Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

24-Gy Low-Voltage X-Ray Irradiation With Ranibizumab Therapy for Neovascular AMD: 6-Month Safety and Functional Outcomes

Virgilio Morales Canton, MD; Hugo Quiroz-Mercado, MD; Raul Velez-Montoya, MD; Miriam J. Lopez-Miranda, MD; Andrew A. Moshfeghi, MD, MBA; Eugene M. Shusterman, MD; Peter K. Kaiser, MD; Steven R. Sanislo, MD; Michael Gertner, MD; Darius M. Moshfeghi, MD

Abstract

BACKGROUND AND OBJECTIVE:

To describe the 6-month safety and preliminary efficacy outcomes of the use of 24-Gy radiation with intravitreal ranibizumab for patients with neovascular age-related macular degeneration (AMD).

PATIENTS AND METHODS:

A single treatment of a non-invasive, externally delivered low-voltage x-ray irradiation at a dose of 24 Gy was administered in one session through three locations in the inferior pars plana in a consecutive series of patients with neo-vascular AMD (treatment naïve and previously treated). Optical coherence tomography (OCT) and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity examinations were performed at 1 week, 1 month, and monthly thereafter with quarterly fluorescein angiography.

RESULTS:

Nineteen patients completed 6 months of follow-up. There was no evidence of radiation retinopathy, optic neuropathy, or cataract. The mean baseline ETDRS score was 38.3 ± 19.5 letters. At 6 months, the corresponding ETDRS score was 44.7 ± 16.8 letters. At 6 months, the mean change in visual acuity was 6.4 ± 9.8 ETDRS letters. Patients received an average of 0.4 additional ranibizumab injections following the initial two mandated injections.

CONCLUSION:

A single treatment of external 24-Gy low-voltage x-ray therapy in conjunction with ranibizumab demonstrated an overall improvement in visual acuity in patients with neovascular AMD at 6 months, with no radiation-related adverse effects.

Abstract

BACKGROUND AND OBJECTIVE:

To describe the 6-month safety and preliminary efficacy outcomes of the use of 24-Gy radiation with intravitreal ranibizumab for patients with neovascular age-related macular degeneration (AMD).

PATIENTS AND METHODS:

A single treatment of a non-invasive, externally delivered low-voltage x-ray irradiation at a dose of 24 Gy was administered in one session through three locations in the inferior pars plana in a consecutive series of patients with neo-vascular AMD (treatment naïve and previously treated). Optical coherence tomography (OCT) and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity examinations were performed at 1 week, 1 month, and monthly thereafter with quarterly fluorescein angiography.

RESULTS:

Nineteen patients completed 6 months of follow-up. There was no evidence of radiation retinopathy, optic neuropathy, or cataract. The mean baseline ETDRS score was 38.3 ± 19.5 letters. At 6 months, the corresponding ETDRS score was 44.7 ± 16.8 letters. At 6 months, the mean change in visual acuity was 6.4 ± 9.8 ETDRS letters. Patients received an average of 0.4 additional ranibizumab injections following the initial two mandated injections.

CONCLUSION:

A single treatment of external 24-Gy low-voltage x-ray therapy in conjunction with ranibizumab demonstrated an overall improvement in visual acuity in patients with neovascular AMD at 6 months, with no radiation-related adverse effects.

From Associacion Para Evitar La Ceguera En Mexico (VMC, HQ-M, RV-M, ML-M), I.A.P., Mexico City, Mexico; the Department of Ophthalmology (HQ-M, RV-M), University of Colorado, Denver, Colorado; Bascom Palmer Eye Institute (AAM), University of Miami Miller School of Medicine, Department of Ophthalmology, Palm Beach Gardens, Florida; Oraya Therapeutics, Inc. (EMS, MG), Newark, California; Cole Eye Institute (PKK), Cleveland Clinic, Cleveland, Ohio; and Byers Eye Institute (DMM), Horngren Family Vitreoretinal Center, Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, California.

Drs. D. Moshfeghi and Kaiser are consultants for and have equity in, Drs. Canton, Velez-Montoya, Lopez-Miranda, Quiroz-Mercado, and Sanislo are consultants for, Dr. Shusterman is an employee of, and Dr. Gertner holds intellectual property with Oraya Therapeutics, Inc. Dr. Kaiser is a consultant for Novartis, Genentech, Bayer, and Regeneron. Dr. D. Moshfeghi is a consultant for Institu Therapeutics, OcuBell, and Realm Global. Dr. A. Moshfeghi is a consultant/speaker for Genentech, Inc., Allergan, Inc., and Bausch & Lomb, Inc., a consultant for Eyetech, Inc. and Alimera, Inc., and receives research funding from Thrombogenics, Inc.

Address correspondence to Darius M. Moshfeghi, MD, Byers Eye Institute, Horngren Family Vitreoretinal Center, Department of Ophthalmology, Stanford University School of Medicine, 2452 Watson Court, Palo Alto, CA 94303. E-mail: dariusm@stanford.edu

Received: January 27, 2011
Accepted: October 28, 2011

Introduction

The IRay (Oraya Therapeutics Inc., Newark, CA) is an office-based, stereotactic x-ray irradiation system for the treatment of neovascular age-related macular degeneration (AMD).1 This system is designed to be placed in a typical clinical suite, to run off standard wall power, and to be operated by retinologists, without additional facility, staff, or patient shielding requirements.1 An active suction apparatus coupled with infrared reflective fiducials allows the eye to be tracked in the X, Y, Z planes or rotational angles.1 A deviation beyond threshold parameters for any of these items individually or a summation threshold for additive deviations in all of the movements will result in immediate gating of the device and interruption of the radiation treatment.1 Additional safety measures include various interlocks designed to prevent unwanted patient interference with system movement, integrated radiation beam-stop and scatter shielding, and emergency shutoff mechanisms.1

Globe axial length, determined via A-scan ultrasound or optical interferometry, is used as a treatment planning parameter. The radiation is delivered during a single treatment session in three separate locations through the inferior pars plana; the x-ray beams overlap on the macula to give the total prescribed dose.1 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 x-ray tube aperture and robotically positioned and tracked) within a 4-mm diameter spot size.2–4 The dosing and targeting accuracy of the IRay has been verified in human cadaver eyes using radiochromic film.5

We described the 6-month outcomes of two separate IRay treatment strategies: 16-Gy radiation first with adjunctive intravitreal ranibizumab 0.5 mg (Novartis Ophthalmics, Inc., Basel, Switzerland) for prospectively defined re-treatment criteria and 16-Gy radiation with two loading doses of intravitreal ranibizumab 0.5 mg injections followed by ranibizumab 0.5 mg on an as-needed basis for prospectively defined re-treatment criteria.6,7 The purpose of the current study was to assess the feasibility, safety, and preliminary outcomes using the IRay non-invasive, robotically controlled, low-voltage stereotactic x-ray irradiation system for treatment of neovascular AMD at a 24-Gy dose.

Patients and Methods

Institutional Review Board approval for this phase I, open-label, non-randomized, uncontrolled safety trial was received from Associacion Para Evitar La Ceguera En Mexico, I.A.P., Mexico City, Mexico to perform this study. Additionally, the government of Mexico approved the use of the radiation device for this trial of patients with neovascular age-related macular degeneration.

Study Entry Criteria

Eligible patients included individuals 50 years or older with evidence of subfoveal choroidal neovascularization activity secondary to neovascular AMD. Pertinent exclusion criteria included previous treatment for AMD with photodynamic therapy or laser photocoagulation in the treatment eye and history of diabetes mellitus or elevated fasting blood glucose.

Examination Protocol

Patients underwent baseline protocol Early Treatment Diabetic Retinopathy Screening (ETDRS) refraction, optical coherence tomography (OCT) testing, and fluorescein angiography (FA). OCT testing was performed monthly and FA testing was performed quarterly, unless there was an unexplained decrease in visual acuity.

Treatment Design

The treatment design consisted of two mandatory intravitreal ranibizumab 0.5 mg injections at days 0 and 30, with a single 24-Gy x-ray treatment between days 1 and 14. Two subgroups were evaluated: treatment-naïve and previously treated. Additional ranibizumab injections were performed on a monthly basis for the following indications: (1) loss of 10 ETDRS letters in conjunction with persistent fluid on OCT compared with baseline, (2) increased central foveal thickness of 100 microns on OCT compared with baseline, (3) development of a new subretinal hemorrhage in the macula, and (4) development of an area of new classic choroidal neovascularization on FA.

Low-Voltage X-ray Treatment System. Oraya Therapeutics, Inc. has developed an externally applied, non-invasive low-voltage x-ray irradiation system specifically for the treatment of neovascular AMD. This system consists of the following components: (1) a robotically controlled x-ray tube, (2) a patient interface, (3) an eye stabilizing device that optically couples the patient’s eye to the x-ray delivery system, (4) an eye tracking system 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 three 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 one fraction of 24 Gy delivered in approximately 15 minutes (approximately 5 minutes of x-ray exposure) over three equal spots in the inferior pars plana.

Results

Nineteen patients completed 6 months of follow-up. Eight patients were treatment-naïve and 11 patients had received a total of 21 anti-vascular endothelial growth factor injections (mean = 1.9, range = 1 to 4 injections) prior to study entry.

Safety

There were no cases of radiation retinopathy, optic neuropathy, cataract advancement, eyelid necrosis, or scleral injury. The only described ocular adverse outcome was an asymptomatic, self-limited superficial punctate keratopathy that resolved spontaneously. No treatment-related systemic adverse outcomes were observed.

Visual Acuity

The mean baseline ETDRS score was 38.3 letters (range: 4 to 68, standard deviation of 19.5 letters). At 6 months, the corresponding ETDRS score was 44.7 letters (range: 21 to 80 letters, standard deviation of 16.8 letters). At 6 months, the mean change in visual acuity was 6.4 ETDRS letters (standard deviation = 9.8 letters). There were two subgroups: treatment-naïve (n = 9) and previously treated (n = 10). Treatment-naïve patients demonstrated a mean change from baseline of 8.5 ETDRS letters (standard deviation 8.6), whereas previously treated patients demonstrated a mean change of 4.8 ETDRS letters (standard deviation = 10.8) (Fig. 1). In the responder analysis, 100% of treated eyes lost 15 or fewer ETDRS letters, 79% of treated eyes gained 0 or more ETDRS letters, and 16% of treated eyes gained 15 or more ETDRS letters (Fig. 2). For treatment-naïve patients, the responder analysis demonstrated 100% of treated eyes lost 15 or fewer ETDRS letters, 75% of treated eyes gained 0 or more ETDRS letters, and 25% of treated eyes gained 15 or more ETDRS letters (Fig. 2). Similarly, in previously treated patients the responder analysis demonstrated 100% of treated eyes lost 15 or fewer ETDRS letters, 82% of treated eyes gained 0 or more ETDRS letters, and 9% of treated eyes gained 15 or more ETDRS letters (Fig. 2).

Mean best-corrected visual acuity.

Figure 1. Mean best-corrected visual acuity.

Responder analysis.

Figure 2. Responder analysis.

Injections

Each patient received two mandatory injections at days 0 and 30. An additional 7 injections were performed, for a total of 45 injections in 19 patients over 6 months (Fig. 3).

Mean change in visual acuity versus number of injections.

Figure 3. Mean change in visual acuity versus number of injections.

Discussion

In this phase I, open-label, single-center, non-randomized, uncontrolled clinical trial, externally applied 24-Gy low-voltage x-ray irradiation with front-end ranibizumab load and adjunctive, as-needed injections has demonstrated safety, a visual acuity response, and the ability to improve both treatment-naïve and previously treated patient populations.

There were no cases of radiation retinopathy, optic neuropathy, eyelid necrosis, scleral injury, or cataract. It is unlikely that IRay therapy would develop any vision-threatening radiation retinopathy or optic neuropathy because the 10% to 90% isodose regions of 24 Gy (range: 2.4 to 21.6 Gy) is constrained to a 4-mm radius circle overlapping on the macula, resulting in a volume of tissue irradiated of 3.14 mm3. The IRay therapy is robotically controlled and electronically gated for any eye movements that exceed a preset threshold, ensuring that the dose to the plane of the macula is reproducible and unvarying.1–5 Similarly, due to the lack of surgery, the highly collimated nature of the beams, and the beam placement through the inferior pars plana, the rate of cataract progression should be low with the IRay as noted in the current report.1–5

The visual acuity results were encouraging in the current study. In particular, the responder analysis demonstrated a strong safety profile: 100% lost 15 or fewer ETDRS letters, 79% gained 0 or more ETDRS letters, and 16% gained 15 or more ETDRS letters. The approach described herein was equally effective in both treatment-naïve and previously treated patients. Three randomized, double-masked, multicenter clinical trials demonstrated the benefit of a 3-month ranibizumab loading dose,8-10 and it has been widely assumed that no substantial visual acuity benefit was possible once a patient has received this treatment load. In the current study, 10 patients had received a total of 18 previous injections (bevacizumab and ranibizumab, mean of 1.8 injections, range: 1 to 4 injections). The previously treated patient population in the current study demonstrated that 82% gained 0 or more ETDRS letters. When comparing with historical studies,11–23 the 24-Gy IRay treatment in conjunction with ranibizumab therapy demonstrated a superior visual acuity outcome. Recently, a surgical epiretinal Sr-90 24-Gy brachytherapy technique in conjunction with two off-label bevacizumab (Novartis Ophthalmics, Inc., Basel, Switzerland) injections followed by adjunctive, as-needed injections24 or with vitrectomy and radiation alone25 has been described for treatment-naïve patients with neovascular AMD, and they reported mean gains of 8.9 and 10.3 letters at 12 months, respectively. A more complete comparison of the two treatment modalities is performed in the 16-Gy plus ranibizumab companion article.

The treatment durability was also enhanced with the use of 24-Gy IRay therapy. Nineteen patients received at total of 45 injections (38 mandatory, 7 as-needed) over a period of 6 months to achieve a mean gain of 6.2 ETDRS letters (standard deviation = 9.8). These results compare favorably to other trials with respect to visual acuity, using only 39.5% of the ranibizumab injections.8,10

Conclusion

Stereotactic, externally applied, robotically controlled 24-Gy x-ray irradiation in conjunction with a loading dose of ranibizumab and adjunctive, as-needed ranibizumab injections for prospectively defined criteria has demonstrated no adverse effects at 6 months of follow-up in both previously treated and treatment-naïve patients. Visual acuity results in both groups are similar to those reported for monthly ranibizumab treatment regimens while using only 39.5% of the injections of a monthly treatment regimen. Longer follow-up is necessary to more fully assess the safety and efficacy profile.

References

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Authors

From Associacion Para Evitar La Ceguera En Mexico (VMC, HQ-M, RV-M, ML-M), I.A.P., Mexico City, Mexico; the Department of Ophthalmology (HQ-M, RV-M), University of Colorado, Denver, Colorado; Bascom Palmer Eye Institute (AAM), University of Miami Miller School of Medicine, Department of Ophthalmology, Palm Beach Gardens, Florida; Oraya Therapeutics, Inc. (EMS, MG), Newark, California; Cole Eye Institute (PKK), Cleveland Clinic, Cleveland, Ohio; and Byers Eye Institute (DMM), Horngren Family Vitreoretinal Center, Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, California.

Drs. D. Moshfeghi and Kaiser are consultants for and have equity in, Drs. Canton, Velez-Montoya, Lopez-Miranda, Quiroz-Mercado, and Sanislo are consultants for, Dr. Shusterman is an employee of, and Dr. Gertner holds intellectual property with Oraya Therapeutics, Inc. Dr. Kaiser is a consultant for Novartis, Genentech, Bayer, and Regeneron. Dr. D. Moshfeghi is a consultant for Institu Therapeutics, OcuBell, and Realm Global. Dr. A. Moshfeghi is a consultant/speaker for Genentech, Inc., Allergan, Inc., and Bausch & Lomb, Inc., a consultant for Eyetech, Inc. and Alimera, Inc., and receives research funding from Thrombogenics, Inc.

Address correspondence to Darius M. Moshfeghi, MD, Byers Eye Institute, Horngren Family Vitreoretinal Center, Department of Ophthalmology, Stanford University School of Medicine, 2452 Watson Court, Palo Alto, CA 94303. E-mail: dariusm@stanford.edu

Received: January 27, 2011
Accepted: October 28, 2011

10.3928/15428877-20111129-01

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