British Journal of Radiology (2005) 78, 827-831
© 2005 British Institute of Radiology
doi: 10.1259/bjr/17631422
A phase I trial of stereotactic external beam radiation for subfoveal choroidal neovascular membranes in age-related macular degeneration
A Barak, MD1,
D Hauser, MD1,
P Yipp1,
L Morse, MD, PhD1,
B Leigh, MD2,
D Kubo, PhD2,
Z Goldberg, MD2,
J Earle, MD2 and
J T Handa, MD1
Departments of 1 Ophthalmology and 2 Radiation Oncology, UC Davis, Sacramento, CA, USA
Correspondence: Dr Adiel Barak, Department of Ophthalmology, Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv, 64239, Israel
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Abstract
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Effective treatment for neovascular age-related macular degeneration (AMD) is currently limited. Radiation therapy, a therapeutic approach with known antiangiogenic properties, has been investigated as a modality to prevent severe visual loss in AMD. Most of the studies using external beam radiation employed <25 Gy to the whole eye, which is below the dose of radiation that is toxic to the retina and optic nerve ( 
50 Gy and 59 Gy, respectively). Stereotactic fractionated external beam radiation (St-EBR) is a method that allows radiation to be delivered to a small, defined area. We investigated the effects of St-EBR in incremental doses up to 40 Gy on neovascular AMD. Patients with clinical signs and fluorescein angiography demonstrating neovascular AMD, visual acuity (VA) better than 20/400 and ineligible for laser treatment (MPS criteria) or who refused to have laser photocoagulation were enrolled in the study. Each patient was treated with radiation at incremental dosages from 20 Gy to 40 Gy. After completion of the radiation course, all patients were followed-up at 3 and 7 weeks and 3, 6, and 12 months. Best-corrected VA (ETDRS), slit-lamp and fluorescein angiographic evaluations were performed at each visit. 94 eyes of 89 patients were treated from October 1997 to April 2000. The VA was 0.82±0.35 before treatment, 0.83±0.36 at 6 months, and 0.89±0.33 at 12 months. No patients suffered any significant acute side effects. No significant benefits in either VA or in membrane size were derived from increasing the doses of radiation. Our results are consistent with trends of a palliative benefit of radiotherapy in neovascular AMD and support further investigation of radiotherapy. Since there is no evidence that therapeutic effectiveness is dose dependent, our data provide no justification for potentially dangerous escalations in radiation dosage for treating neovascular AMD.
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Introduction
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Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in Western societies. Neovascular AMD, characterized by choroidal neovascularization, occurs in a minority of patients, but accounts for 90% of registered blindness in AMD [1]. Treatment of neovascular AMD located in the fovea is a significant problem for ophthalmologists today. Photodynamic therapy with Verteporfirin® (Novartis AG, Basel, Switzerland) is an effective treatment for a select group of patients [2], but only a fraction of eyes meet the eligibility criteria for such therapeutic interventions, and those which had been treated have high recurrence rates. Thus, additional treatments for neovascular AMD are required. Low-dose whole eye radiation has been a potential treatment for neovascular AMD since the initial report of Chakravarthy et al in 1993 [3]. Most clinical studies have employed external beam irradiation using standard fractions of approximately 2 Gy to a total of 10–20 Gy for new subfoveal neovascular AMD. A large number of studies on this approach have been performed, and the reported results have been mixed [4–7]. The nine well-controlled, randomized published studies comparing radiation with observation [8–16] do not provide satisfactory evidence that external beam radiotherapy is an effective treatment for neovascular AMD [17]. Analysis of the collective results, however, indicates that dose per fraction is important. Bergink et al [8] reported that 52% of observed eyes versus 32% of treated eyes experienced a 3-line loss of vision at 1 year following treatment with 4 fractions of 6 Gy. In a small clinical trial involving 27 patients with varying lengths of follow-up, Char et al [10] reported fewer incidences of vision loss among patients treated with 1 fraction of 7.5 Gy proton beam irradiation than among observed patients.
The dose of radiation that is toxic to the retina and optic nerve is 50 Gy and 59 Gy, respectively, when given in divided daily doses of 1.8–2 Gy [18]. Doses in excess of 40 Gy for orbital and conjunctival lymphoma were clearly safe to the eye. One potential limiting factor for delivering increased radiation, however, is the unwanted irradiation of normal ocular structures adjacent to the neovascular AMD. As an alternative, we became interested in using a non-invasive delivery of external beam radiation that could be focused to a defined area in an attempt to reduce such unwanted irradiation.
Stereotactic fractionated external beam radiation (St-EBR) is a method that allows radiation to be delivered to a small, defined area. In fact, this approach could theoretically deliver radiation to a 13 mm diameter area of the fovea. We hypothesized that higher doses of radiation than previously utilized would be needed to reduce visual loss from neovascular AMD. Evaluation of the safety of this therapeutic approach would need a double blind, randomized trial. Therefore, we designed a phase I study to examine the safety and feasibility of using high energy St-EBR on eyes with neovascular AMD. The primary outcome was the appearance of any dose-related complications in AMD patients treated with St-EBR in escalating doses. The secondary outcome was the ability of a maximum dose of radiation to stabilize or improve vision in patients with subfoveal neovascular AMD.
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Methods
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Study design
The aim of our study was to report the results of a 12-month follow-up of applying St-EBR for subfoveal neovascular AMD. The protocol for this prospective study was approved by the Ethical Committee of the University of California, Davis. Informed consent was obtained from patients after a detailed discussion of treatment outcomes and alternative treatments of exudative AMD by an ophthalmologist, and a detailed discussion of radiation therapy, the risks and possible complications of radiation by a radiation oncologist. The selection and control of the patients were performed in the department of ophthalmology. The treatment was performed in the department of radiation oncology.
Patient selection and eligibility criteria
To be eligible for this study, patients had to have a best corrected visual acuity (VA) of 20/400 or better using an Early Treatment Diabetic Retinopathy Study (ETDRS) chart, to demonstrate clinical signs of AMD such as drusen, characteristic retinal pigment epithelial derangement, and to have ophthalmoscopic (subretinal fluid, haemorrhage, hard exudates, pigment epithelial detachment, grey-green subretinal membrane) and fluorescein angiographic evidence of a subfoveal neovascular AMD. The choroidal neovascular membranes which were considered for treatment were those that did not meet the Macular Photocoagulation Study Group criteria of small well-defined neovascular AMD. Alternatively, patients could be enrolled if they did not want foveal laser photocoagulation. At the beginning of the study (1998), we did not exclude patients with predominantly classic neovascular AMD from participating in the study but, after approval of Verteporfirin®, these patients were excluded and were offered photodynamic therapy for treatment of their membrane. Exclusion criteria included having a choroidal neovascular membrane from an eye disease other than AMD or another ophthalmoscopic disease that could contribute to loss of vision, such as visually significant cataract, pseudophakic bullous keratopathy or other retinal disease, and prior history of radiation or chemotherapy treatment.
Baseline evaluation
Each patient had an extensive ophthalmological evaluation and gave a comprehensive history. The ocular exam included best-corrected VA using the ETDRS chart and carried out by a certified technician, an Amsler grid evaluation, comprehensive slit-lamp biomicroscopy of the anterior segment, and slit-lamp biomicroscopy and indirect ophthalmoscopy of the retina. Fluorescein angiography using a Topcon TRC 50X Fundus camera (Paramus, NJ) interfaced to the Ophthalmic Imaging System was used on every patient. Indocyanine green angiography was performed for clinical identification of neovascular AMD only as needed according to clinical impression, and not considered indicated for the study nor analysed in our results.
Delivery of radiation by the stereotactic fractionated method
Each study patient underwent a consultation with the radiation oncologists at UC Davis Medical Center. A custom-made aquaplast mask (BrainLAB) was used to immobilize the patient's head. Treatment planning included CT and a standardized three-field treatment plan. The treated fields included an ipsilateral inferior oblique, a contralateral superior oblique, and a vertex beam that avoided the contralateral eye. The target volume (macula) was 5 mm in maximum diameter. The circular radiation beam provided a 4 mm margin of normal tissue around the gross target volume, resulting in a standard collimator diameter of 13 mm. The macula and adjacent tissues of the involved eye received 20, 24, 28, 32, 36, and 40 Gy delivered 5 days per week at 2 Gy daily. The doses were prescribed and calculated at the intersection of the central axes of the beams (isocentre). A 6 MV photon beam was delivered from the Varian 600C linear accelerator (Varian, Palo Alto, CA). During the radiation treatments, the patient focused on a light source fixed to the treatment room ceiling directly above the treated eye so that the horizontal beam did not obliquely intersect the lens of the eye, the most radiosensitive tissue. All treatments began within 2 weeks of enrollment in the study.
Patient follow-up
Follow-up examinations were scheduled at 3 and 7 weeks, 3 and 6 months, and every 6 months after completion of the radiation treatment. The patients underwent best corrected ETDRS VA measurement, Amsler grid evaluation, afferent pupillary defect evaluation, slit-lamp biomicroscopy of the anterior segment, and slit-lamp biomicroscopy and indirect ophthalmoscopy of the retina. Special attention was paid to identify any signs of radiation keratitis, increase in cataract, optic neuropathy or radiation retinopathy, which may be related to the radiation treatment. Fluorescein angiography was performed at each visit, and the graph was analysed with special attention on identifying any presentation of radiation retinopathy.
Evaluation of neovascular AMD size
An angiographic image from the high-resolution digital fundus imaging system was selected that showed the extent of the neovascular AMD and the optic disc, and it was imported into a PCX file format. The image was subsequently imported into the University of Texas Health Science Center at San Antonio (UTHSCSA) ImageTool 32-bit image analysis program operating in a Windows NT Workstation 4.0 (this program is available on the Internet by anonymous FTP from ftp://maxrad6.uthscsa.edu). The image was sharpened, the contrast was enhanced, the outline of the membrane was drawn manually on the image and the membrane surface was calculated. The outline of the disc was also drawn and saved. Measurements were imported into an Excel 7.0 spreadsheet for analysis. To correct for magnification error, the disc/neovascular AMD ratio was calculated for each image. The pre-treatment neovascular AMD size was defined as 100%, and all post-treatment measurements were assessed relative to that baseline
Statistical method
The difference in the best-corrected VA and the neovascular AMD size at baseline and after 6 and 12 months of follow-up was analysed as a continuous variable. All VAs were recorded on a standardized ETDRS chart and reported in the results section as Log MR. Summary statistics, such as mean, median and standard deviation (SD), were generated. The non-parametric Mann-Whitney U-test compared the changes in VA and differences in neovascular AMD size subgroups.
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Results
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A total of 94 eyes of 89 patients were treated from October 1997 to April 2000 (both eyes of five patients were treated during the study due to the evolvement of new neovascular AMD in the second eye after completion of treatment for the first eye). 22 eyes received 20 Gy radiation, 10 eyes received 24, 11 eyes received 28 and 32 Gy, eight eyes received 36 Gy, respectively, and 32 eyes received 40 Gy. Of the 89 treated patients, 92% returned for the 6 months follow-up and 82% returned for the 12-month follow-up. The baseline characteristics of all study patients appear in Table 1
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No patients suffered any significant acute side effect. One patient who received 20 Gy radiation, however, had massive pre-retinal and subretinal bleeding with iris rubeosis 14 months after completion of radiation, and subsequently developed neovascular glaucoma, an effect which could be due to radiation retinopathy. No cases of radiation keratitis, cataract, or optic neuropathy were identified.
The mean pre-treatment VA was 0.82±0.35, with no significant gender or dosage related differences. The mean VA was 0.83±0.36 at 6 months and 0.89±0.33 at 12 months. Figure 1 demonstrates the distribution of mean VA change of patients in the different dosage categories 12 months after radiation: there was no significant change in the VA of any of the treated patients. Figure 2 shows the percentage of patients who lost 3 and 
6 lines at 12 months following treatment: the VA remained within ±3 lines of baseline values in 82% of the study patients.
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Figure 1. The distribution of mean visual acuity (VA) change (y-axis, Log MAR) of patients in the different dosage categories (x-axis, Gy) 12 months after radiation. The mean VA before treatment was 0.82±0.35, with no significant difference among dosage groups. The mean VA was 0.83±0.36 at 6 months and 0.89±0.33 at 12 months. There was no significant change in VA in any treated patient.
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A comparison between the percentage of patients who lost 3 and 6 lines at 12 months following treatment and the number of eyes that received escalating doses of radiation revealed no significant change (p=0.43) among the treatment groups. In other words, higher doses did not bestow a better outcome.
There was a significant increase in membrane size at the end of the 1 year follow-up. The initial membrane size was 5.5±5.03 disc areas, and this value increased 1.3-fold (range 0.4–10.3 disc area) (p=0.017). The significant increase in membrane size was seen among all treated patients, with no change in the eyes that received escalating doses of radiation (p=0.28).
We could not detect any difference in treatment outcome between eyes with predominantly classic AMD according to treatment of AMD with photodynamic therapy (TAP) criteria (n=20) and eyes with occult neovascular AMD (n=74). There was also no significant difference between the final visual outcome and change in VA among the two groups (p=0.22). Again, an escalating dose did not induce any change in treatment outcome.
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Discussion
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In the current study, we demonstrated that high-energy St-EBR has no short-term side effects (up to 1 year) after treatment for neovascular AMD. Escalating doses of radiation conferred no treatment benefits in terms either of VA or membrane size increase.
The ability of the stereotactic fractionated technique to deliver an increased dose within a limited area reduces the potential morbidity associated with high-dose radiation and obviates the need for surgical intervention, i.e. plaque brachytherapy. One patient in our study suffered massive sub-retinal bleeding 14 months after completion of the course of radiation. We cannot exclude the possibility that this patient represents a severe case of radiation-associated choroidal neovascularization as described by Spaide et al [19]. Therefore, we classified this patient as having had a possible complication of the radiation-associated choroidal neovascularization. Our results differ from the Zurich group [20, 21], which terminated a study of high dose EBR (36 Gy) due to radiation-induced retinopathy in 4 out of the 16 enrolled patients. We believe that the high accuracy of the stereotactic delivery system may be responsible for the lack of change in our patients. Radiation-induced retinopathy, however, usually occurs more than 12 months after termination of the treatment, thus further follow-up is mandatory for analysing the long-term outcome.
Due to the study design, which did not include a control group, we must be cautious in interpreting the effects of radiation therapy on VA. Our data clearly indicate that there was no significant decrease in acuity at the 12-month follow up. Among our study patients, 20% lost 3 or more lines of VA while 10% lost 6 lines of VA. In 80% of the patients, however, the VA remained within ±3 lines of the baseline VA. When comparing our data with previously reported changes in VA with occult neovascular AMD, it emerges that the percentage of patients in our study with a moderate loss of acuity (up to 3 lines) was comparable with that previously reported at a similar time point (20% vs 19.5%) [22, 23]. The percentage of patients with severe visual loss, however, was markedly lower than that reported by others [23, 24] (10% vs 47% and 31%, respectively). Finally, we could not detect any significant benefits either in VA changes or in membrane size derived from escalating the dose from 20 Gy to 40 Gy.
Our study suffers from several limitations. Our sample size is small and there is no control group. In addition, radiotherapy outcomes for neovascular AMD may have an effect later than 1 year following treatment, thus a longer follow-up is needed to draw any conclusion on treatment outcome. Despite these limitations, if our results are confirmed by other studies, potentially dangerous escalations in radiation dosage might be avoided in using this treatment for neovascular AMD.
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Footnotes
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Current address for Dr James T Handa, Wilmer Eye Institute, Baltimore, MD, USA. 
Grant support: Unrestricted grant from Research to Prevent Blindness, New York City, NY, USA.
Received for publication November 13, 2003.
Revision received November 29, 2004.
Accepted for publication April 5, 2005.
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Abstract
Introduction
