STEREOTACTIC RADIOTHERAPY FOR WET AGE-RELATED MACULAR DEGENERATION (INTREPID) Influence of Baseline Characteristics on Clinical Response TIMOTHY L. JACKSON, PHD, FRCOPHTH,* E. MARK SHUSTERMAN, MD,† MARK ARNOLDUSSEN, PHD,† ERIK CHELL, PHD,† KUN WANG, MD, MSC,‡ DARIUS M. MOSHFEGHI, MD§; ON BEHALF OF THE INTREPID STUDY GROUP Purpose: To determine which patients respond best to stereotactic radiotherapy (SRT) for neovascular age-related macular degeneration. Methods: Participants (n = 230) receiving intravitreal anti-vascular endothelial growth factor injections for neovascular age-related macular degeneration enrolled in a randomized, double-masked sham-controlled trial comparing 16 Gray, 24 Gray, or Sham SRT. In a post hoc analysis, participants were grouped according to their baseline characteristics, to determine if these influenced SRT efficacy. Results: At 52 weeks, SRT was most effective for lesions #4 mm in greatest linear dimension and with a macular volume greater than the median value of 7.4 mm3. For 26% of the participants with both these characteristics, SRT resulted in 55% fewer ranibizumab injections (2.08 vs. 4.60; P = 0.0002), a mean visual acuity change that was 5.33 letters superior to sham (+2.18 vs. −3.15 letters; P = 0.0284), and a 71.1-mm greater reduction in mean central subfield thickness (−122.6 vs. −51.5 mm; P = 0.027). Other features associated with a positive response to SRT included pigment epithelial detachment and the absence of fibrosis. Conclusion: Stereotactic radiotherapy is most effective for neovascular age-related macular degeneration lesions that are actively leaking at the time of treatment, and no larger than the 4-mm treatment zone. RETINA 35:194–204, 2015

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chronic, active wet AMD.6 Participants were randomized to 16 Gray, 24 Gray, or sham SRT. The study met its primary endpoint, showing a statistically significant one-third reduction in the number of ranibizumab injections that participants required.6 The 16 and 24 Gray arms had similar results, with each showing significantly fewer injections than the sham arm.6 The trial recruited patients with lesions that were up to 6 mm in greatest linear dimension (GLD), as determined by fluorescein angiography (FA). This was a typical inclusion criteria for AMD studies at the time INTREPID was designed,7–9 yet the 90% isodose treatment zone at the macula was only 4 mm in diameter, with a steep decline in dose beyond this border (Figure 1).10,11 The median GLD of the trial population was 3.68 mm, and 39% of participants had

tereotactic radiotherapy (SRT) has been used as a treatment for neovascular (wet) age-related macular degeneration (AMD) since the 1990s,1 but there has been renewed interest after the recent introduction of a device designed specifically for use in the eye.2–5 The IRay System (Oraya Therapeutics, Inc, Newark, CA) uses low voltage X-rays to generate three highly collimated beams of radiation that pass through the inferior pars plana, and overlap at the macula. After initial positive results,2,3 a dose-ranging, shamcontrolled double-masked randomized clinical trial was undertaken to determine if SRT reduced the frequency of intravitreal ranibizumab injections over 12 months.6 The IRay in Conjunction with Anti-Vascular Endothelial Growth Factor Treatment for Patients with Wet AMD (INTREPID) trial recruited 230 patients with 194

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Methods

Fig. 1. The figure shows a typical color map of the radiation dose received at different parts of the macula for patients treated with 24 Gray. The central 4-mm zone received at least 90% of the 24 Gray total, but there is a steep attenuation of exposure beyond this margin. The treatment zone was centered on the fovea. The eye was held in position by a suction coupled contact lens. Tracking software interrupted treatment if the eye moved out of position. The color map shown above was provided in real time for each case, as the treatment progressed.

lesions with a GLD .4 mm. We hypothesized that the lesions #4 mm in GLD may respond better to SRT. We also hypothesized that actively leaking lesions may be more responsive to SRT, on the assumption that these lesions had actively proliferating endothelial cells within their neovascular complexes. Radiation is known to preferentially damage proliferating cells, which are less able to repair damaged DNA than mature retinal cells.12,13 To test these hypotheses, we undertook a post hoc analysis of the INTREPID data to determine if these or other baseline characteristics might help identify the patients who may be the most responsive to SRT. Appropriate case selection is important now that the device is being used commercially in Europe. From the *Department of Ophthalmology, School of Medicine, King’s College London, London, United Kingdom; †Oraya Therapeutics, Inc, Newark, California; ‡The International Drug Development Institute, Louvain-la-Neuve, Belgium; and §Byers Eye Institute, Horngren Family Vitreoretinal Center, Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, California. Supported by Oraya Therapeutics for the INTREPID study. M. Arnoldussen, and E. Chell are employees of Oraya. K. Wang’s employer received funding from Oraya to support the statistical analysis. D. M. Moshfeghi and E. M. Shusterman are consultants to Oraya. T. L. Jackson’s employer received contract research funding from Oraya and he received a single advisory board payment. The members of the INTREPID Study Group are listed in Appendix 1. Reprint requests: Timothy L. Jackson, PhD, FRCOphth, Department of Ophthalmology, King’s College London, King’s College Hospital, London SE 59RS, United Kingdom; e-mail: t.jackson1@ nhs.net

The INTREPID study (clinical trial registration at www.clinicaltrials.gov; identifier: NCT01016873; accessed June 9, 2013) methodology has been reported.6 Briefly, 230 participants with chronic, active wet AMD were enrolled at 21 European sites. Institutional review board/research ethics committee review was obtained for each site, and the study complied with the tenets of the Declaration of Helsinki. Participants were older than 50 years, with wet AMD diagnosed in the study eye within last 3 years. They were required to have received $3 ranibizumab or bevacizumab injections within the preceding 52 weeks, and to have also needed treatment at the time of enrollment because of active disease. The choroidal neovascular lesion had to be ,12 disk areas in size, with a GLD #6 mm. The distance from the center of the fovea to the farthest point on the choroidal neovascular lesion perimeter had to be #3 mm. Full inclusion and exclusion criteria have been reported.6 Participants were randomized to 16 Gray, 24 Gray, or sham SRT. All received a 0.5-mg intravitreal ranibizumab injection at baseline. Thereafter, ranibizumab was administered on a monthly pro re nata (PRN) basis, using defined retreatment criteria: a 100mm increase in optical coherence tomography (OCT) central subfield thickness from the lowest previous OCT measurement; new or increased macular hemorrhage; and .5 letter decrease in best-corrected visual acuity since the last visit or baseline, with other evidence of disease activity such as intraretinal fluid on OCT.6 Best-corrected visual acuity was measured using the Early Treatment of Diabetic Retinopathy (ETDRS) chart, with all OCT and FA images evaluated by an independent masked reading center. The three outcome measures used in the present analysis were the number of PRN ranibizumab injections, mean change in visual acuity, and mean change in OCT central subfield thickness. The first two were predefined INTREPID protocol outcome measures, and the latter was exploratory. All were assessed in terms of their change from baseline to Week 52. Statistical Analysis To test our hypothesis that lesions within the 4-mm treatment zone responded better to SRT than lesions extending beyond this perimeter, we classified eyes into those with a GLD #4 mm, or those .4 mm. To test our hypothesis that the most actively leaking lesions responded best, we classified eyes into those

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with an OCT macular volume greater than the median value of 7.4 mm3, or #7.4 mm3 (Figure 2). The measurement of total macular volume was taken from the time domain Stratus OCT (Carl Zeiss Meditec, Inc, Dublin, CA), which uses 6 radial scans to interpolate the volume of retinal tissue inside the ETDRS 6-mm diameter grid. As the results in 16 Gray and 24 Gray were similar in the INTREPID study, with no definite dose response,6 both groups were combined for the present responder analyses. In addition to the analysis of lesion size and macular volume, various other exploratory subgroup analyses were undertaken in relation to

Fig. 2. This shows a typical retinal thickness analysis of a patient scanned with time domain optical coherence tomography (OCT). The average retinal thickness and macular volume for each sector of the Early Treatment of Diabetic Retinopathy (ETDRS) grid is computed and compared with normative values. The total macula volume is the summation of all sector volumes and is highlighted in the red box. The median total macular volume (7.4 mm3) was determined based on these data. This value is very close to the threshold (7.42 mm3) that defines the 99% value of the Normative Distribution Percentile, as shown with the red arrow.

baseline characteristics. For each subgroup analysis, eyes in the combined SRT group were compared with eyes in the sham group with the same baseline characteristics. The group definitions were based on the reading center analysis of the baseline fundus photograph, angiogram, and OCT, except for patient age, lens status, and visual acuity, which were determined by baseline history and examination. The responder analyses were based on the intent-totreat population, which consisted of all randomized patients. All analyses were performed by randomized group assignment and based on the observed data. No imputation was done for any missing data at Week 52.

INTREPID RESPONDER ANALYSIS  JACKSON ET AL

The three outcomes measures, namely number of PRN ranibizumab injections, mean change in visual acuity, and mean change in central subfield thickness were analyzed by comparing the mean of the combined treated group with the sham group, estimated by

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restricted maximum likelihood-based repeated measures analyses adjusted by the factors used in randomization.14 To evaluate whether the treatment effect was the same across all subgroups, Cochran’s Q test, a classical measure to test the significant heterogeneity in

Fig. 3. The figure depicts a forest plot of the treatment effects across subgroups, in relation to the mean number of pro re nata (PRN) ranibizumab injections over 52 weeks, in the intent to treat analysis set, comparing the combined 16 and 24 Gray arms with the sham arm. The subgroups were defined by the participants’ baseline ocular characteristics or their age. The group labeled fluorescein angiography (FA) distance lesion edge refers to the distance from the fovea to the furthest point on lesion circumference, determined using FA. The lesion size group was based on the greatest linear dimension (GLD), determined using FA. Fibrosis was determined using a combination of fundus photograph and FA. All images were assessed by an independent, masked reading center. The size of each black filled box is proportional to the group size, and the error bars show the 95% confidence interval. Boxes to the left of the midline favor the stereotactic radiotherapy (SRT) group and indicate that the SRT group had fewer PRN ranibizumab injections than participants in the sham group with the same baseline characteristics. If the error bars lie fully to the left of the midline, then the difference would be statistically significant compared with the sham group. Les. size, lesion size; PED, pigment epithelial detachment; SD, standard deviation; tot mac vol, total macular volume.

The table shows the mean number of ranibizumab injections ± one standard deviation, mean change in best-corrected visual acuity (number of letters), and mean change in central subfield thickness (in micrometers) from baseline to Week 52. The values of P compare the combined 16 and 24 Gray SRT arms with the sham arm. The macular volume was determined using OCT, and the GLD was determined angiographically.

−114.57 ± 104.69 (35) −93.97 ± 115.26 (35) −104.27 ± 109.79 (70) −52.39 ± 141.05 (38) 0.0349 −86.02 ± 123.58 (108) −102.73 ± 89.09 (44) −73.85 ± 96.99 (40) −88.98 ± 93.50 (84) −43.72 ± 103.84 (43) 0.0135 −73.65 ± 99.07 (127) −141.84 ± 86.76 (19) −103.37 ± 116.68 (19) −122.61 ± 103.27 (38) −51.55 ± 135.50 (20) 0.0270 −98.10 ± 119.18 (58)

−0.68 ± 10.09 (108) 0.79 ± 9.26 (128) −0.34 ± 9.03 (58) 0.1247 0.1550 0.0284 −2.68 ± 11.55 (38) −0.84 ± 10.51 (43) −3.15 ± 9.58 (20) 0.60 ± 9.62 (35) 2.59 ± 9.72 (41) 1.89 ± 9.73 (19) 0.23 ± 8.71 (35) 0.70 ± 7.19 (44) 2.47 ± 6.76 (19)

0.41 ± 9.11 (70) 1.61 ± 8.50 (85) 2.18 ± 8.27 (38)

0.0001 0.0089 0.0002 4.42 ± 2.66 (38) 3.48 ± 2.37 (44) 4.60 ± 2.35 (20) 2.42 ± 2.50 (74) 2.31 ± 2.41 (87) 2.08 ± 2.35 (40) 2.29 ± 2.51 (38) 2.16 ± 2.18 (43) 2.05 ± 2.09 (21)

Sham Combined 16 and 24 Gray (N) 24 Gray (N) 16 Gray (N) Subgroup

A total of 230 patients were randomized to 16 Gray (n = 75), 24 Gray (n = 75), and sham SRT (n = 80). The groups shared similar baseline characteristics including age, duration of disease, visual acuity, and retinal thickness.6 Compared with the sham arm, the 16 Gray arm had a 30% reduction in ranibizumab retreatment (P = 0.0077), and the 24 Gray arm had a 35% reduction (P = 0.0026). The mean change in visual acuity was −0.28 (P = 0.839), +0.40 (P = 0.397), and −0.58 letters in the 16 Gray, 24 Gray, and sham arms, respectively. The mean change in OCT central subfield thickness was −85.12 (P = 0.0054), −68.56 (P = 0.0186), and −33.46, respectively. The subgroup analyses of the INTREPID primary outcome measure (mean number of PRN ranibizumab retreatments) are shown in Figure 3. Lesions #4 mm in GLD and those with the most active leakage (macular volume, .7.4 mm3) seemed to do well. Further results in this subgroup, which comprised 26.1% of the total trial population, are shown in Table 1. Other features associated with a favorable response to SRT included age above 75 years, the presence of a pigment epithelial detachment, and an absence of fibrosis. The results for the mean change in visual acuity are shown in Figure 4, with the mean change in central subfield thickness shown in Figure 5. For eyes with lesions #4 mm in GLD and macular volume .7.4 mm3, the mean number of ranibizumab retreatments in the SRT arm was 55% lower than that in the sham arm (2.08 vs. 4.60 injections), as shown in Figure 6. This difference was highly significant (P = 0.0002). For this subgroup, the mean visual acuity change in the SRT arm was 5.33 letters superior to that in the sham arm (+2.18 vs. −3.15 letters; P = 0.0284), as shown in Figure 7. Likewise the OCT response in this subgroup favored the SRT arm, with a 71.1-mm greater reduction in central subfield thickness in the SRT arm (−122.6 vs. −51.5 mm; P = 0.027) (Figure 8). In contrast to the best responding profile, patients with the exact opposite characteristics (lesions .4 mm in GLD and macular volume #7.4 mm3)

Table 1. Subgroup Analysis in Relation to Lesion Size and Macular Fluid Volume

Results

2.56 ± 2.51 (36) 2.45 ± 2.63 (44) 2.11 ± 2.66 (19)

P

All Arms Combined

a treatment effect, was also performed for each endpoint. A nominal significance level of 5% was used for the analyses of all endpoints, and the corresponding 95% confidence intervals were also calculated unless the analysis was purely descriptive in nature. The treatment effects across the exploratory subgroups were shown in forest plots.

3.10 ± 2.71 (112) 2.70 ± 2.45 (131) 2.93 ± 2.64 (60)

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No. ranibizumab retreatments Macular volume .7.4 mm3 GLD #4 mm Macular volume .7.4 mm3 and GLD #4 mm Change in visual acuity Macular volume .7.4 mm3 GLD #4 mm Macular volume .7.4 mm3 and GLD #4 mm Change in central subfield thickness Macular volume .7.4 mm3 GLD #4 mm Macular volume .7.4 mm3 and GLD #4 mm

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Fig. 4. The figure shows a forest plot of the mean change in bestcorrected Early Treatment of Diabetic Retinopathy (ETDRS) visual acuity over 52 weeks in the intent to treat analysis set, comparing the combined 16 and 24 Gray arms with the sham arm. Positive values indicate a gain in visual acuity. Boxes to the right of the midline favor the combined SRT group, and indicate that this group had a smaller loss, or greater gain of visual acuity than the sham group. The subgroup definitions, analysis, abbreviations, and data presentation are as detailed in Figure 3.

seemed to have the worst outcomes. Eyes in this subgroup had a mean number of ranibizumab retreatments that was very similar to that in the sham arm (3.50 vs. 3.63 injections; not significant). For this subgroup, the mean visual acuity change in the SRT arm was 3.96 letters inferior to that in the sham arm (−1.83 vs. +2.13; not significant). This poor response was also reflected in the OCT analysis, with a 51.6-mm decrease in central subfield thickness

relative to the control arm (+9.25 vs. −42.33 mm; not significant).

Discussion The INTREPID study reported a 30% to 35% reduction in the ranibizumab injection frequency following SRT, compared with ranibizumab

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Fig. 5. The figure depicts a forest plot of the treatment effect across subgroups, in relation to the change in optical coherence tomography (OCT) central subfield thickness. The mean values shown are in micrometers, with negative values representing a reduction in thickness from baseline to Week 52. The subgroups were defined by the patients’ baseline ocular characteristics, or their age. The subgroup definitions, analysis, abbreviations, and data presentation are as detailed in Figure 3. Boxes to the left of the midline favor the combined radiotherapy arm.

monotherapy.6 In the present post hoc analysis, we hypothesized that lesions within the 90% isodose treatment zone may respond better to SRT, as may lesions with the most active leakage. Our analysis supports these hypotheses. For participants with a GLD #4

mm and macular volume greater than the median, there was a highly significant 55% reduction in ranibizumab injection frequency, and significantly better visual acuity, compared with ranibizumab monotherapy. These results are of interest because there are

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Fig. 6. The figure shows the cumulative number of PRN ranibizumab injections administered over 52 weeks in the intent to treat analysis, for eyes with lesions that had a GLD #4 mm and an OCT total macular volume greater than the median value of 7.4 mm3. The black dotted line shows the result (mean ± standard error) in the combined 16 and 24 Gray SRT arm, compared with the sham arm in blue. At 52 weeks, those in the SRT arm had received a mean of 2.07 injections, and those in the sham arm had received 4.60 injections (P = 0.0002), representing a 55% reduction in the SRT arm.

scant new treatments that offer the prospect of fewer injections but better visual acuity, compared with ranibizumab monotherapy. The worst responding group comprised 15% of the original study population. The characteristics of this population were diametrically opposite to the best responders. The smaller macular volumes most likely represent less active lesions, possibly associated with photoreceptor loss. Having a lesion GLD of .4 mm would likely result in a less effective treatment

because the margins of the lesion would not fit within the x-ray beam diameter (Figure 1).10,11 More targeted case selection will lower the number of patients deemed suitable for SRT, and the combination of GLD #4 mm and macular volume .7.4 mm3 reduced the study population to 26% of the original group. Given the high prevalence of wet AMD, this nonetheless remains a large number of patients.15 Further, it is not known if the selection of a macular volume .7.4 mm3 will exclude patients, or simply delay

Fig. 7. The figure shows the mean change in the Early Treatment of Diabetic Retinopathy (ETDRS) best-corrected visual acuity over 52 weeks, in the subset of eyes with lesions #4 mm in GLD and macular volume .7.4 mm3. The black dotted line shows the visual acuity in the combined SRT arms, compared with the sham arm in blue. At 52 weeks, the SRT arm had gained 2.18 letters, whereas the sham arm had lost 3.15 letters, a significant difference of 5.33 letters (P = 0.0284). Data are from the intent to treat analysis and are shown as mean ± one standard error.

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Fig. 8. The figure shows the mean change in OCT central subfield thickness over 52 weeks, in eyes with lesions #4 mm in GLD and macular volume .7.4 mm3. The black dotted line shows the OCT thickness in the combined SRT arms, and the blue line shows the sham arm. The SRT arm showed a 122.6-mm reduction in OCT thickness at Week 52, versus 51.5 mm in the sham arm, a significant difference of 71.1 mm (P = 0.027). Data are from the intent to treat population and shown as mean ± one standard error.

treatment, until such time as they have significant fluid accumulation. It is possible then that the results are, at least partly, as dependent on the timing of treatment as on case selection. The value of the total macular volume on the Stratus OCT does not directly map to other OCT systems, especially the newer spectral domain devices. However, the Stratus normative database recognizes a total macular volume above 7.42 mm3 as exceeding the 99th percentile for a normal healthy subject, which matches well with the profile of the “best responders” addressed in this article who had macular volumes .7.4 mm3 (Figure 2). Therefore, a patient with a macular volume that exceeds the 99th percentile of the normative database on any particular OCT system would likely have significant fluid, as defined in this article. The INTREPID study was not sized to test for the presence of treatment-by-subgroup interactions. Thus, true treatment-by-subgroup interactions would likely have been missed, unless they were quite substantial. If any particular subgroup seemed to benefit more or less from the treatment than the total trial population, such an observation could have been due to chance alone. As such, subgroup analyses were considered to be exploratory, to identify any major effect that might be worth testing in future trials. Therefore, as with all post hoc analyses, the results need to be treated with caution. The findings are, however, biologically plausible, in that actively leaking lesions may well contain a high proportion of proliferating cells, and these are likely to be radiosensitive.12,13 The findings are also consistent with other

studies using radiation to treat wet AMD. The macular epiretinal brachytherapy in treated age-related macular degeneration (MERITAGE) study enrolled patients with chronic active wet AMD, similar to those in this study, and found that eyes with small lesions responded best to epimacular brachytherapy.16–18 The Choroidal neovascularization secondary to AMD treated with BEta RadiatioN Epiretinal Therapy (CABERNET) study enrolled patients with treatment-naive disease, therefore the results are not directly comparable, but it also found that smaller lesions seemed to do better than larger lesions.19,20 The results outlined in this article are notable when compared with other studies of patients with wet AMD previously treated with anti-vascular endothelial growth factor drugs. The integrated analysis of the vascular endothelial growth factor Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW 1 and VIEW 2) studies showed that patients who had been treated with 2 mg of aflibercept during the first year lost 0.8 letters after 44 weeks into the second year with an average of 4.2 injections.21 The second year of the Comparison of Age-related Macular Degeneration Treatments Trial (CATT) also demonstrated gradual loss of vision with continued therapy.22,23 After 1 year of receiving monthly injections of ranibizumab, continued monthly treated patients lost 0.3 letters with an average of 10.5 injections, whereas PRN-treated patients lost 1.8 letters with an average of 5 injections. For patients receiving PRN treatments throughout the first year, the second year of PRN treatments did not show visual improvement, while requiring an average of almost 6 injections. The CATT results for bevacizumab showed

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a similar second year response.22,23 Treating patients with SRT who match the best responder profile offers a potential improvement in vision with half the number of injections over the course of a year. A particular strength of this trial is its randomized, double-masked sham-controlled design. Further studies would be needed to prospectively test the findings of this post hoc analysis in a larger number of patients. Longer follow-up is important to determine the durability of treatment and to detect delayed microvascular changes or radiation retinopathy. Also, we selected lesions with a GLD #4 mm, on the assumption that they are more likely to be within the 4-mm treatment zone than larger lesions; however, lesions approaching 4 mm in size may not lie fully within the 90% isodose line if they are not centered on the fovea. This is because the SRT device delivers treatment centered on the presumptive fovea regardless of the lesion location. The retreatment criteria were consistent with those used at the time the INTREPID study was designed,7–9 but they are less intensive than current “treat until dry” regimens.23 Consequently, the number of ranibizumab injections in both arms of INTREPID was lower than might currently occur. The results cannot be directly compared with those of studies that enroll treatmentnaive disease because those studies have substantial visual improvement at the start of treatment, unlike studies that enroll previously treated disease, which often show reduced visual acuity over time. Patients transitioning from Year 1 to 2 of studies such as CATT and VIEW 1/VIEW 2 may also not be directly comparable, because patients entering INTREPID had a longer duration of disease; also, they may possibly have been more refractory to anti-vascular endothelial growth factor treatment, if they (and their clinician) elected to try another treatment modality. We made no manual corrections to the automated identification of retinal boundaries; therefore, there is a risk that segmentation errors result in incorrect macular volume calculations. For patients with neovascular AMD measured using the Stratus OCT, errors tend to underestimate the macular volume.24,25 In summary, this study may potentially refine our knowledge of whom best to treat with SRT, suggesting that lesions smaller than the 4-mm treatment zone do better. It also suggests patients are more likely to respond to SRT when they have significant fluid accumulation. These hypotheses, generated from a subgroup analysis, need to be tested in a prospective trial. Key words: neovascular age-related macular degeneration, wet age-related macular degeneration, radiation, stereotactic radiotherapy, ranibizumab, anti-vascular endothelial growth factor, INTREPID study.

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18. Dugel PU, Petrarca R, Bennett M, et al. Macular epiretinal brachytherapy in treated age-related macular degeneration: MERITAGE study: twelve-month safety and efficacy results. Ophthalmology 2012;119:1425–1431. 19. Dugel PU, Bebchuk JD, Nau J, et al. Epimacular brachytherapy for neovascular age-related macular degeneration: a randomized, controlled trial (CABERNET). Ophthalmology 2013; 120:317–327. 20. Jackson TL, Dugel PU, Bebchuk JD, et al. Epimacular brachytherapy for neovascular age-related macular degeneration (CABERNET): fluorescein angiography and optical coherence tomography. Ophthalmology 2013;120:1597–1603. 21. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012;119:2537–2548. 22. Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology 2012;119: 1388–1398. 23. Group CR, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364:1897–1908. 24. Krebs I, Hagen S, Smretschnig E, et al. Reproducibility of segmentation error correction in age-related macular degeneration: stratus versus cirrus OCT. Br J Ophthalmol 2012;96:271–275. 25. Patel PJ, Chen FK, da Cruz L, Tufail A. Segmentation error in stratus optical coherence tomography for neovascular agerelated macular degeneration. Invest Ophthalmol Vis Sci 2009;50:399–404.

Appendix 1. Members of the INTREPID Study Group Austria: Graz, Landeskrankenhaus (LKH), Augenklinik; Professor Anton Haas (PI), Tamara Pichler, Mag.; Innsbruck, Medizinische Universität Innsbruck, Augenklinik; Professor Martina Kralinger (PI), Stefan Huber, MD; Vienna, Vienna Institute for Research in Ocular Surgery (VIROS), Hanusch Krankenhaus,; Professor Oliver Findl (PI), Yen-An Chen, MD, Sophie Tatzreiter, MD; Vienna, Netzhautklinik Univ, Professor Michael Stur (PI), Karin Vogl; Czech Republic: Brno, University Hospital Brno; Petr Kolar, MD, PhD (PI), Daniela Vyslouzilova, MD; Hradec Kralove, University Hospital Hradec Kralove; Jan Studnicka, MD, PhD (PI), Jaroslava Dusova, MD; Jana Breznayova, MD.

Olomouc, University Hospital Olomouc; Assoc. Prof. Jiri Rehak, MD (PI), Oldrich Chrapek, MD, PhD; Barbora Jirkova, MD; Ondrej Vlacil, MD; Prague, Central Military Hospital; Jan Ernest, MD, PhD (PI), Libor Hejsek, MD, Pavel Nemec, MD, Leos Rejmont, MD; Zaneta Benesova, MD; Prague, University Hospital Kralovske Vinohrady; Jan Hamouz, MD (PI), Jitka Pokorna, MD, Stanislava Pokorna, MD, Miroslav Veith, MD; Prague, General University Hospital; Zora Dubska, MD (PI), Bohdan Kousal, MD; Germany: Heidelberg, Augenklinik, University Hospital; Professor Stefan Dithmar, (PI), Stefanie Pollithy, MD; Tubingen, University Eye Hospital, Eberhard-KarlsUniversity; Professor K.U. Bartz-Schmidt (PI), Tobias Peters, MD, Professor Barbara Wilhelm; Neubrandenburg, Diakonie Klinikum Dietrich Bonhoeffer; Professor Helmut Hoh (PI), Theodoros Kontopoulos, MD; Italy: Milano, Università Vita-Salute, Ospedale San Raffaele, Istituto di Ricovero e Cura a Carattere Scientifico; Professor Francesco Bandello, MD, FEBO, Ugo Introini, MD, Jacopo Milesi, MD, Giacinto Triolo, MD; United Kingdom: Belfast, The Belfast Health and Social Care Trust; Usha Chakravarthy, MD, FRCOphth, PhD (PI); Karen Gillvray, MB BChBAO; Lisa Kelly, MB BChBAO, MRCOphth; Michael Williams, BMedSci, MB BChBAO, MD, MRCOphth, PGCME; Bradford, Bradford Royal Infirmary; Faruque Ghanchi, MBBS, MS, FRCOphth, FRCS, MML (PI); Devon, Torbay Hospital; Mick Cole, FRCOphth (PI), Edward Doyle, FRCOphth (PI), Osoba Olayinka, FRCSEd. London, King’s College Hospital; Timothy L. Jackson, PhD, FRCOphth (PI); Manchester, Manchester Royal Eye Hospital; Tariq Aslam, DM (Oxon), FRCSEd (Ophth), Dip IT, PhD, (PI); Southampton, Southampton General Hospital; Professor Andrew Lotery, MD, FRCOphth, MB BChBAO. Wolverhampton, Wolverhampton Eye Infirmary, Nirodhini Narendran, MD, FRCOphth (PI), Professor Yit Yang, MBChB, FRCOphth.

Stereotactic radiotherapy for wet age-related macular degeneration (INTREPID): influence of baseline characteristics on clinical response.

To determine which patients respond best to stereotactic radiotherapy (SRT) for neovascular age-related macular degeneration...
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