall, PT may be an effective, noninvasive modality tocomplement anti-VEGF therapy. Because dose spillage could leadto a higher rate of RR than seen with SRT, lower doses per fraction(to 12 CGE) should be used (73); combination therapy with anti-VEGF may also limit the risk of RR (26, 93). The ongoing sham-controlled PBAMD2 trial will provide stronger evidence for theeffectiveness of this combination therapy.
Epimacular Brachytherapy
In traditional EBRT plans, the lens can receive as much as 30%-50% of the maximum dose (30, 52). If the macular lesion wereto receive 24 Gy in a modern brachytherapy plan, the optic nerveand lens could receive 2.4 and 0.00056 Gy, respectively (94).This has led to the widespread usage of ophthalmic plaquebrachytherapy, particularly for choroidal melanomas (95-97).Typical isotopes include the g-emitter palladium 103 (103Pd) andb-emitter strontium 90 (90Sr). Finger et al, who originally re-ported the feasibility of 103Pd plaque therapy (35), initiallyexamined its utility in cohorts of 23 (98) and 30 (99) patientswith ARMD (Table 5). There were no serious adverse effects,and 45%-69% of patients had either improvements or only minorchanges in VA.
It has since become appreciated that 90Sr is superior for ocularbrachytherapy because of its long half-life (28.7 years) and rapiddose dropoff (100, 101). Indeed, the dose rate attenuates by 50%after a depth of 1.5 mmddeep enough to target CNV withoutcausing damage to nearby structures (94, 102). Jaakkola et alinitially reported the results of 32.4 Gy 90Sr plaque therapy (103).At 1 year, 15% and 50% of treated and control eyes, respectively,experienced severe visual loss, with the treated eyes losingsignificantly less VA (P<.05). Subsequently, the same grouptreated 89 lesions with 90Sr plaque therapy to doses of either32.4 Gy or 12.6 Gy (corrected doses; initially reported as 15 Gyand 12.6 Gy) (64). Patients receiving 32.4 Gy treatment lost 2.41lines at 24 months of follow up, compared with 4.90 lines amongcontrol individuals. The 12.6 Gy group did not have differentoutcomes from those in control individuals through 24 months,and neither treatment group differed from control individuals at36 months. By angiography, CNV was markedly reduced in bothtreatment groups, with 43.6% of macula being clinically dry at24 months, compared with 31.3% of dry macula in control indi-viduals. One patient experienced RR-like changes at 36 months.The treatment lasted 5 minutes, compared with an average of34 hours with 103Pd (99).
Subsequent advances in brachytherapy technique led to thedevelopment of epimacular brachytherapy (EMB). In EMB, a parsplana vitrectomy is performed, and a 90Sr source is placed at thefovea (101). In the initial feasibility study, 34 patients receivedeither 15 or 24 Gy. At 1 year, the 24 Gy group had a mean VA gainof 10.3 letters, whereas the 15 Gy group had a mean loss of1.0 letters; there were no radiation-related side effects. Subse-quently, 34 patients were treated with 24 Gy and followed up for3 years (92, 101); 90% of eyes lost <15 letters from baseline, and21% gained �15 letters. At 36 months, 11 eyes required additionalbevacizumab injections, with patients receiving a mean of3.0 injections over the study period; this is far less than the15 injections that would be expected in the “as-needed” protocolexplored by the PrONTO study (84). Notably, the VA stabilityachieved was comparable to that demonstrated in the ANCHOR(83) and MARINA (6) studies, in which eyes were treated with
ranibizumab monthly for 24 months. Fifty percent of patientsexperienced cataracts. One case of nonproliferative retinopathy ofno clinical consequence was identified at 36 months.
The MERITAGE trial targeted patients who already requiredfrequent injections of anti-VEGF therapeutics (91). Fifty-threepatients were treated with 24 Gy via EMB and were then fol-lowed up with monthly ocular coherence tomography. Beforeenrollment, the average rate of anti-VEGF injection was 0.45/patient/month; during the 12-month follow up period, the rate ofretreatment was 0.29/patient/month. Common adverse eventsincluded conjunctival hemorrhage (71.7%) and cataract (30.2%).
The high incidence of cataracts in these studies is likelysecondary to vitrectomy, because EMB delivers 0.0056 Gy to thelens, and the threshold for cataract formation is 2 Gy (98).Cataract formation after vitrectomy is common and has beendescribed in 80% of eyes after 2 years, and although complicationrates of cataract removal may be higher in vitrectomized eyes,cataract removal remains relatively safe and routine in suchcases (104). Further, vitrectomy itself may be helpful in treatingARMD by limiting vitromacular adhesion (105).
Overall, these results suggest that combination therapy withEMB can stabilize ARMD, thus decreasing the requirement foranti-VEGF therapy. Two large, randomized controlled trials willprovide further data: the CABERNET study will compare rani-bizumab plus EMB with ranibizumab alone in treatment-naı̈vepatients, and the MERLOT study will do the same for patientsalready receiving ranibizumab. Finally, although the lack of RRseen in these studies is promising, none of these reports had longenough follow-up times to definitively demonstrate a low risk ofRR (71).The simultaneous treatment with anti-VEGF therapeutics,however, may limit the risk of RR (26, 93).
Conclusions
Considerable evidence suggests a benefit for using radiationtherapy to treat ARMD. Early EBRT studies suggested thathypofractionation to larger total doses may be superior toconventional 1.8-2 Gy schemes. Newer modalities, such as PT,SRT, and brachytherapy, allow enhanced precision and accuracy,and thus larger doses per fraction. PT appears to carry the greatestrisk of RR, though fractions of up to 12 CGE (to a total dose of24 CGE) can minimize this risk. Kilovoltage SRT with 24 Gy ina single fraction, as delivered by the IRay, generates less internalscatter; however, its widespread use may be limited by the needfor centers to purchase and gain expertise with the device. EMBoffers very precise dosing of large fractions at the expense ofrequiring a vitrectomy, which leads to cataract formation in up to50% of patients with phakic eyes at baseline. However, thevitrectomy itself may be beneficial in treating ARMD by virtue ofreducing retinal tension.
Intriguingly, all 3 modalities function well in concert with anti-VEGF therapy, which has become the gold standard in exudativeARMD treatment. Although this treatment is effective, patientsreceiving anti-VEGF therapy require frequent injections (rangingin frequency from 10 per 24 months to monthly) to maintain VA.Combination therapy could drastically decrease the frequency ofinjections needed to maintain VA, lessening the burden onpatients, health care providers, and the health care industry.Specifically, each injection of ranibizumab costs $2000, andbetween 2008 and 2009, ranibizumab cost Medicare Part B over$1.1 billion (106). Additionally, each injection carries the risk of
Volume 85 � Number 3 � 2013 Radiation therapy for neovascular age-related macular degeneration 595
retinal detachment, infection, patient travel, and pain, in additionto requiring patient reliability in follow up. Further, combinationtherapy may reduce the risk of RR.
Given the enormous public health burden imposed by ARMD,the identification of effective and efficient treatment strategies isof paramount importance. Ongoing, phase 3 trials examining theutility of combining anti-VEGF therapy with SRT, PT, and EMBwill be instrumental in providing level I evidence on which tomake rational clinical decisions. The future of ARMD manage-ment will likely include individualized treatment protocols.Radiation therapy will likely play an important role in a largesubset of patients. Ultimately, head-to-head comparisons of thesemodalities may be needed to identify the most effective means ofusing radiation therapy to treat ARMD.
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