Background and objective To describe ‘radiation-first’ combination treatment with a non-invasive, low-voltage x-ray irradiation system followed by as needed ranibizumab for neovascular age-related macular degeneration (AMD).
Study design and methods Phase I study of non-invasive, low-voltage 16 Gy x-ray irradiation delivered in three beams via the inferior pars plana in patients with active neovascular AMD. Ranibizumab was administered as needed per protocol. Patients were followed monthly for safety and efficacy over 12 months.
Results 13 patients were enrolled and completed 12 months follow-up. Safety was good with no serious ocular/non-ocular adverse events or radiation-related ocular complications. 11 patients lost <15 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters, seven gained ≥0 ETDRS letters and 0 gained ≥15 ETDRS letters. Patients received a total of 31 subsequent ranibizumab injections (of possible 156) over the 12 months following x-ray irradiation. Mean time to first injection was 3.9 months. One patient received no ranibizumab injections, three patients received one injection, four patients received two injections, and five patients received three or more injections.
Conclusions After 12 months, non-invasive, low-voltage x-ray irradiation with as needed ranibizumab rescue therapy demonstrated good safety with a visual acuity stabilising effect and reduction in retinal thickness in patients with neovascular AMD.
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There is ample historical evidence that treatment with external beam radiation therapy1–12 and plaque brachytherapy13–18 for neovascular age-related macular degeneration (AMD) can prevent progression of choroidal neovascular membranes (CNV). Unfortunately, the visual acuity results have been less impressive, and this is likely due to inaccurate targeting in the case of external beam radiotherapy or difficulty in optimising the seed placement in plaque brachytherapy. Recently, positive results have been described using a novel method of delivering strontium-90 (Sr-90) brachytherapy (Vidion, NeoVista, Inc., Newark, California, USA) by a transvitreal surgical approach that applies the radiation source directly to the retina, overlying the CNV.19 ,20 The Sr-90 epimacular surgical technique virtually eliminates the targeting uncertainty with respect to localisation that marred the earlier radiation studies.19 ,20
Oraya Therapeutics, Inc. (Newark, California, USA) has developed a novel, non-invasive, low-voltage x-ray irradiation system (IRay) for the treatment of neovascular AMD. This system has been described in detail previously.21 In brief, it consists of the following components: (1) a precision-controlled x-ray tube, (2) a patient interface, (3) an eye stabilising device that optically couples the patient's eye to the x-ray delivery system, (4) an eye tracking system that monitors X, Y and rotational movements of the eye for dose determination and safety gating, (5) graphical user interface and (6) treatment planning software. This system is intended for the clinic or ambulatory surgery centre without additional shielding requirements, minimising the reconfiguration of the physician's facility. The patient is seated at the device with the treatment eye held in position with a contact lens connected to an active suction apparatus (I-Guide, Oraya Therapeutics, Inc., Newark, California, USA).22 Eye tracking is performed using infrared cameras in conjunction with reflective fiducials on the I-Guide.22 If the patient's eye exceeds predetermined threshold movements in the X, Y, Z planes or rotational angles, as indicated by actively-tracked lens fiducials, the device will gate, and will immediately interrupt the delivery of radiation.22 The system is designed to place three overlapping 4 mm x-ray beams to a specified point in space that corresponds to the patient's macula, as determined by a treatment planning algorithm using globe axial length. Actual dose distribution is calculated from analysis of the ocular movements during the treatment session.
We recently published 6 months safety and efficacy data from a phase I trial using two different treatment strategies: (1) 16 Gy radiation plus two loading injections of ranibizumab, followed by monthly as needed ranibizumab and (2) 16 Gy radiation followed by monthly as needed ranibizumab.21 ,23 In this paper, we discuss the extended follow-up of this novel, stereotactically-targeted, low-voltage x-ray therapy in patients with neovascular AMD who received the radiation-first strategy. By providing initial x-ray irradiation monotherapy to the macula in these patients, we were able to isolate the effects of radiation alone on the CNV in the short term, and evaluate safety and visual outcomes after 1 year of therapy.
Patients and methods
This was a prospective, non-randomised, open-label, safety study of low-voltage, stereotactic radiotherapy in patients with neovascular AMD. Approval from the Institutional Review Board of Associacion Para Evitar La Ceguera En Mexico, I.A.P., Mexico City, Mexico, and the Government of Mexico for the use of the IRay (Oraya Therapeutics, Inc.) radiation device for this trial of patients with neovascular AMD was obtained prior to the start of the study. The main outcome measure was the development of ocular and non-ocular adverse events. Secondary outcome metrics included proportion of patients losing more than 15 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters of visual acuity at 12 months compared with baseline, mean change in ETDRS visual acuity from baseline, mean change in central retinal thickness on optical coherence tomography (OCT) and mean change in CNV lesion size on fluorescein angiography (FA).
Inclusion criteria were as follows: subjects had to be age 50 or older; women had to be postmenopausal ≥1 year or be surgically sterilised; subjects must have had choroidal neovascularisation lesion size of ≤11 total disc areas (28.26 mm) and a greatest linear dimension of ≤6 mm; subjects must have had ETDRS best corrected visual acuity of 69–24 letters (20/40–20/320 Snellen equivalent) in the study eye; and subretinal haemorrhage (if any) must not have comprised more than 50% of total lesion size and may not involve the subfoveal space. Exclusion criteria were as follows: subjects with prior or concurrent therapies including submacular surgery; subjects who received prior thermal laser photocoagulation (with or without photographic evidence); subjects who received prior photodynamic therapy and/or transpupillary thermotherapy; subjects who demonstrated concomitant disease in the study eye, including uveitis, diabetic retinopathy, presence of retinal pigment epithelium tears or rips, acute ocular or periocular infection; subjects with advanced glaucoma (>0.8 cup to disk ratio) or intraocular pressure ≥30 mm Hg in the study eye; subjects who underwent previous glaucoma filtering surgery in the study eye; subjects who had a refractive error in the study eye of more than 8 dioptres of myopia (or globe axial length ≥26 mm); subjects who underwent prior refractive or cataract surgery in the study eye, in whom the preoperative refractive error could not have exceeded 8 dioptres of myopia; and subjects with any retinal vasculopathies, including diabetic retinopathy, retinal vein occlusions or other similar potentially confounding conditions (as determined by the screening investigator) in the study eye. Patients underwent baseline clinical examination, intraocular pressure determination, best-corrected protocol visual acuity testing using ETDRS starting at 4 m, spectral domain OCT (Cirrus HD-OCT, Carl Zeiss Meditec, Dublin, California, USA) and FA. The OCT images were evaluated by a faculty consultant at Stanford University (Palo Alto, California, USA), and the angiograms were evaluated by a faculty consultant at the University of Wisconsin (Madison, Wisconsin, USA). After meeting all inclusion and exclusion criteria and signing a written informed consent, radiation therapy was administered to the study subjects. This consisted of one fraction of 16 Gy delivered in three sequential beams over approximately 15 min. The total x-ray exposure time approximated 3 min for each treatment. Follow-up examinations were scheduled at 1 week, 1 month, 5 weeks and monthly thereafter, up to an anticipated 24 month follow-up period. The 5 week follow-up visit was an added safety visit that was used in our other clinical trials that used adjuvant antivascular endothelial growth factor (VEGF) therapy prior to x-ray exposure (approximately 1 month following anti-VEGF administration). Patients in that study were examined 1 week after x-ray exposure to check for ocular safety metrics. This visit was kept in this study for the purposes of future study comparison.23 Examinations included evaluation for adverse events, best-corrected protocol visual acuity, clinical assessment and OCT testing. Additionally, FA was repeated at 3-month intervals in the first year (and at 6-month intervals in the second year.) Intravitreal ranibizumab (Lucentis, Genentech, South San Francisco, California, USA) rescue therapy was offered beginning 1 month following radiotherapy if any of the following criteria were met: (1) loss of ≥10 ETDRS letters compared with previous visit, in conjunction with persistent fluid on OCT, (2) increase of ≥100 microns central subfield thickness on OCT compared with previous visit, (3) development of a new subretinal haemorrhage in the macula and (4) development of new classic choroidal neovascularisation on FA. Ranibizumab could be administered no more frequently than every 4 weeks as indicated.
Thirteen patients were enrolled in the clinical trial (table 1). All 13 patients completed 12 months of follow-up that is described in this report. Patients ranged in age between 62 and 86 years (mean 72.7±7 years). Eight women and five men participated in this pilot study; all of Hispanic origin (table 1). All patients except for one were treatment-naive for subfoveal CNV due to neovascular AMD. This one patient, a protocol deviation, received three intravitreal bevacizumab injections prior to study enrolment; the last bevacizumab injection was approximately 2 months prior to study entry. Despite extensive history taking during the screening visit, this patient's previous treatment with intravitreal bevacizumab was only discovered incidentally after study enrolment of this subject. All patients received one radiation treatment without complications. Twelve patients received a total of 31 ranibizumab injections at various points throughout the 12 months following radiation treatment. Mean time to first injection was 3.9 months. One patient received no ranibizumab injections, three patients received one injection, four patients received two injections and five patients received three or more injections (figure 1).
Safety in this study was good with no serious ocular adverse events and no serious non-ocular adverse events reported. Specifically, no arteriothromboembolic events, endophthalmitis or evidence of radiation-related adverse events were noted. Asymptomatic and self-limited superficial punctate keratopathy was observed in 10 of 13 patients following the study procedure, likely due to the I-Guide device.
Secondary outcome: visual acuity
Baseline study subject characteristics are listed in table 1. The mean baseline ETDRS score was 45.5±17.5 letters (range, 18–73 letters, Snellen equivalent ∼20/200). At 12 months, the mean ETDRS score was 45.2±17.6 letters (range, 22–80, Snellen equivalent ∼20/200). Eleven patients lost <15 ETDRS letters, seven gained ≥0 ETDRS letters and no patient gained ≥15 ETDRS letters (figures 2 and 3).
Secondary outcome: OCT and FA assessment
The mean baseline OCT central subfield thickness measurement was 365 microns (range, 193–740 microns). Mean OCT central subfield thickness was 361 microns (range, 166–598 microns) at month 1; 299 microns (range, 151–442 microns) at month 3; 261 microns (range, 156–423 microns) at month 6; 258 microns (range, 158–509 microns) at month 9; and 293 microns (range, 183–453 microns) at month 12. The mean change in OCT central subfield thickness from baseline to month 3 was −66 microns (range, −373 to +60); −124 microns (range, −439 to +53) at month 6; and −127 microns (range, −362 to +11) at month 9. The mean change in OCT central retinal thickness from baseline to month 12 was −117 microns (range, −380 to +127). The greatest linear dimension of the CNV lesion measured a mean of 3.2±2.0 mm at baseline and then changed by +0.8±2 mm at month 1, +0.4±1.6 mm at month 3, −1.9±1.2 mm at month 6, −2.4±2.0 mm at month 9 and −2.1±2.4 mm at month 12.
In this phase I study, externally applied, stereotactically delivered, non-invasive, low-voltage, x-ray irradiation using the IRay system combined with ranibizumab rescue was safe in the short term, and led to stabilisation of CNV and visual acuity in patients with neovascular AMD. The observed trend on OCT testing was normalisation of foveal contours with a reduction in intraretinal fluid. To date, over the first 12 months of follow-up, 12 patients required a total of 31 ranibizumab injections. The visual outcome was obtained with few re-treatments in comparison with the number of re-treatments observed in the ‘as needed’ treatment arms of the Comparison of Age-related macular degeneration Treatment Trial (CATT) arms,24 We acknowledge that visual outcomes observed in the present study are not comparable with that observed in the ‘as needed’ treatment arms of the CATT; however, the CATT protocol employed a much more aggressive retreatment regimen and this may have resulted in the relatively higher rate of injections in that study and the higher visual acuity outcomes.24 In addition, the CATT protocol evaluated only treatment-naive patients whereas the present study included previously treated patients and those with more advanced AMD pathology.24
Previous experience with radiation therapy demonstrated a trend towards involution of the CNV, but inconclusive visual acuity results.1–18 Recently, the Sr-90 epimacular surgical irradiation approach as monotherapy for CNV demonstrated a mean gain of +10.3 letters using 24 Gy and a mean loss of 1 ETDRS letters using 15 Gy at 12 months.19 ,20 The 12 month follow-up using a combination of bevacizumab and Sr-90 epimacular approach demonstrated a mean change of +8.9 ETDRS letters, with 38% gaining ≥3 lines of vision.19 Interestingly, maximal visual acuity effects in the Sr-90 epimacular surgical approach occur ≥3 months.
Unfortunately, direct comparison of the present study with the Sr-90 epimacular surgical approach is confounded by numerous differences between the treatments.19 The five significant differences between the Sr-90 epimacular surgical approach and the non-invasive, low-voltage, x-ray irradiation approach are as follows: (1) the Sr-90 epimacular technique requires surgery versus the non-surgical IRay treatment; (2) the Sr-90 epimacular approach uses a β-emitting radioactive isotope versus low-voltage x-ray irradiation; (3) dose delivery; (4) total dose applied; and (5) dose control at the plane of the retina. In addition, the study design of the clinical trials differed in that the phase I trial of the Sr-90 epimacular surgical approach used intravitreal bevacizumab, as opposed to intravitreal ranibizumab anti-VEGF therapy and the treatment strategy in the Sr-90 epimacular surgical approach involved two mandatory bevacizumab injections, either one before radiation and one after, or both after radiation, as opposed to the current study's strategy of radiation-first followed by ranibizumab rescue.20
As noted, it is difficult to parse out the effects of the vitrectomy, if any, which may accompany the Sr-90 epimacular surgical technique. It is well known that cataract advancement is nearly universal following vitrectomy. Additionally, maximal visual acuity is usually not attained for several months after any vitrectomy. These variables are eliminated with the non-invasive, low-voltage x-ray approach, giving greater confidence that the effect noted after treatment is due solely to the radiation. The main difference with β-emitting radioactive isotope versus low-voltage x-ray irradiation comes down to the need for accurately determining the activity of the radioisotope, which necessitates the involvement of a radiation physicist as well as a radiation oncologist when using the Sr-90 source. As a corollary, not all radiation emitters are equally powerful, leading to the concept of equivalent doses. The relative biological effectiveness of very low voltage (20–40 keV) x-ray irradiation with respect to Sr-90 at a depth of 0 mm and dose of 4.62 Gy is 1.60, meaning that these 20–40 keV x-rays are exhibiting 60% more biological effect than an equivalent dose of Sr-90. For the Oraya device, the peak energy is 100 keV with an average energy of approximately 50 keV. The estimated relative biological effectiveness is 1.3 with respect to Sr-90 at the treatment depth (personal communication, Wayne Newhauser, PhD, MD Anderson Cancer Center). Using this concept, the IRay device would be 30% more effective on a Gy-for-Gy basis than the Sr-90 epimacular surgical approach, and therefore a 30% lower dose, or 16 Gy, was chosen as our initial treatment choice. The results of the current study justify this dose as biologically meaningful. Finally, because the precision-controlled system is constrained to overlapping beams always converging at a point 150 mm from the x-ray tube anode and any eye movement is accurately monitored, we have confidence in the location where the radiation dose is delivered. In contrast, there is uncertainty in the Sr-90 epimacular surgical approach due to the high level of dose variability associated with small changes in distance away from the target (10% total dose error for each 0.1 mm difference in distance from the target—personal communication Eugene de Juan) and the fact that the probe is hand-held in contact to the retina by the operating surgeon. However, dose uncertainty with Sr-90 epimacular surgical approach may be mitigated by the near certainty of targeting the CNV.
There are several deficiencies of this clinical study including the small sample size, non-randomised study design and most importantly short follow-up period to find radiation-related complications. Nonetheless, the treatment approach was well tolerated with no significant ocular or systemic adverse effects noted during the first 12 months. This study illustrated that there is evidence of biological activity of the radiation treatment, with improvement in retinal thickness, reduction in leakage on angiography and visual acuity stabilisation. Additional trials combining anti-VEGF therapy with low-voltage irradiation at baseline are underway, and this multi-pathway approach may optimise anatomic and visual outcomes.
Originally presented, in part, at the 2009 American Academy of Ophthalmology Retina Subspecialty Day Meeting. Clinicaltrials.gov identifier: NCT01217762.
Contributors (1) Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data: all authors (2) Drafting the article or revising it critically for important intellectual content: all authors (3) Final approval of the version to be published: all authors
Funding DMM (Oraya, Inc., consultant, equity); VMC, RVM, HQM, SRS (Oraya, Inc., consultant), MG (Oraya, Inc., intellectual property, equity); PKK (Research to Prevent Blindness, research; Bayer, Genentech, Regeneron, Kanghong, Novartis, consultant; Oraya, Inc., consultant, equity); AAM (Genentech, Inc., Allergan, Inc., Bausch & Lomb, Inc,, consultant/speaker; Eyetech, Inc., Alimera, Inc., consultant; Thrombogenics, Inc., research funding; Palm Beach Community Trust Fund; funding); EMS (Oraya, Inc employee, equity).
Competing interests This work was funded by Oraya Therapeutics, Neovista, Novartis.
Ethics approval Approval from the Institutional Review Board of Associacion Para Evitar La Ceguera En Mexico, I.A.P., (Mexico City, Mexico) and the government of Mexico for the use of the IRay (Oraya Therapeutics, Inc., Newark, CA) radiation device for this trial of patients with neovascular AMD was obtained prior to the start of the study.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Data available upon request from DMM.
Patient consent Informed consent was obtained from all study participants upon enrollment into the study.