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Macular Epiretinal Brachytherapy in Treated Age-related Macular Degeneration
Macular Epiretinal Brachytherapy in Treated Age-related Macular Degeneration MERITAGE Study: Twelve-Month Safety and Efficacy Results Pravin U. Dugel, MD,1 Robert Petrarca, MBBS,2,3 Michael Bennett, MD,4 Adiel Barak, MD,5 Dov Weinberger, MD,6 Jeffrey Nau, MMS,7 Timothy L. Jackson, PhD, FRCOphth2,3 Purpose: To evaluate the safety and efficacy of epimacular brachytherapy (EMB) for the treatment of chronic, active, neovascular age-related macular degeneration (AMD). Design: Prospective, multicenter, interventional, noncontrolled clinical trial. Participants: Fifty-three eyes of 53 participants with neovascular AMD requiring frequent anti–vascular endothelial growth factor (VEGF) retreatment. Methods: Participants underwent pars plana vitrectomy with a single 24-Gy dose of EMB delivered using an intraocular, handheld cannula containing a strontium 90/yttrium 90 source positioned over the active lesion. Participants were retreated with ranibizumab administered monthly as needed, using predefined retreatment criteria. Optical coherence tomography (OCT) was undertaken monthly, with images assessed by an independent reading center. Main Outcome Measures: Coprimary outcomes at 12 months were proportion of participants with stable vision (losing ⬍15 Early Treatment Diabetic Retinopathy Study [ETDRS] letters) and mean number of anti-VEGF retreatments. Results: Before enrollment, participants had received an average of 12.5 anti-VEGF injections. After a single treatment with EMB, 81% maintained stable vision, with a mean of 3.49 anti-VEGF retreatments in 12 months. Mean ⫾ standard deviation change in visual acuity was – 4.0⫾15.1 ETDRS letters. Mean ⫾ standard deviation OCT central retinal thickness increased by 50⫾179 m. Common adverse events included conjunctival hemorrhage (n ⫽ 38), cataract (n ⫽ 16), resolving vitreous hemorrhage (n ⫽ 6), and eye pain (n ⫽ 5). Conclusions: Epimacular brachytherapy produces stable visual acuity in most participants with previously treated, active disease. Epimacular brachytherapy may reduce the need for frequent anti-VEGF retreatment. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2012;119:1425–1431 © 2012 by the American Academy of Ophthalmology.
The current standard of care for neovascular age-related macular degeneration (AMD) is antiangiogenic therapy targeting vascular endothelial growth factor (VEGF). Two anti-VEGF drugs have been approved for use to treat AMD: one is an aptamer (pegaptanib)1 and the other is a humanized antigen binding fragment (ranibizumab).2,3 A third antiangiogenic compound, bevacizumab, is a full-length anti-VEGF antibody approved for the treatment of systemic neoplasms and is used off-label to treat neovascular AMD.4 Pegaptanib and ranibizumab stabilize visual acuity (VA), with fewer than 3 lines lost in approximately 70% and 95% of patients, respectively.1–3 Because pegaptanib is not as effective, its use has declined. Bevacizumab has been shown to offer a similar (noninferior) visual outcome to ranibizumab.5 Anti-VEGF therapy for neovascular AMD requires delivery by intravitreal injection. This is generally safe and well tolerated by patients, but each injection carries a small risk of cataract formation, retinal tears or detachments, and infectious endophthalmitis.1–3 The approved drugs are labeled for indefinite monthly injections. In clinical practice, © 2012 by the American Academy of Ophthalmology Published by Elsevier Inc.
because of logistic constraints, patients are not usually treated monthly and instead are treated with a treat-andextend6 or as-needed7 regimen, after 3 initial loading-dose injections. This as-needed regimen may reduce the frequency of intravitreal injections, but it typically requires approximately monthly clinic or hospital review, and patients typically require 7 to 8 injections in the first year alone.5 Given the risks, patient inconvenience, and costs associated with regular and frequent office visits, diagnostics, and intravitreal injections, there remains an unmet need for a therapy that either replaces or extends the therapeutic benefit of intravitreal anti-VEGF therapy. The role of radiation therapy for neovascular AMD was explored as early as 1993.8 The rationale for this approach was based on the known effects of radiation therapy on tumor microvasculature. Localized radiation treatment has the ability to prevent proliferation of vascular tissue9,10 by inhibiting neovascularization. After low-dose radiation, vascular endothelium demonstrates morphologic11 and ISSN 0161-6420/12/$–see front matter doi:10.1016/j.ophtha.2012.01.014
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Ophthalmology Volume 119, Number 7, July 2012 DNA9,12,13 changes, inhibition of replication,10,14,15 and apoptosis.16 Fibroblast proliferation and subsequent scar formation, hallmarks of end-stage neovascular AMD, also are inhibited.17 Choroidal neovascularization (CNV) complexes are composed of rapidly replicating endothelial cells that are more sensitive to radiation treatment than the nonproliferating capillary endothelial cells seen in mature retinal vessels.18,19 Jaakkola et al20 evaluated episcleral strontium 90 (Sr90) plaque brachytherapy in a single fraction dose of 12.6, 29, or 32.4 Gy in patients with CNV (doses differ from those published, based on recent recalibration measurements; Jaakkola A, personal communication, 2007). To deliver the radiation, an applicator was introduced surgically on the episcleral surface under the macula and was held in place manually for the treatment period of up to 54 minutes. Favorable efficacy results were reported with the higher doses (29 and 32.4 Gy), but not with the 12.6-Gy dose. After 3 years of follow-up, only 1 incidence of radiation retinopathy-like symptoms was reported in an eye treated with 32.4 Gy radiation. Non–sight-threatening localized microvascular changes developed in the eye. Furthermore, early radiation studies demonstrated resolution of subretinal fluid, hemorrhages, and exudates, with maintenance of VA in many, although not all, patients.18,21,22,23 Results of feasibility studies using ocular plaque applicators suggest that Sr90 may be a safe choice for a radioisotope.24,25 Strontium 90/yttrium 90 (Sr90/Y90) emits  radiation that penetrates approximately 2 mm into the human retina,26 enough to target the abnormal CNV that occurs in wet AMD. Moreover, Sr90/Y90 has a very rapid reduction in energy: an approximate 10% decrease in dose for each 0.1 mm from the source.27,28 These favorable isotope characteristics allow for a maximum dose delivered to a small volume of tissue while minimizing the dose delivered to neighboring ocular tissue. Theoretically, this should translate into lower risk of radiation complications compared with other treatment methods such as proton beam or x-ray, where a larger volume of tissue receives the maximum treatment dose. The absence of radiation retinopathy, optic neuropathy, or cataract formation attributable to Sr90/Y90 in published studies of Sr90/Y90 plaque brachytherapy for subretinal CNV is consistent with the safety profile of Sr90/Y90 therapy for intraocular tumors.25 Epiretinal brachytherapy, also called epimacular brachytherapy (EMB), is delivered using a novel intraocular Sr90/ Y90 applicator device (NeoVista, Newark, CA) designed to deliver local, targeted radiation to the neovascular tissue that causes wet AMD. After pars plana vitrectomy, a standard vitreoretinal operation, the sealed radiation source is placed temporarily over the fovea in the vitreous cavity via an intraocular cannula. The objective of the Macular EpiRetinal brachytherapy In Treated AGE-related macular degeneration (MERITAGE) trial is to assess whether EMB is a safe and effective treatment for neovascular AMD. In particular, the MERITAGE Trial targeted patients who required frequent injections of antiVEGF therapy to treat their disease, because they had the most to gain from a treatment that may reduce neovascular activity. It was hypothesized that EMB would reduce the need for
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such frequent anti-VEGF injections in this difficult-to-treat population, while maintaining an acceptable visual outcome.
Patients and Methods The MERITAGE trial (ClinicalTrials.gov identifier: NCT00809419) is a 3-year prospective interventional trial undertaken in accordance with the tenets of the Declaration of Helsinki. The results presented in this article represent data from 5 centers in the United Kingdom, United States, and Israel. Enrollment ran from November 2008 through October 2009. The protocol was reviewed and approved by local institutional review boards or ethics committees at each center, and all participants provided written informed consent before enrollment. This report presents the preliminary safety and functional efficacy outcomes at 12 months; the study is designed to follow up subjects for 36 months to monitor for the presence of long-term radiation damage.
Participants Participants were men and women 50 years of age and older who were diagnosed with subfoveal CNV associated with wet AMD, confirmed by fluorescein angiography (FA), in the study eye. Subjects with predominantly classic, minimally classic, or occult subtype CNV lesions were eligible for enrollment. Because the study aimed to target patients requiring frequent anti-VEGF therapy, a minimum frequency of rescue injections was stipulated in the period before enrollment: 3 injections in 6 months or 5 injections in 12 months. A complete list of eligibility criteria is given in Appendix I (available at http://aaojournal.org). One eye per participant was deemed the study eye and received EMB. If the participant had bilateral disease and both eyes were eligible for treatment, the eye with the worse VA was treated.
Schedule of Visits and Assessments All participants underwent a comprehensive screening evaluation to determine eligibility, which included a review of medical history including the dates of all prior anti-VEGF treatments, full refraction, determination of best-corrected VA (BCVA), examination of the anterior and posterior segments of the eye, lens grading using the Lens Opacification Classification System II,29 intraocular pressure measurement, fundus photography, FA, and optical coherence tomography. Independent digital angiography or fundus photography and optical coherence tomography reading centers evaluated all respective images (Digital Angiography Reading Center, New York, New York; Duke Reading Center, Durham, North Carolina). Best-corrected visual acuity was assessed using the protocol described in the Early Treatment Diabetic Retinopathy Study (ETDRS), using trial-certified examiners and testing rooms and ETDRS charts starting at 4 m distant from the participant.30 Patients deemed eligible based on these assessments underwent EMB within 14 days, as described below. Baseline BCVA was assessed on the day of surgery. Postoperative visits were scheduled 1 day and 1 week after surgery. Thereafter, safety and efficacy were evaluated monthly for 36 months after treatment.
Treatment Epimacular brachytherapy was performed as a single treatment at the baseline visit. Before treatment, the surgeon confirmed the location of the lesion using retinal vascular landmarks and a preoperative FA. Surgery was performed using either retrobulbar, peribulbar, or subTenon anesthesia, or general anesthesia if indicated. After lid specu-
Dugel et al 䡠 MERITAGE Study of Epimacular Brachytherapy for AMD Table 1. Demographics and Baseline Disease Characteristics of the Study Cohort (n ⫽ 53) Demographics Gender Male Female Ethnicity White Other Lens status at baseline Phakic Pseudophakic Mean age (yrs) Mean no. of previous anti-VEGF injections Mean baseline BCVA (ETDRS letters) Median baseline BCVA (ETDRS letters) Mean baseline lesion size (mm2)
been treated with ranibizumab or bevacizumab before enrollment were retreated with ranibizumab.
Statistical Analysis 15 (28.3) 38 (71.7) 50 (94.3) 3 (5.7) 22 (41.5) 31 (58.5) 78 (58–92) 12.5 (6–38) 51 (11–73) 55 14.9 (1.7–35.1)
The primary goals of this feasibility study were to describe the safety and preliminary efficacy of EMB in participants with neovascular AMD who require persistent injections of anti-VEGF therapy. Efficacy outcomes included the proportions of patients losing fewer than 15 and more than 30 ETDRS letters, as well as the proportion gaining more than 0 and more than 15 ETDRS letters, and change in mean BCVA from baseline at 52 weeks. The number of retreatments with anti-VEGF therapy also are reported. Safety outcomes included both solicited and nonsolicited adverse events recorded at each study visit. Results are presented as descriptive statistics.
Results BCVA ⫽ best-corrected visual acuity; ETDRS ⫽ Early Treatment Diabetic Retinopathy Study; VEGF ⫽ vascular endothelial growth factor. Data are presented as number (%) or mean (range), unless otherwise indicated.
lum placement, a standard 3-port pars plana vitrectomy was performed. Surgeons had discretion as to whether to perform a full vitrectomy or a core vitrectomy, removing enough vitreous to create an access channel to the retina for the device. Vitrectomies were performed with 20-gauge, 23-gauge, or 25-gauge systems, depending on the surgeon’s preference. If a posterior vitreous detachment was not present, the surgeon determined whether to induce a posterior vitreous detachment surgically. If a 23-gauge or 25-gauge system was used, then the temporal sclerotomy site was enlarged to accommodate the 20-gauge device. The neovascular complex was approached from the temporal side to minimize radiation exposure to the optic nerve. The surgeon then placed the delivery probe into the midvitreous cavity and instructed the assistant to engage the device, allowing the radiation source to travel down the cannula, near to the tip. The position where the radiation source stopped within the probe was etched with a cross. The cross then was positioned directly above the center of the CNV complex or over the area of greatest disease activity as demonstrated by FA, with the tip of the probe resting lightly on the surface of the retina. The prescribed radiation dose of 24 Gy then was delivered by precisely controlling the time that the tip was held in position above the neovascular complex. The treatment time required to delivery 24 Gy was determined from previous calibration of each device and was between 3 and 5 minutes, depending on the individual Sr90/Y90 source activity. After the prescribed radiation dose was delivered, the probe tip was moved to the midvitreous cavity, the radiation source was retracted, and the delivery probe was removed from the eye. The vitrectomy was concluded in a standard fashion, and the enlarged sclerotomy was sutured. An appropriate antibiotic and steroid regimen was administered in the subconjunctival space. Immediately after the procedure, a patch and shield were applied to the treated eye and a postoperative regimen of topical antibiotics, steroids, and cycloplegics were initiated from the following day. Participants were eligible for intravitreal anti-VEGF therapy at the conclusion of the EMB procedure and at each of the subsequent monthly follow-up visits if 1 or more of the retreatment criteria were met. The retreatment criteria are provided in Appendix II (available at http://aaojournal.org). At baseline, the observations used to decide on retreatment were compared with those acquired before enrollment; thereafter, comparisons were all in relation to observations made within the trial. Participants who had
Demographics Overall, 53 participants with neovascular AMD were enrolled in this trial. Demographic and baseline ocular and disease characteristics are given in Table 1. The mean duration of disease at the time of enrollment was 27.9⫾21.4 months, and patients had received an average of 12.5⫾7.6 intravitreal antiVEGF treatments before enrollment, with 1 patient receiving a maximum of 38 prior injections.
Efficacy The proportions of participants maintaining VA (losing ⬍15 ETDRS letters) over 12 months of follow-up is illustrated in Figure 1. The primary VA end point was met in 81% of participants at month 12. Four participants (7.5%) lost more than 30 ETDRS letters. The proportion of participants gaining more than 0 letters, and more than 15 letters are shown in Figure 1. At month
Figure 1. Graph showing the proportion of subjects with a loss of fewer than 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, gaining 1 or more ETDRS letters, and gaining 15 or more ETDRS letters after treatment with 24-Gy epimacular brachytherapy. All available data (n ⫽ 53). (, Losing less than 15 letters; , gaining 1 or more letters; , gaining 15 or more letters.)
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Ophthalmology Volume 119, Number 7, July 2012 Table 2. Common Adverse Events Deemed Possibly or Probably Related to Epimacular Brachytherapy in the Safety Population from Baseline to Month 12 (n ⫽ 53)
Figure 2. Graph showing the mean (⫾1 standard deviation) central retinal thickness (CRT) of the optical coherence tomography (OCT). The OCT images were read by an independent reading center at each time point. The mean CRT increased by 50 m over 12 months, from 186 to 236 m, but with substantial variability in response, as shown by the large error bars.
12, almost half of participants (47.2%) had some degree of visual improvement relative to baseline. Mean⫾standard deviation change in ETDRS BCVA at 3, 6, 9, and 12 months was – 0.1⫾11.6, – 0.6⫾10.1, –2.1⫾14.4, and – 4.0⫾15.1 ETDRS letters, respectively. The mean⫾standard deviation optical coherence tomography central retinal thickness was 186⫾123 m at baseline, and 236⫾202 m at 12 months, an increase of 50⫾179 m (Fig 2).
Injection Frequency Thirty-five subjects received an anti-VEGF injection at the time of EMB, reflecting baseline disease activity. During the following 12 months, a total of 185 retreatments were administered, with a mean of 3.49 injections (range, 0 –11) per subject (Fig 3). More than half of participants (31/53) needed no more than 3 injections, and more than 75% (41/53) needed no more than 5 injections over the 12-month period. The rate of intravitreal anti-VEGF injections before enrollment was 0.45 injections per participant per month. In the 12 months of this study, the comparable rate of retreatment was 0.29 injections per subject per month, but it should be noted that it is not known how closely the pre-enrollment retreatment criteria matched those used within the trial.
Figure 3. Bar graph showing the number of intravitreal ranibizumab retreatment injections in the study eye during the first 12 months of the study. The mean number of retreatment injections was 3.2. All available data (n ⫽ 53).
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Event Preferred Term (n ⴝ 53)
Number (%)
Relationship*
Cataract† Subconjunctival hemorrhage Retinal hemorrhage
3 (13.6) 3 (5.7) 3 (5.7)
Vitreous hemorrhage Anterior chamber cells
2 (3.8) 1 (1.9)
Possible (3) Possible (3) Probable (2), possible (1) Possible (2) Probable (1)
*As determined by the principal investigator. Development or progression of existing cataract. Cataracts were deemed serious if they warranted surgical removal. Calculated from subjects who were phakic at baseline (n ⫽ 22).
†
Safety Epimacular brachytherapy was safe and well tolerated by most subjects. Adverse events generally were mild to moderate in intensity and were unrelated to EMB. Adverse and serious events determined by the principal investigator as possibly or probably related to EMB or to the vitrectomy procedure are given in Tables 2 and 3. The most common were subconjunctival hemorrhage (38 subjects), cataract development or progression (16 subjects), vitreous hemorrhage (6 subjects), and ocular pain or discomfort (5 subjects). Cataract surgery was performed on 59% (13/22) of phakic subjects in the first 12 months. In this 12-month follow-up, there were no cases of radiation retinopathy or microvascular changes observed by the investigators, medical monitors, or the independent FA reading center. Because radiation-related retinal changes can manifest over many years, these subjects will continue to be followed up closely with examination and FA and photography at intervals up to 36 months.
Discussion The emergence of anti-VEGF therapy has driven a paradigm shift in the management of neovascular AMD during the past decade. The landmark MARINA2 and ANCHOR3 trials of ranibizumab demonstrated for the first time that VA could be stabilized in most patients, and vision improvement was seen in a substantial proportion.2,3 Optimal efficacy outcomes, however—including the maintenance of VA gains—were achieved using monthly therapy. Many studies showed that reducing to an as-needed dosing regimen resulted in inferior vision gains and suboptimal maintenance of vision (Brown DM, Wang PW, Scott LC. HORIZON extension trial of ranibizumab for wet AMD: subanalysis of year 1 results [abstract P0248]. Paper presented at: AAO/SOE Joint Annual Meeting, November 8 –11, 2008; Atlanta).31,32 The Comparisons of Age-Related Macular Degeneration Treatments Trials study reported that visual outcomes were similar when comparing as-needed versus monthly dosing but still mandated monthly clinic or hospital review, and patients received approximately 7 to 8 as-needed injections per year.5 Furthermore, not all patients respond to anti-VEGF therapy, and sometimes those who initially respond subsequently lost vision, perhaps because
Dugel et al 䡠 MERITAGE Study of Epimacular Brachytherapy for AMD Table 3. Common Adverse Events Deemed Possibly or Probably Related to Vitrectomy in the Safety Population from Baseline to Month 12 (n ⫽ 53) Event Preferred Term (n ⴝ 53) Cataract† Subconjunctival hemorrhage/hyperemia Vitreous hemorrhage
Number (%) 16 (72.7) 38 (71.7) 6 (11.3)
Anterior chamber cells
5 (9.4)
Eye pain/discomfort
5 (9.4)
Corneal edema
4 (7.5)
Eye irritation Retinal hemorrhage Headache Hypotony of globe Corneal erosion Ecchymosis Floaters
4 (7.5) 2 (3.8) 2 (3.8) 1 (1.9) 1 (1.9) 1 (1.9) 1 (1.9)
Relationship (n)* Probable (16) Probable (36), possible (2) Probable (3), possible (3) Probable (4), possible (1) Probable (4), possible (1) Probable (1), possible (3) Probable (4) Possible (2) Possible (2) Probable (1) Probable (1) Probable (1) Possible (1)
*As determined by the principal investigator. Development or progression of existing cataract. Calculated from subjects who were phakic at baseline (n ⫽ 22).
†
of tachyphylaxis33 or some other unidentified factor. For example, responder analysis of the SUSTAIN study of ranibizumab showed that 47% of patients did not manifest any improvement in vision or lost the initial gain they achieved.34 Given that not all patients respond to antiVEGF therapy, and even those who do face a burdensome treatment regimen, there is an unmet need for a treatment that reduces disease activity in a more durable manner. The preliminary safety and efficacy results using EMB support its potential role in meeting this need. Participants in this study had been treated with ranibizumab or bevacizumab before enrollment and were required to meet minimum prior injection criteria before enrollment. As a result, this study selectively recruited participants with the most active disease who otherwise might be predicted to have a poor outcome. This differs from studies that recruited treatment-naïve disease, where the case mix may be more typical. Further, most studies of treatment-naïve disease show an initial improvement in VA that is at best stable over time—results seldom exceed the peak in mean vision observed toward the start of therapy. For this reason, it is difficult to show an improvement in mean vision in patients who already are receiving anti-VEGF therapy. Despite this, the proportion of eyes maintaining VA (losing ⬍15 ETDRS letters) was 81% 12 months after EMB. This stability of BCVA in the current study was maintained with an average of only 3.49 intravitreal anti-VEGF injections over 12 months. The apparent reduction in demand for antiVEGF therapy is of interest, given that vitrectomy is known to reduce drug half-lives and would be expected to reduce the duration of action of ranibizumab.35 This observation, however, should be interpreted with caution, because this study did not have a control arm, and it is difficult to compare the
treatment before enrollment with that occurring subsequently within the context of a clinical trial. Although the reinjection frequency was less than that of the as-needed arms of the Comparisons of Age-Related Macular Degeneration Treatments Trials study,5 that study had more aggressive retreatment criteria that would tend to produce a better visual outcome, but a higher frequency of injections. If EMB reduces the frequency of injections, then this may have important implications for patient safety. With anti-VEGF monotherapy, both drug-related and injectionrelated adverse events are cumulative over multiple injections. It may be that the surgical and radiation-related risks associated with EMB are offset by reduced exposure to anti-VEGF retreatment. This study cannot determine if any reduction in demand for anti-VEGF retreatment might have translated to fewer hospital visits, because all patients underwent mandated monthly review within the study. In the current study, only 10 serious adverse events were deemed related to the device; of these, 7 (70%) were cataract related and resolved without sequelae on cataract extraction. The confounding effect of cataract formation occurring after pars plana vitrectomy potentially is important. At 12 months, 59% of phakic patients had undergone cataract surgery. It is possible that this artificially lifts the mean vision, if mild pre-existing lens opacity is removed, despite the fact that patients with significant lens opacity were excluded. Alternatively, the 41% of patients who remained phakic at 12 months may have reduced the mean vision because of lens opacity that did not yet warrant surgery. What is of note, however, is that the participants who were pseudophakic from baseline had a similar vision outcome to the phakic population, with 80% losing fewer than 15 letters and a mean vision of –3.8 ETDRS letters. The high incidence of cataract is to be expected, given the known association with vitrectomy. It seems unlikely that the cataract was the result of radiation, because the threshold for cataract formation is reported as 2 Gy,36 and EMB exposes the lens to a much lower dose of only 0.0056 Gy. This feasibility study of EMB had no control group. As such, it is difficult to attribute all adverse events to treatment versus other causes, such as the underlying disease process or common comorbidities. Although it is assumed that this cohort of patients would have tended to have had a poor outcome with continued monotherapy, the lack of a control arm means that this assumption cannot be validated with this study. It should also be noted that radiation retinopathy may not present within the first year of treatment, and patients will be followed up for 3 years. In light of these limitations, the efficacy and safety results observed in this study should be used primarily to support further evaluation of this innovative therapeutic method for patients with neovascular AMD.
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Ophthalmology Volume 119, Number 7, July 2012 2. Rosenfeld PJ, Brown DM, Heier JS, et al, MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419 –31. 3. Brown DM, Michels M, Kaiser PK, et al, ANCHOR Study Group. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: twoyear results of the ANCHOR Study. Ophthalmology 2009; 116:57– 65. 4. Tufail A, Patel PJ, Egan C, et al, ABC Trial Investigators. Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study [report online]. BMJ 2010;340:c2459. Available at: http://www. bmj.com/content/340/bmj.c2459?view⫽long&pmid⫽20538634. Accessed December 31, 2011. 5. CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364:1897–908. 6. Engelbert M, Zweifel SA, Freund KB. Long-term follow-up for type 1 (subretinal pigment epithelium) neovascularization using a modified “treat and extend” dosing regimen of intravitreal antivascular endothelial growth factor therapy. Retina 2010;30:1368 –75. 7. Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular agerelated macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol 2009;148:43–58. 8. Chakravarthy U, Houston RF, Archer DB. Treatment of agerelated subfoveal neovascular membranes by teletherapy: a pilot study. Br J Ophthalmol 1993;77:265–73. 9. Rubin DB, Drab EA, Kang HJ, et al. WR-1065 and radioprotection of vascular endothelial cells. I. Cell proliferation, DNA synthesis and damage. Radiat Res 1996;145:210 – 6. 10. Hosoi Y, Yamamoto M, Ono T, Sakamoto K. Prostacyclin production in cultured endothelial cells is highly sensitive to low doses of ionizing radiation. Int J Radiat Biol 1993; 63:631– 8. 11. Krishnan L, Krishnan EC, Jewell WR. Immediate effect of irradiation on microvasculature. Int J Radiat Oncol Biol Phys 1988;15:147–50. 12. Mooteri SN, Podolski JL, Drab EA, et al. WR-1065 and radioprotection of vascular endothelial cells. II. Morphology. Radiat Res 1996;145:217–24. 13. Rosander K, Zackrisson B. DNA damage in human endothelial cells after irradiation in anoxia. Acta Oncol 1995;34:111– 6. 14. Verheij M, Koomen GC, van Mourik JA, Dewit L. Radiation reduces cyclooxygenase activity in cultured human endothelial cells at low doses. Prostaglandins 1994;48:351– 66. 15. Hallahan D, Clark ET, Kuchibhotla J, et al. E-selectin gene induction by ionizing radiation is independent of cytokine induction. Biochem Biophys Res Commun 1995;217:784 –95. 16. Eissner G, Kohlhuber F, Grell M, et al. Critical involvement of transmembrane tumor necrosis factor-alpha in endothelial programmed cell death mediated by ionizing radiation and bacterial endotoxin. Blood 1995;86:4184 –93. 17. Chakravarthy U, Gardiner TA, Archer DB, Maguire CJ. A light microscopic and autoradiographic study of non-irradiated and irradiated ocular wounds. Curr Eye Res 1989;8:337– 48. 18. Archer DB, Amoaku WM, Gardiner TA. Radiation retinopathy— clinical, histopathological, ultrastructural and experimental correlations. Eye (Lond) 1991;5:239 –51. 19. Parsons JT, Fitzgerald CR, Hood CI, et al. The effects of irradiation on the eye and optic nerve. Int J Radiat Oncol Biol Phys 1983;9:609 –22. 20. Jaakkola A, Heikkonen J, Tommila P, et al. Strontium plaque brachytherapy for exudative age-related macular degeneration:
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three-year results of a randomized study. Ophthalmology 2005;112:567–73. Bergink GJ, Hoyng CB, van der Maazen RW, et al. A randomized controlled clinical trial on the efficacy of radiation therapy in the control of subfoveal choroidal neovascularization in agerelated macular degeneration: radiation versus observation. Graefes Arch Clin Exp Ophthalmol 1998;236:321–5. Maguire AM, Schachat AP. Radiation retinopathy. In Ryan SJ, ed-in-chief; Ogden TE, Hinton DR, Schachat AP, Wilkinson CP, eds. Retina. 3rd ed. Vol 2. St. Louis, MO: Mosby, 2001:1510 – 4. Char DH, Irvine AI, Posner MD, et al. Randomized trial of radiation for age-related macular degeneration. Am J Ophthalmol 1999;127:574 – 8. Jaakkola A, Heikkonen J, Tommila P, et al. Strontium plaque irradiation of subfoveal neovascular membranes in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 1998;236:24 –30. van Ginderdeuren R, van Limbergen E, Spileers W. 18 years’ experience with high dose rate strontium-90 brachytherapy of small to medium sized posterior uveal melanoma. Br J Ophthalmol 2005;89:1306 –10. Hokkanen J, Heikkonen J, Holmberg P. Theoretical calculations of dose distributions for beta-ray eye applicators. Med Phys 1997;24:211–3. Avila MP, Farah ME, Santos A, et al. Twelve-month shortterm safety and visual-acuity results from a multicentre prospective study of epiretinal strontium-90 brachytherapy with bevacizumab for the treatment of subfoveal choroidal neovascularisation secondary to age-related macular degeneration. Br J Ophthalmol 2009;93:305–9. Avila MP, Farah ME, Santos A, et al. Twelve-month safety and visual acuity results from a feasibility study of intraocular, epiretinal radiation therapy for the treatment of subfoveal CNV secondary to AMD. Retina 2009;29:157– 69. Chylack LT Jr, Leske MC, McCarthy D, et al. Lens Opacities Classification System II (LOCS II). Arch Ophthalmol 1989; 107:991–7. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 1985;103:1796 – 806. Boyer DS, Heier JS, Brown DM, et al. A Phase IIIb study to evaluate the safety of ranibizumab in subjects with neovascular age-related macular degeneration. Ophthalmology 2009; 116:1731–9. Regillo CD, Brown DM, Abraham P, et al, PIER Study Group. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol 2008; 145:239 – 48. Forooghian F, Cukras C, Meyerle C, et al. Tachyphylaxis after intravitreal bevacizumab for exudative age-related macular degeneration. Retina 2009;29:723–31. Holz FG, Amoaku W, Donate J, et al, SUSTAIN Study Group. Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: the SUSTAIN Study. Ophthalmology 2011;118:663–71. Chin HS, Park TS, Moon YS, Oh JH. Difference in clearance of intravitreal triamcinolone acetonide between vitrectomized and nonvitrectomized eyes. Retina 2005;25:556 – 60. Finger PT, Berson A, Ng T, Szechter A. Ophthalmic plaque radiotherapy for age-related macular degeneration associated with subretinal neovascularization. Am J Ophthalmol 1999; 127:170 –7.
Dugel et al 䡠 MERITAGE Study of Epimacular Brachytherapy for AMD
Footnotes and Financial Disclosures Originally received: July 5, 2011. Final revision: January 8, 2012. Accepted: January 9, 2012. Available online: March 30, 2012.
Timothy L. Jackson - Financial support - NeoVista, Inc. Pravin Dugel - Financial support, Equity owner - NeoVista, Inc. Manuscript no. 2011-994.
Michael Bennett - Financial support - NeoVista, Inc.
1
Retinal Consultants of Arizona, Phoenix, Arizona.
Dov Weinberger - Financial support - NeoVista, Inc.
2
King’s College Hospital, London, United Kingdom.
Adiel Barak - Financial support - NeoVista, Inc.
3
King’s College London, United Kingdom.
Jeffrey Nau - Employee, Patents - NeoVista, Inc.
4
Retina Institute of Hawaii, Honolulu, Hawaii.
5
Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
This work forms part contribution to a MDRes degree at King’s College London (RP).
6
Rabin Medical Center, Tel Aviv, Israel.
7
NeoVista, Newark, California. Financial Disclosure(s): The author(s) have made the following disclosure(s):
Correspondence: Timothy L. Jackson, PhD, FRCOphth, King’s Health Partners, Department of Ophthalmology, King’s College Hospital, London SE5 9RS, United Kingdom. E-mail: [email protected].
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The current standard of care for neovascular age-related macular degeneration (AMD) is antiangiogenic therapy targeting vascular endothelial growth factor (VEGF). Two anti-VEGF drugs have been approved for use to treat AMD: one is an aptamer (pegaptanib)1 and the other is a humanized antigen binding fragment (ranibizumab).2,3 A third antiangiogenic compound, bevacizumab, is a full-length anti-VEGF antibody approved for the treatment of systemic neoplasms and is used off-label to treat neovascular AMD.4 Pegaptanib and ranibizumab stabilize visual acuity (VA), with fewer than 3 lines lost in approximately 70% and 95% of patients, respectively.1–3 Because pegaptanib is not as effective, its use has declined. Bevacizumab has been shown to offer a similar (noninferior) visual outcome to ranibizumab.5 Anti-VEGF therapy for neovascular AMD requires delivery by intravitreal injection. This is generally safe and well tolerated by patients, but each injection carries a small risk of cataract formation, retinal tears or detachments, and infectious endophthalmitis.1–3 The approved drugs are labeled for indefinite monthly injections. In clinical practice, © 2012 by the American Academy of Ophthalmology Published by Elsevier Inc.
because of logistic constraints, patients are not usually treated monthly and instead are treated with a treat-andextend6 or as-needed7 regimen, after 3 initial loading-dose injections. This as-needed regimen may reduce the frequency of intravitreal injections, but it typically requires approximately monthly clinic or hospital review, and patients typically require 7 to 8 injections in the first year alone.5 Given the risks, patient inconvenience, and costs associated with regular and frequent office visits, diagnostics, and intravitreal injections, there remains an unmet need for a therapy that either replaces or extends the therapeutic benefit of intravitreal anti-VEGF therapy. The role of radiation therapy for neovascular AMD was explored as early as 1993.8 The rationale for this approach was based on the known effects of radiation therapy on tumor microvasculature. Localized radiation treatment has the ability to prevent proliferation of vascular tissue9,10 by inhibiting neovascularization. After low-dose radiation, vascular endothelium demonstrates morphologic11 and ISSN 0161-6420/12/$–see front matter doi:10.1016/j.ophtha.2012.01.014
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Ophthalmology Volume 119, Number 7, July 2012 DNA9,12,13 changes, inhibition of replication,10,14,15 and apoptosis.16 Fibroblast proliferation and subsequent scar formation, hallmarks of end-stage neovascular AMD, also are inhibited.17 Choroidal neovascularization (CNV) complexes are composed of rapidly replicating endothelial cells that are more sensitive to radiation treatment than the nonproliferating capillary endothelial cells seen in mature retinal vessels.18,19 Jaakkola et al20 evaluated episcleral strontium 90 (Sr90) plaque brachytherapy in a single fraction dose of 12.6, 29, or 32.4 Gy in patients with CNV (doses differ from those published, based on recent recalibration measurements; Jaakkola A, personal communication, 2007). To deliver the radiation, an applicator was introduced surgically on the episcleral surface under the macula and was held in place manually for the treatment period of up to 54 minutes. Favorable efficacy results were reported with the higher doses (29 and 32.4 Gy), but not with the 12.6-Gy dose. After 3 years of follow-up, only 1 incidence of radiation retinopathy-like symptoms was reported in an eye treated with 32.4 Gy radiation. Non–sight-threatening localized microvascular changes developed in the eye. Furthermore, early radiation studies demonstrated resolution of subretinal fluid, hemorrhages, and exudates, with maintenance of VA in many, although not all, patients.18,21,22,23 Results of feasibility studies using ocular plaque applicators suggest that Sr90 may be a safe choice for a radioisotope.24,25 Strontium 90/yttrium 90 (Sr90/Y90) emits  radiation that penetrates approximately 2 mm into the human retina,26 enough to target the abnormal CNV that occurs in wet AMD. Moreover, Sr90/Y90 has a very rapid reduction in energy: an approximate 10% decrease in dose for each 0.1 mm from the source.27,28 These favorable isotope characteristics allow for a maximum dose delivered to a small volume of tissue while minimizing the dose delivered to neighboring ocular tissue. Theoretically, this should translate into lower risk of radiation complications compared with other treatment methods such as proton beam or x-ray, where a larger volume of tissue receives the maximum treatment dose. The absence of radiation retinopathy, optic neuropathy, or cataract formation attributable to Sr90/Y90 in published studies of Sr90/Y90 plaque brachytherapy for subretinal CNV is consistent with the safety profile of Sr90/Y90 therapy for intraocular tumors.25 Epiretinal brachytherapy, also called epimacular brachytherapy (EMB), is delivered using a novel intraocular Sr90/ Y90 applicator device (NeoVista, Newark, CA) designed to deliver local, targeted radiation to the neovascular tissue that causes wet AMD. After pars plana vitrectomy, a standard vitreoretinal operation, the sealed radiation source is placed temporarily over the fovea in the vitreous cavity via an intraocular cannula. The objective of the Macular EpiRetinal brachytherapy In Treated AGE-related macular degeneration (MERITAGE) trial is to assess whether EMB is a safe and effective treatment for neovascular AMD. In particular, the MERITAGE Trial targeted patients who required frequent injections of antiVEGF therapy to treat their disease, because they had the most to gain from a treatment that may reduce neovascular activity. It was hypothesized that EMB would reduce the need for
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such frequent anti-VEGF injections in this difficult-to-treat population, while maintaining an acceptable visual outcome.
Patients and Methods The MERITAGE trial (ClinicalTrials.gov identifier: NCT00809419) is a 3-year prospective interventional trial undertaken in accordance with the tenets of the Declaration of Helsinki. The results presented in this article represent data from 5 centers in the United Kingdom, United States, and Israel. Enrollment ran from November 2008 through October 2009. The protocol was reviewed and approved by local institutional review boards or ethics committees at each center, and all participants provided written informed consent before enrollment. This report presents the preliminary safety and functional efficacy outcomes at 12 months; the study is designed to follow up subjects for 36 months to monitor for the presence of long-term radiation damage.
Participants Participants were men and women 50 years of age and older who were diagnosed with subfoveal CNV associated with wet AMD, confirmed by fluorescein angiography (FA), in the study eye. Subjects with predominantly classic, minimally classic, or occult subtype CNV lesions were eligible for enrollment. Because the study aimed to target patients requiring frequent anti-VEGF therapy, a minimum frequency of rescue injections was stipulated in the period before enrollment: 3 injections in 6 months or 5 injections in 12 months. A complete list of eligibility criteria is given in Appendix I (available at http://aaojournal.org). One eye per participant was deemed the study eye and received EMB. If the participant had bilateral disease and both eyes were eligible for treatment, the eye with the worse VA was treated.
Schedule of Visits and Assessments All participants underwent a comprehensive screening evaluation to determine eligibility, which included a review of medical history including the dates of all prior anti-VEGF treatments, full refraction, determination of best-corrected VA (BCVA), examination of the anterior and posterior segments of the eye, lens grading using the Lens Opacification Classification System II,29 intraocular pressure measurement, fundus photography, FA, and optical coherence tomography. Independent digital angiography or fundus photography and optical coherence tomography reading centers evaluated all respective images (Digital Angiography Reading Center, New York, New York; Duke Reading Center, Durham, North Carolina). Best-corrected visual acuity was assessed using the protocol described in the Early Treatment Diabetic Retinopathy Study (ETDRS), using trial-certified examiners and testing rooms and ETDRS charts starting at 4 m distant from the participant.30 Patients deemed eligible based on these assessments underwent EMB within 14 days, as described below. Baseline BCVA was assessed on the day of surgery. Postoperative visits were scheduled 1 day and 1 week after surgery. Thereafter, safety and efficacy were evaluated monthly for 36 months after treatment.
Treatment Epimacular brachytherapy was performed as a single treatment at the baseline visit. Before treatment, the surgeon confirmed the location of the lesion using retinal vascular landmarks and a preoperative FA. Surgery was performed using either retrobulbar, peribulbar, or subTenon anesthesia, or general anesthesia if indicated. After lid specu-
Dugel et al 䡠 MERITAGE Study of Epimacular Brachytherapy for AMD Table 1. Demographics and Baseline Disease Characteristics of the Study Cohort (n ⫽ 53) Demographics Gender Male Female Ethnicity White Other Lens status at baseline Phakic Pseudophakic Mean age (yrs) Mean no. of previous anti-VEGF injections Mean baseline BCVA (ETDRS letters) Median baseline BCVA (ETDRS letters) Mean baseline lesion size (mm2)
been treated with ranibizumab or bevacizumab before enrollment were retreated with ranibizumab.
Statistical Analysis 15 (28.3) 38 (71.7) 50 (94.3) 3 (5.7) 22 (41.5) 31 (58.5) 78 (58–92) 12.5 (6–38) 51 (11–73) 55 14.9 (1.7–35.1)
The primary goals of this feasibility study were to describe the safety and preliminary efficacy of EMB in participants with neovascular AMD who require persistent injections of anti-VEGF therapy. Efficacy outcomes included the proportions of patients losing fewer than 15 and more than 30 ETDRS letters, as well as the proportion gaining more than 0 and more than 15 ETDRS letters, and change in mean BCVA from baseline at 52 weeks. The number of retreatments with anti-VEGF therapy also are reported. Safety outcomes included both solicited and nonsolicited adverse events recorded at each study visit. Results are presented as descriptive statistics.
Results BCVA ⫽ best-corrected visual acuity; ETDRS ⫽ Early Treatment Diabetic Retinopathy Study; VEGF ⫽ vascular endothelial growth factor. Data are presented as number (%) or mean (range), unless otherwise indicated.
lum placement, a standard 3-port pars plana vitrectomy was performed. Surgeons had discretion as to whether to perform a full vitrectomy or a core vitrectomy, removing enough vitreous to create an access channel to the retina for the device. Vitrectomies were performed with 20-gauge, 23-gauge, or 25-gauge systems, depending on the surgeon’s preference. If a posterior vitreous detachment was not present, the surgeon determined whether to induce a posterior vitreous detachment surgically. If a 23-gauge or 25-gauge system was used, then the temporal sclerotomy site was enlarged to accommodate the 20-gauge device. The neovascular complex was approached from the temporal side to minimize radiation exposure to the optic nerve. The surgeon then placed the delivery probe into the midvitreous cavity and instructed the assistant to engage the device, allowing the radiation source to travel down the cannula, near to the tip. The position where the radiation source stopped within the probe was etched with a cross. The cross then was positioned directly above the center of the CNV complex or over the area of greatest disease activity as demonstrated by FA, with the tip of the probe resting lightly on the surface of the retina. The prescribed radiation dose of 24 Gy then was delivered by precisely controlling the time that the tip was held in position above the neovascular complex. The treatment time required to delivery 24 Gy was determined from previous calibration of each device and was between 3 and 5 minutes, depending on the individual Sr90/Y90 source activity. After the prescribed radiation dose was delivered, the probe tip was moved to the midvitreous cavity, the radiation source was retracted, and the delivery probe was removed from the eye. The vitrectomy was concluded in a standard fashion, and the enlarged sclerotomy was sutured. An appropriate antibiotic and steroid regimen was administered in the subconjunctival space. Immediately after the procedure, a patch and shield were applied to the treated eye and a postoperative regimen of topical antibiotics, steroids, and cycloplegics were initiated from the following day. Participants were eligible for intravitreal anti-VEGF therapy at the conclusion of the EMB procedure and at each of the subsequent monthly follow-up visits if 1 or more of the retreatment criteria were met. The retreatment criteria are provided in Appendix II (available at http://aaojournal.org). At baseline, the observations used to decide on retreatment were compared with those acquired before enrollment; thereafter, comparisons were all in relation to observations made within the trial. Participants who had
Demographics Overall, 53 participants with neovascular AMD were enrolled in this trial. Demographic and baseline ocular and disease characteristics are given in Table 1. The mean duration of disease at the time of enrollment was 27.9⫾21.4 months, and patients had received an average of 12.5⫾7.6 intravitreal antiVEGF treatments before enrollment, with 1 patient receiving a maximum of 38 prior injections.
Efficacy The proportions of participants maintaining VA (losing ⬍15 ETDRS letters) over 12 months of follow-up is illustrated in Figure 1. The primary VA end point was met in 81% of participants at month 12. Four participants (7.5%) lost more than 30 ETDRS letters. The proportion of participants gaining more than 0 letters, and more than 15 letters are shown in Figure 1. At month
Figure 1. Graph showing the proportion of subjects with a loss of fewer than 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, gaining 1 or more ETDRS letters, and gaining 15 or more ETDRS letters after treatment with 24-Gy epimacular brachytherapy. All available data (n ⫽ 53). (, Losing less than 15 letters; , gaining 1 or more letters; , gaining 15 or more letters.)
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Ophthalmology Volume 119, Number 7, July 2012 Table 2. Common Adverse Events Deemed Possibly or Probably Related to Epimacular Brachytherapy in the Safety Population from Baseline to Month 12 (n ⫽ 53)
Figure 2. Graph showing the mean (⫾1 standard deviation) central retinal thickness (CRT) of the optical coherence tomography (OCT). The OCT images were read by an independent reading center at each time point. The mean CRT increased by 50 m over 12 months, from 186 to 236 m, but with substantial variability in response, as shown by the large error bars.
12, almost half of participants (47.2%) had some degree of visual improvement relative to baseline. Mean⫾standard deviation change in ETDRS BCVA at 3, 6, 9, and 12 months was – 0.1⫾11.6, – 0.6⫾10.1, –2.1⫾14.4, and – 4.0⫾15.1 ETDRS letters, respectively. The mean⫾standard deviation optical coherence tomography central retinal thickness was 186⫾123 m at baseline, and 236⫾202 m at 12 months, an increase of 50⫾179 m (Fig 2).
Injection Frequency Thirty-five subjects received an anti-VEGF injection at the time of EMB, reflecting baseline disease activity. During the following 12 months, a total of 185 retreatments were administered, with a mean of 3.49 injections (range, 0 –11) per subject (Fig 3). More than half of participants (31/53) needed no more than 3 injections, and more than 75% (41/53) needed no more than 5 injections over the 12-month period. The rate of intravitreal anti-VEGF injections before enrollment was 0.45 injections per participant per month. In the 12 months of this study, the comparable rate of retreatment was 0.29 injections per subject per month, but it should be noted that it is not known how closely the pre-enrollment retreatment criteria matched those used within the trial.
Figure 3. Bar graph showing the number of intravitreal ranibizumab retreatment injections in the study eye during the first 12 months of the study. The mean number of retreatment injections was 3.2. All available data (n ⫽ 53).
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Event Preferred Term (n ⴝ 53)
Number (%)
Relationship*
Cataract† Subconjunctival hemorrhage Retinal hemorrhage
3 (13.6) 3 (5.7) 3 (5.7)
Vitreous hemorrhage Anterior chamber cells
2 (3.8) 1 (1.9)
Possible (3) Possible (3) Probable (2), possible (1) Possible (2) Probable (1)
*As determined by the principal investigator. Development or progression of existing cataract. Cataracts were deemed serious if they warranted surgical removal. Calculated from subjects who were phakic at baseline (n ⫽ 22).
†
Safety Epimacular brachytherapy was safe and well tolerated by most subjects. Adverse events generally were mild to moderate in intensity and were unrelated to EMB. Adverse and serious events determined by the principal investigator as possibly or probably related to EMB or to the vitrectomy procedure are given in Tables 2 and 3. The most common were subconjunctival hemorrhage (38 subjects), cataract development or progression (16 subjects), vitreous hemorrhage (6 subjects), and ocular pain or discomfort (5 subjects). Cataract surgery was performed on 59% (13/22) of phakic subjects in the first 12 months. In this 12-month follow-up, there were no cases of radiation retinopathy or microvascular changes observed by the investigators, medical monitors, or the independent FA reading center. Because radiation-related retinal changes can manifest over many years, these subjects will continue to be followed up closely with examination and FA and photography at intervals up to 36 months.
Discussion The emergence of anti-VEGF therapy has driven a paradigm shift in the management of neovascular AMD during the past decade. The landmark MARINA2 and ANCHOR3 trials of ranibizumab demonstrated for the first time that VA could be stabilized in most patients, and vision improvement was seen in a substantial proportion.2,3 Optimal efficacy outcomes, however—including the maintenance of VA gains—were achieved using monthly therapy. Many studies showed that reducing to an as-needed dosing regimen resulted in inferior vision gains and suboptimal maintenance of vision (Brown DM, Wang PW, Scott LC. HORIZON extension trial of ranibizumab for wet AMD: subanalysis of year 1 results [abstract P0248]. Paper presented at: AAO/SOE Joint Annual Meeting, November 8 –11, 2008; Atlanta).31,32 The Comparisons of Age-Related Macular Degeneration Treatments Trials study reported that visual outcomes were similar when comparing as-needed versus monthly dosing but still mandated monthly clinic or hospital review, and patients received approximately 7 to 8 as-needed injections per year.5 Furthermore, not all patients respond to anti-VEGF therapy, and sometimes those who initially respond subsequently lost vision, perhaps because
Dugel et al 䡠 MERITAGE Study of Epimacular Brachytherapy for AMD Table 3. Common Adverse Events Deemed Possibly or Probably Related to Vitrectomy in the Safety Population from Baseline to Month 12 (n ⫽ 53) Event Preferred Term (n ⴝ 53) Cataract† Subconjunctival hemorrhage/hyperemia Vitreous hemorrhage
Number (%) 16 (72.7) 38 (71.7) 6 (11.3)
Anterior chamber cells
5 (9.4)
Eye pain/discomfort
5 (9.4)
Corneal edema
4 (7.5)
Eye irritation Retinal hemorrhage Headache Hypotony of globe Corneal erosion Ecchymosis Floaters
4 (7.5) 2 (3.8) 2 (3.8) 1 (1.9) 1 (1.9) 1 (1.9) 1 (1.9)
Relationship (n)* Probable (16) Probable (36), possible (2) Probable (3), possible (3) Probable (4), possible (1) Probable (4), possible (1) Probable (1), possible (3) Probable (4) Possible (2) Possible (2) Probable (1) Probable (1) Probable (1) Possible (1)
*As determined by the principal investigator. Development or progression of existing cataract. Calculated from subjects who were phakic at baseline (n ⫽ 22).
†
of tachyphylaxis33 or some other unidentified factor. For example, responder analysis of the SUSTAIN study of ranibizumab showed that 47% of patients did not manifest any improvement in vision or lost the initial gain they achieved.34 Given that not all patients respond to antiVEGF therapy, and even those who do face a burdensome treatment regimen, there is an unmet need for a treatment that reduces disease activity in a more durable manner. The preliminary safety and efficacy results using EMB support its potential role in meeting this need. Participants in this study had been treated with ranibizumab or bevacizumab before enrollment and were required to meet minimum prior injection criteria before enrollment. As a result, this study selectively recruited participants with the most active disease who otherwise might be predicted to have a poor outcome. This differs from studies that recruited treatment-naïve disease, where the case mix may be more typical. Further, most studies of treatment-naïve disease show an initial improvement in VA that is at best stable over time—results seldom exceed the peak in mean vision observed toward the start of therapy. For this reason, it is difficult to show an improvement in mean vision in patients who already are receiving anti-VEGF therapy. Despite this, the proportion of eyes maintaining VA (losing ⬍15 ETDRS letters) was 81% 12 months after EMB. This stability of BCVA in the current study was maintained with an average of only 3.49 intravitreal anti-VEGF injections over 12 months. The apparent reduction in demand for antiVEGF therapy is of interest, given that vitrectomy is known to reduce drug half-lives and would be expected to reduce the duration of action of ranibizumab.35 This observation, however, should be interpreted with caution, because this study did not have a control arm, and it is difficult to compare the
treatment before enrollment with that occurring subsequently within the context of a clinical trial. Although the reinjection frequency was less than that of the as-needed arms of the Comparisons of Age-Related Macular Degeneration Treatments Trials study,5 that study had more aggressive retreatment criteria that would tend to produce a better visual outcome, but a higher frequency of injections. If EMB reduces the frequency of injections, then this may have important implications for patient safety. With anti-VEGF monotherapy, both drug-related and injectionrelated adverse events are cumulative over multiple injections. It may be that the surgical and radiation-related risks associated with EMB are offset by reduced exposure to anti-VEGF retreatment. This study cannot determine if any reduction in demand for anti-VEGF retreatment might have translated to fewer hospital visits, because all patients underwent mandated monthly review within the study. In the current study, only 10 serious adverse events were deemed related to the device; of these, 7 (70%) were cataract related and resolved without sequelae on cataract extraction. The confounding effect of cataract formation occurring after pars plana vitrectomy potentially is important. At 12 months, 59% of phakic patients had undergone cataract surgery. It is possible that this artificially lifts the mean vision, if mild pre-existing lens opacity is removed, despite the fact that patients with significant lens opacity were excluded. Alternatively, the 41% of patients who remained phakic at 12 months may have reduced the mean vision because of lens opacity that did not yet warrant surgery. What is of note, however, is that the participants who were pseudophakic from baseline had a similar vision outcome to the phakic population, with 80% losing fewer than 15 letters and a mean vision of –3.8 ETDRS letters. The high incidence of cataract is to be expected, given the known association with vitrectomy. It seems unlikely that the cataract was the result of radiation, because the threshold for cataract formation is reported as 2 Gy,36 and EMB exposes the lens to a much lower dose of only 0.0056 Gy. This feasibility study of EMB had no control group. As such, it is difficult to attribute all adverse events to treatment versus other causes, such as the underlying disease process or common comorbidities. Although it is assumed that this cohort of patients would have tended to have had a poor outcome with continued monotherapy, the lack of a control arm means that this assumption cannot be validated with this study. It should also be noted that radiation retinopathy may not present within the first year of treatment, and patients will be followed up for 3 years. In light of these limitations, the efficacy and safety results observed in this study should be used primarily to support further evaluation of this innovative therapeutic method for patients with neovascular AMD.
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Ophthalmology Volume 119, Number 7, July 2012 2. Rosenfeld PJ, Brown DM, Heier JS, et al, MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419 –31. 3. Brown DM, Michels M, Kaiser PK, et al, ANCHOR Study Group. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: twoyear results of the ANCHOR Study. Ophthalmology 2009; 116:57– 65. 4. Tufail A, Patel PJ, Egan C, et al, ABC Trial Investigators. Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study [report online]. BMJ 2010;340:c2459. Available at: http://www. bmj.com/content/340/bmj.c2459?view⫽long&pmid⫽20538634. Accessed December 31, 2011. 5. CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364:1897–908. 6. Engelbert M, Zweifel SA, Freund KB. Long-term follow-up for type 1 (subretinal pigment epithelium) neovascularization using a modified “treat and extend” dosing regimen of intravitreal antivascular endothelial growth factor therapy. Retina 2010;30:1368 –75. 7. Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular agerelated macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol 2009;148:43–58. 8. Chakravarthy U, Houston RF, Archer DB. Treatment of agerelated subfoveal neovascular membranes by teletherapy: a pilot study. Br J Ophthalmol 1993;77:265–73. 9. Rubin DB, Drab EA, Kang HJ, et al. WR-1065 and radioprotection of vascular endothelial cells. I. Cell proliferation, DNA synthesis and damage. Radiat Res 1996;145:210 – 6. 10. Hosoi Y, Yamamoto M, Ono T, Sakamoto K. Prostacyclin production in cultured endothelial cells is highly sensitive to low doses of ionizing radiation. Int J Radiat Biol 1993; 63:631– 8. 11. Krishnan L, Krishnan EC, Jewell WR. Immediate effect of irradiation on microvasculature. Int J Radiat Oncol Biol Phys 1988;15:147–50. 12. Mooteri SN, Podolski JL, Drab EA, et al. WR-1065 and radioprotection of vascular endothelial cells. II. Morphology. Radiat Res 1996;145:217–24. 13. Rosander K, Zackrisson B. DNA damage in human endothelial cells after irradiation in anoxia. Acta Oncol 1995;34:111– 6. 14. Verheij M, Koomen GC, van Mourik JA, Dewit L. Radiation reduces cyclooxygenase activity in cultured human endothelial cells at low doses. Prostaglandins 1994;48:351– 66. 15. Hallahan D, Clark ET, Kuchibhotla J, et al. E-selectin gene induction by ionizing radiation is independent of cytokine induction. Biochem Biophys Res Commun 1995;217:784 –95. 16. Eissner G, Kohlhuber F, Grell M, et al. Critical involvement of transmembrane tumor necrosis factor-alpha in endothelial programmed cell death mediated by ionizing radiation and bacterial endotoxin. Blood 1995;86:4184 –93. 17. Chakravarthy U, Gardiner TA, Archer DB, Maguire CJ. A light microscopic and autoradiographic study of non-irradiated and irradiated ocular wounds. Curr Eye Res 1989;8:337– 48. 18. Archer DB, Amoaku WM, Gardiner TA. Radiation retinopathy— clinical, histopathological, ultrastructural and experimental correlations. Eye (Lond) 1991;5:239 –51. 19. Parsons JT, Fitzgerald CR, Hood CI, et al. The effects of irradiation on the eye and optic nerve. Int J Radiat Oncol Biol Phys 1983;9:609 –22. 20. Jaakkola A, Heikkonen J, Tommila P, et al. Strontium plaque brachytherapy for exudative age-related macular degeneration:
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Dugel et al 䡠 MERITAGE Study of Epimacular Brachytherapy for AMD
Footnotes and Financial Disclosures Originally received: July 5, 2011. Final revision: January 8, 2012. Accepted: January 9, 2012. Available online: March 30, 2012.
Timothy L. Jackson - Financial support - NeoVista, Inc. Pravin Dugel - Financial support, Equity owner - NeoVista, Inc. Manuscript no. 2011-994.
Michael Bennett - Financial support - NeoVista, Inc.
1
Retinal Consultants of Arizona, Phoenix, Arizona.
Dov Weinberger - Financial support - NeoVista, Inc.
2
King’s College Hospital, London, United Kingdom.
Adiel Barak - Financial support - NeoVista, Inc.
3
King’s College London, United Kingdom.
Jeffrey Nau - Employee, Patents - NeoVista, Inc.
4
Retina Institute of Hawaii, Honolulu, Hawaii.
5
Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
This work forms part contribution to a MDRes degree at King’s College London (RP).
6
Rabin Medical Center, Tel Aviv, Israel.
7
NeoVista, Newark, California. Financial Disclosure(s): The author(s) have made the following disclosure(s):
Correspondence: Timothy L. Jackson, PhD, FRCOphth, King’s Health Partners, Department of Ophthalmology, King’s College Hospital, London SE5 9RS, United Kingdom. E-mail: [email protected].
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