Purpose
To describe the 12-month safety and efficacy outcomes of 16 or 24 Gy radiation using low-voltage x-ray irradiation in conjunction with intravitreal ranibizumab for neovascular age-related macular degeneration (AMD).
Design
Prospective, phase I, open-label, nonrandomized uncontrolled safety study.
Methods
setting : Institutional. study population : Neovascular AMD patients. intervention : One x-ray irradiation treatment at 16 or 24 Gy was administered externally through 3 locations in the inferior pars plana. After 2 initial monthly loading doses of ranibizumab, subsequent ranibizumab was administered according to predetermined criteria. main outcome measures : Visual acuity, number of ranibizumab injections, safety and efficacy metrics at 12 months.
Results
Forty-seven eyes of 47 patients were enrolled and completed 12 months of follow-up: 16 Gy (n = 28) and 24 Gy (n = 19). There was no evidence of radiation retinopathy, optic neuropathy, or cataract. The mean visual acuity improved in both groups: +8.4 ± 11.9 letters and +7.8 ± 12 letters for 16 and 24 Gy, respectively. In both groups, 100% of subjects lost <15 letters, with 76% and 79% gaining ≥0 letters in the 16 Gy and 24 Gy groups, respectively. Patients received a mean of 1.0 additional injection over 12 months. The mean change in optical coherence tomography central subfield thickness from baseline to month 12 was −107 and −87 μm for the 16 Gy and 24 Gy groups, respectively.
Conclusion
One treatment of 16 or 24 Gy low-voltage x-ray therapy with as-needed ranibizumab appears safe in subjects with neovascular AMD at 12 months. An overall improvement in visual acuity was observed. No radiation-related adverse effects were reported.
The IRay (Oraya Therapeutics, Inc, Newark, California, USA) is an office-based, stereotactic, low-dose x-ray irradiation system for the treatment of neovascular age-related macular degeneration (AMD). This device is designed to be placed in a typical clinical or outpatient suite, to run off commonly available electrical supply, and to be operated by a retinologist, without additional facility, staff, or patient shielding requirements. An active suction apparatus coupled with infrared reflective fiducials allows for the eye to be tracked in the X, Y, Z planes or rotational angles. An accumulated deviation beyond threshold values for any of these parameters individually or in combination will result in gating of the device and interruption of the radiation treatment. Additional safety measures include various interlocks designed to prevent patient interference with system motion, integrated radiation beam-stop and scatter shielding, and emergency shut-off mechanism. Globe axial length, determined via A-scan ultrasound or optical interferometry, is used as a treatment planning input. The radiation is delivered during a single session in 3 consecutive and separate locations through the inferior pars plana, with the x-ray beams overlapping on the macula to deliver the total prescribed dose. We have previously demonstrated that the device delivers the full dose to the plane of the macula (which is situated exactly 150 mm from the robotically positioned and tracked x-ray tube aperture) within a 4-mm-diameter spot size. The dosing and targeting accuracy of the low-voltage stereotactic x-ray irradiation system has been verified in human cadaver eyes using radiochromic film, as well as in animal models.
We recently described the 6-month outcomes of 2 separate low-voltage stereotactic x-ray irradiation system treatment strategies: (1) 16 Gy radiation first with adjunctive, as-needed (pro re nata; PRN) intravitreal ranibizumab 0.5 mg (Lucentis; Genentech, South San Francisco, California, USA, and Novartis Ophthalmics, Inc, Basel, Switzerland) based on prospectively defined re-treatment criteria ; and (2) 16 Gy radiation with 2 loading doses of intravitreal ranibizumab 0.5 mg injections followed by ranibizumab 0.5 mg PRN based on prospectively defined re-treatment criteria. Additionally, 12-month safety data on 16 Gy radiation first with adjunctive PRN ranibizumab was recently published. The purpose of the present study is to assess the feasibility, safety, and preliminary efficacy using the low-voltage, stereotactic x-ray irradiation system for treatment of neovascular AMD at either 16 or 24 Gy dose, in conjunction with 2 loading injections of ranibizumab, followed by as-needed ranibizumab, based on predefined re-treatment criteria, as part of a safety evaluation.
Methods
This was a prospective, nonrandomized, open-label safety study of low-voltage radiation therapy and ranibizumab in subjects 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 low-voltage stereotactic x-ray irradiation system for this trial of subjects with neovascular AMD was obtained prior to the start of the study. After proper informed consent was obtained in the patient’s native language, subjects were enrolled into the trial. The main outcome measure was the development of ocular and nonocular adverse events. Secondary outcome metrics included proportion of subjects losing more than 15 ETDRS (Early Treatment of Diabetic Retinopathy Study) 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 choroidal neovascularization (CNV) lesion size on fluorescein angiography (FA).
Study Entry Criteria
Eligible subjects included individuals aged 50 years or older with evidence of subfoveal CNV activity secondary to neovascular AMD. Pertinent exclusion criteria included previous treatment for AMD and history of diabetes mellitus or elevated fasting blood glucose. Additionally, previous history of ipsilateral photodynamic therapy was an exclusion criterion. Details of inclusion and exclusion criteria are shown in Table 1 .
| Inclusion Criteria | Exclusion Criteria |
|---|---|
| 1. Subjects must be aged 50 years or older | 1. Subjects with prior or concurrent therapies including submacular surgery, thermal laser photocoagulation (with or without photographic evidence), photodynamic therapy, and transpupillary thermotherapy |
| 2. Women must be postmenopausal ≥1 year or surgically sterilized | 2. Subjects with concomitant disease in the study eye, including uveitis, diabetic retinopathy, presence of RPE tears or rips, acute ocular or periocular infection |
| 3. Subjects must sign (and be given) a copy of the informed consent form | 3. Subjects with advanced glaucoma (>0.8 cup-to-disc ratio) or intraocular pressure ≥30 mm Hg in the study eye |
| 4. Subjects must be willing and able to return for scheduled treatment and follow-up examinations for the 2-year duration of the study | 4. Previous glaucoma filtering surgery in the study eye |
| 5. Subjects must have choroidal neovascularization lesion size of ≤11 total disc areas (28.26 mm 2 ) and a greatest linear dimension of ≤6 mm | 5. Refractive error in the study eye demonstrating more than −8 diopters of myopia (or globe axial length ≥26 mm). For subjects who had undergone prior refractive or cataract surgery in the study eye, the preoperative refractive error could not exceed −8 diopters of myopia |
| 6. Subjects must have ETDRS best-corrected visual acuity of 69 to 24 letters (20/40 to 20/320 Snellen equivalent) in the study eye | 6. Subjects with any retinal vasculopathies, including diabetic retinopathy or retinal vein occlusions, in the study eye |
| 7. Only 1 eye will be assessed in the study. If both eyes have active disease, the one with the worst acuity will be selected. The eye selected for treatment will receive a single treatment of 11, 16, or 24 Gy to the macula, up to and including 14 days following intravitreal injection of 0.5 mg ranibizumab. | 7. Subjects with inadequate pupillary dilation or significant media opacities in the study eye, including cataract, which could interfere with visual acuity or the evaluation of the posterior segment |
| 8. Subretinal hemorrhage (if any) must not comprise more than 50% of total lesion size, and may not involve the subfoveal space | 8. Current vitreous hemorrhage in the study eye |
| 9. Patient has neovascular AMD characterized by leakage on FA in conjunction with fluid accumulation on OCT, with a fellow eye that has characteristics consistent with AMD (drusen, hyperpigmentation, previous but not active choroidal neovascularization [eg, disciform scar], and/ or geographic atrophy) as determined by the treating physician, and is treatment naïve OR Subject has known neovascular AMD as determined by the treating physician, subject has received anti-VEGF injections during a continuous sequential treatment course for AMD, and the physician determines the need for additional treatment with the following criteria: Fluorescein leakage on FA from CNV Increased intraretinal, subretinal, or sub-RPE fluid Persistent cystoid macular edema on OCT | 9. History of rhegmatogenous retina detachment in the study eye |
| 10. Subjects who present with choroidal neovascularization due to causes other than AMD, including ocular histoplasmosis syndrome, angioid streaks, multifocal choroiditis, choroidal rupture, or pathologic myopia (spherical equivalent ≥8 diopters or axial length ≥26 mm) | |
| 11. Other than cataract surgery, subjects who have undergone any intraocular surgery of the study eye within 30 days prior to treatment with the IRay system; in the instance of cataract surgery within 30 days, the investigator examination must reveal a healed corneal incision | |
| 12. Subjects with known serious allergies to fluorescein dye used in angiography unless subject has received an anti-allergenic regimen successfully in the past and agrees to receive the regimen again | |
| 13. Subjects who underwent previous radiation therapy to the eye, head, or neck | |
| 14. Subjects with an intravitreal device or drug in the study eye | |
| 15. Subjects with any other condition that, in the judgment of the investigator, would prevent the subject from completing the study (eg, dementia, mental illness) | |
| 16. History of other disease, metabolic dysfunction, physical examination finding, or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of intravitreal ranibizumab or that might affect interpretation of the results of the study or render the subject at high risk for treatment complication | |
| 17. Known sensitivity or allergy to ranibizumab | |
| 18. Subjects with a history of optic neuritis | |
| 19. Subjects that have been previously diagnosed or have retinal findings consistent with type 1 or type 2 diabetes mellitus | |
| 20. Subjects with a questionable history of type 1 or type 2 diabetes mellitus without retinal findings and fasting blood glucose level (recent test) ≥99 mg/dL | |
| 21. Current treatment for active systemic infection or history of significant recurrent/chronic infections | |
| 22. Subjects currently receiving chemotherapy, having completed a course within the 90 days preceding study enrollment, or expecting to begin chemotherapy while participating in the study | |
| 23. Evidence of significant uncontrolled concomitant diseases such as cardiovascular disease or nervous system, pulmonary, renal, hepatic, endocrine, or gastrointestinal disorders | |
| 24. Current participation in another drug or device clinical trial or previous enrollment in a trial involving the study in the last year | |
| 25. History of use of drugs with known retinal toxicity, including chloroquine, hydroxychloriquine, phenothiazines, chlorpromazine, thioridazine, fluphenazine, perphenazine, and trifluoperazine | |
| 26. Concurrent use of systemic anti-VEGF agents | |
| 27. History of corneal transplant in the study eye | |
| 28. Any additional concurrent intraocular condition in the study eye that, in the opinion of the investigator, could either require medical or surgical intervention during the 24-month study period to prevent or treat visual loss that might result from that condition or that, if allowed to progress untreated, could likely contribute to a loss of at least 2 Snellen equivalent lines of BCVA over the 24-month study period | |
| 29. Implantable cardioverter defibrillator or pacemaker |
Examination Protocol
Subjects underwent baseline clinical examination, intraocular pressure determination, best-corrected protocol acuity testing with ETDRS charts starting at 4 meters, spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, California, USA), and fluorescein angiography. Clinical examination, safety assessment, and OCT testing were performed monthly; FA testing was performed quarterly, unless there was an unexplained decrease in visual acuity. The OCT images were evaluated at Stanford University (Palo Alto, California, USA). Fluorescein angiograms were read at the University of Wisconsin, Madison (Madison, Wisconsin, USA).
Treatment Protocol
All subjects received 2 mandatory intravitreal ranibizumab 0.5 mg injections at day 0 and day 30 and a single 16 or 24 Gy x-ray treatment (see below) between days 1 and 14. Additional ranibizumab injections were performed on a monthly as-needed basis based on the following re-treatment criteria: (1) loss of ≥10 ETDRS letters compared with previous visit, in conjunction with persistent fluid on OCT; (2) increase of ≥100 μm central foveal thickness on OCT compared with previous visit; (3) development of a new subretinal hemorrhage in the macula; and (4) development of new classic choroidal neovascularization on FA.
Treatment System
The low-voltage stereotactic x-ray irradiation system consists of the following components: (1) a precision-controlled x-ray tube; (2) a patient interface; (3) an eye stabilizing device (I-Guide) that optically couples the patient’s eye to the x-ray delivery system; (4) an eye tracking subsystem that monitors X, Y, Z and rotational movements of the eye for dose determination and safety gating; (5) graphical user interface; and (6) treatment planning software. The system is designed to deliver 3 overlapping 4-mm radiation 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 over the entire macula is calculated from analysis of the ocular movements during the treatment session. Radiation therapy consisted of 1 fraction of 16 or 24 Gy delivered in approximately 15 minutes (about 3-5 minutes of x-ray exposure) over 3 equal spots in the inferior pars plana.
Results
16 Gy
Twenty-eight subjects were enrolled and treated, but 1 was subsequently excluded from the efficacy analysis as he was discovered to have had central retinal vein occlusion rather than CNV attributable to AMD. One subject died between the month 10 and month 11 follow-up visits, and another subject missed the month 12 visit; they are consequently not included in the aggregate 12-month visual acuity data presented in this paper. (These subjects’ injection history is included, however.) Twenty-five subjects (92.8%) completed 12 months of follow-up and are included in the visual acuity analyses. Baseline OCT could not be quantified for 3 of the 27 protocol subjects because of technical reasons, and month 12 OCT examinations were available for 22 of the 27 protocol subjects.
24 Gy
Nineteen subjects were enrolled and treated. All completed 12 months of follow-up and are included in the safety, visual acuity, and injection analysis. Twelve-month OCT data were available for 18 of the 19 subjects (95%).
Safety
Safety was good, with no serious ocular or nonocular adverse events reported related to the study device. Specifically, there were no arteriothromboembolic events, endophthalmitis, or evidence of radiation-related adverse events, including retinopathy, optic neuropathy, cataract advancement, lid necrosis, or scleral injury. The only described ocular adverse outcome was an asymptomatic, self-limited superficial punctate keratopathy that resolved spontaneously, likely attributable to the I-Guide ( Table 2 ). No treatment-related systemic adverse outcomes were observed. One subject in the 16 Gy group died between the month 10 and month 11 follow-up visits because of a myocardial infarct. The event is not considered related to study treatment.
| Eye Disorder | 16 Gy (n = 28) | 24 Gy (n = 19) |
|---|---|---|
| Temporary keratopathy | 28 (100%) | 10 (53%) |
| Conjunctivitis | 2 (7%) | 4 (21%) |
| Blepharitis | 4 (14%) | 2 (11%) |
| Vitreous floaters | 1 (4%) | 3 (16%) |
| Conjunctival hemorrhage | 3 (11%) | 0 (0%) |
| Decreased vision | 3 (11%) | 1 (5%) |
| Eye pain | 1 (4%) | 1 (5%) |
| Increased lacrimation | 1 (4%) | 1 (5%) |
| Photopsia | 0 (0%) | 0 (0%) |
| Asthenopia | 2 (7%) | 0 (0%) |
| Cataract | 2 (7%) | 0 (0%) |
| Keratitis | 0 (0%) | 0 (0%) |
| Ocular hyperemia | 1 (4%) | 1 (5%) |
| Trichisias | 1 (4%) | 1 (5%) |
| Blurred vision | 2 (7%) | 0 (0%) |
| Conjunctivitis, allergic | 0 (0%) | 1 (5%) |
| Corneal infiltrates | 0 (0%) | 0 (0%) |
| Corneal leukoma | 0 (0%) | 0 (0%) |
| Eye irritation | 0 (0%) | 1 (5%) |
| Eye pruritis | 0 (0%) | 1 (5%) |
| Foreign body sensation | 1 (4%) | 0 (0%) |
| Retinal vein occlusion | 0 (0%) | 0 (0%) |
| Conjunctivitis, viral | 3 (11%) | 0 (0%) |
| Herpes zoster | 1 (4%) | 0 (0%) |
| Hordeolum | 1 (4%) | 0 (0%) |
| Intraocular pressure increased | 2 (7%) | 0 (0%) |
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