BlueCross and BlueShield of Montana Medical Policy/Codes
Epiretinal Radiation Therapy for Age-Related Macular Degeneration
Chapter: Medicine: Treatments
Current Effective Date: April 09, 2012
Original Effective Date: April 09, 2012
Publish Date: April 09, 2012
Description

Epiretinal radiation describes the intraocular administration of radiation to the choroidal vascular bed of the retina to treat age-related macular degeneration (AMD).

Background

Age-related macular degeneration (AMD) is characterized in its earliest stages by minimal visual impairment and the presence of large drusen and other pigmentary abnormalities on ophthalmoscopic examination. Two distinctively different forms of degeneration may be observed. The first, called the atrophic or areolar or dry form, evolves slowly. Atrophic AMD is the most common form of degeneration and may be a precursor of the more visually impairing exudative neovascular form, also referred to as disciform or wet AMD. The wet form is distinguished from the atrophic form by the development of choroidal neovascularization (CNV) and serous or hemorrhagic detachment of the retinal pigment epithelium. Risk of developing severe irreversible loss of vision is greatly increased by the presence of CNV.

The NeoVista Epi-Rad90™ Ophthalmic System has been developed to treat CNV by focal delivery of radiation to a subfoveal choroidal neovascular lesion. Using a standard vitrectomy procedure, the cannula tip of a handheld (pipette-like) surgical device is inserted into the vitreous cavity and positioned under visual guidance over the target lesion. The radiation source (strontium-90) is advanced down the cannula until it reaches the tip, which is then held in place over the lesion for a “prescribed” time to deliver focused radiation. The system is designed to deliver a one-time peak dose of beta particle energy (24 Gy) for a target area 3 mm in depth and up to 5.4 mm in diameter. This is believed to be below the dose that is toxic to the retina and optic nerve, and radiation exposure outside of the target area is expected to be minimal.

Other Treatments for AMD

Other available therapeutic options for AMD not addressed in this policy include photodynamic therapy (policy No. 9.03.08) and vascular endothelial growth factor (VEGF) antagonists or angiostatics. These may be administered alone or in combination. Angiostatic agents target various points in the pathway leading to new blood vessel formation (angiogenesis): messenger RNA, VEGFs, and endothelial cell proliferation; migration; and proteolysis. Pegaptanib (Macugen®, Eyetech and Pfizer) and ranibizumab (Lucentis™, Genentech) are presently the only angiostatic drugs approved by the U.S. Food and Drug Administration (FDA) for use in AMD. Pegaptanib and ranibizumab bind extracellular VEGF to inhibit the angiogenesis pathway and are administered by intravitreous injections every 4–6 weeks. Bevacizumab (Avastin, Genentech) has been used off label to treat AMD. It is derived from the same murine monoclonal antibody precursor as ranibizumab and is FDA approved for the treatment of metastatic cancer of the colon or rectum.

For those whose visual losses impair their ability to perform daily tasks, low-vision rehabilitative services offer resources to compensate for deficits. Other treatments for AMD that are considered investigational and/or not medically necessary are addressed in policy Nos. 9.03.10 (transpupillary thermotherapy), and 9.03.11 (photocoagulation of macular drusen).

Regulatory Status

An investigational device exemption (IDE) has been granted by the U.S. Food and Drug Administration (FDA) for a Phase III multicenter trial to provide data for application to the FDA; this is a category B procedure.

Policy

Investigational

Blue Cross Blue Shield of Montana (BCBSMT) Considers intraocular placement of a radiation source for the treatment of choroidal neovascularization investigational

Federal Mandate

Federal mandate prohibits denial of any drug, device, or biological product fully approved by the FDA as investigational for the Federal Employee Program (FEP). In these instances coverage of these FDA-approved technologies are reviewed on the basis of medical necessity alone. Call the BCBSMT FEP Customer Service Department at 1-800-634-3569 for benefit information.

Policy Guidelines

There is a CPT category III code for this procedure effective July 2008:

  • 0190T

CPT code 0190T is to be used in conjunction with 67036.

CPT code 0190T differs from code 67218 because the radiation source is not implanted.

Rationale

This policy was created in 2008 and has since been periodically updated with literature searches using the MEDLINE database. The most recent literature search covers the period of January 2011 through November 2011.

A search of the MEDLINE database when this policy was created did not identify any peer-reviewed publications on epiretinal radiation. The original search did identify some older randomized trials using external beam radiotherapy for age-related macular degeneration (AMD)-associated choroidal neovascularization (CNV). Little to no benefit in visual acuity was observed following repeated single treatments of 2 Gy to a total of 12–20 Gy. (1, 2) The absence of recent literature on external beam radiotherapy suggests that this treatment approach is not being pursued.

Proton Beam

The potential use of proton beam focal epiretinal radiation for management of choroidal neovascularization was described in 2011 using choroidal endothelial cells for an in vitro dose-response study. (3) The investigators noted that, given the radiation complications reported in clinical trials (including radiation retinopathy), further study is needed to test the differential toxicity of proton beam therapy in choroidal endothelial, retinal ganglion, and pigment epithelial cells.

EPI-RAD90™

Three publications from 2 studies have been reported by Avila and colleagues on epiretinal radiation using the EPI-RAD90™ system. (4-6) These are case series that describe outcomes of treatment with EPI-RAD90™ alone or in conjunction with other treatments. No controlled trials of EPI-RAD90™ were identified.

One report described 12-month safety and visual acuity results of a feasibility study in 34 treatment-naïve patients from Turkey, Mexico, and Brazil recruited between February 2005 and February 2006. (4) Patients received a single treatment with either 15 Gy (n=8) or 24 Gy (n=26). Of the 21 patients (62%) who met inclusion criteria and were treated according to protocol, 50% (2 of 4) of the 15 Gy-treated patients and 76% (13 of 17) of the 24 Gy-treated patients improved or maintained their visual acuity at 12 months. In the 24-Gy group, 29% (5 of 17) gained 3 lines or more in visual acuity.

The second report described 12-month safety and visual acuity results from 24-Gy epiretinal radiation combined with bevacizumab in 34 treatment-naïve patients enrolled between June 2006 and April 2007. (5) A second intravitreal injection of bevacizumab was given 1 month after epimacular brachytherapy, and additional injections of bevacizumab could be given at any subsequent visits at the investigator’s discretion. During the first year of the study, a total of 4 additional injections were administered to 3 eyes. Although only 24 of the 34 patients enrolled met the protocol-specified eligibility criteria, all patients were included in the intent-to-treat (ITT) safety and efficacy analysis. Twelve-month follow-up showed an average gain in best-corrected visual acuity (BCVA) of 8.9 letters; 68% of patients had stable or improved vision; and approximately 40% of patients had a gain of 15 or more letters (3 lines). No radiation exposure-related adverse events were detected within the first 12 months, although these events may not be detected for several years. Adverse events related to the device or procedure included subretinal hemorrhage (n=1), retinal tear (n=1), subretinal fibrosis (n=2), epiretinal membrane (n=1), and cataract (6 of 24; 24 patients were phakic at baseline). All occurrences of cataracts were deemed to be related to the vitrectomy procedure.

Two- and 3-year results from this trial were published in 2012. (6) All 34 subjects were followed up for 24 months; 1 site that enrolled 19 patients agreed to re-consent and follow-up the patients for 3 years. In the second year of the study, a total of 10 bevacizumab injections were administered to 7 eyes; and in the third year, a total of 4 injections were administered to 4 eyes. On average, the cohort of subjects followed for 36 months received 3.0 bevacizumab injections.

At 24 months’ follow-up, 35% of patients had gained >1 letter and 15% had gained >15 letters. The mean change in visual acuity at 24 months was -5.6 letters. Twelve of the 24 phakic patients (50%) developed cataracts, and 4 had phacoemulsification with intraocular lens implantation. At 36 months, 53% of patients had gained >1 letter and 21% had gained >15 letters. The mean change in visual acuity at 36 months was +3.9 letters. Seven of 13 phakic patients (54%) developed cataracts, and 4 had phacoemulsification with intraocular lens implantation. One case of nonproliferative radiation retinopathy was observed at 36 months of follow-up.

These uncontrolled case series are not adequate evidence to determine the efficacy of EPI-RAD90™ compared to alternative treatments. Controlled studies are needed to evaluate whether epiretinal radiation therapy improves visual outcomes compared to available alternatives and/or reduces the need for anti-vascular endothelial growth factor (VEGF) therapy.

A search of online site www.clinicaltrials.gov in December 2011 identified the following studies:

NCT00809419 – This is a Phase I and II study of the NeoVista Ophthalmic System (EPI-RAD90™) for the treatment of subfoveal CNV associated with wet AMD in patients who require persistent anti-VEGF therapy to maintain an adequate response to treatment (MERITAGE). This study, which is being conducted at one site in the U.S., has closed recruiting with an estimated enrollment of 32 subjects. The expected study completion date is November 2012.

NCT00679445 – This is a Phase II feasibility study to evaluate the safety and tolerability of the EPI-RAD90™ system, combined with an injection of ranibizumab (Lucentis®), in patients with AMD who have failed primary anti-VEGF therapy. This study has closed recruiting (from 2 sites in the United States) with a projected enrollment of 20 subjects with AMD-related wet CNV. This study has been completed.

NCT00454389 This Phase III, CNV secondary to AMD treated with beta radiation epiretinal therapy (CABERNET) trial is a multicenter, randomized, controlled study to evaluate the safety and efficacy of beta radiation epiretinal therapy combined with 2 injections of ranibizumab (Lucentis®) versus ranibizumab alone. This study has closed recruiting with a projected enrollment of 450 subjects with AMD-related wet CNV from international locations in addition to 30 sites in the U.S. Final data collection for the primary outcome measure was expected to be completed September 2011. The projected study completion date is August 2012.

NCT01006538 This is a multicenter Phase IV randomized controlled trial of macular epiretinal brachytherapy (VIDION® system by NeoVista) versus Lucentis [ranibizumab]-only treatment (MERLOT). The trial is sponsored by King’s College Hospital National Health Service Trust in the United Kingdom (UK) and targets patients who are requiring frequent injections of ranibizumab to try to reduce or eliminate the need for ongoing, regular eye injections. The active control group will continue to receive intravitreal injections of ranibizumab on a monthly basis as required. Twenty-nine sites in the U.K. will be participating. The study has an estimated enrollment of 363 patients with study completion expected in 2014.

Summary

Epiretinal radiation describes the intraocular administration of radiation to the choroidal vascular bed of the retina to treat age-related macular degeneration (AMD). Evidence to date consists of 2 small case series. Controlled studies, which are ongoing, are needed to evaluate whether epiretinal radiation therapy improves health outcomes compared to alternative treatments. In addition, no devices have been approved by the FDA. As a result, this procedure is considered investigational.

Practice Guidelines and Position Statements

The 2011 guidance from the United Kingdom’s National Institute for Health and Clinical Excellence (NICE) states that current evidence on the efficacy of epiretinal brachytherapy for wet age-related macular degeneration (AMD) is inadequate and limited to small numbers of patients. With regard to safety, vitrectomy has well-recognized complications and there is a possibility of subsequent radiation retinopathy. Therefore this procedure should only be used in the context of research. (7)

Rationale for Benefit Administration

This medical policy was developed through consideration of peer reviewed medical literature, FDA approval status, accepted standards of medical practice in Montana, Technology Evaluation Center evaluations, and the concept of medical necessity. BCBSMT reserves the right to make exceptions to policy that benefit the member when advances in technology or new medical information become available.

The purpose of medical policy is to guide coverage decisions and is not intended to influence treatment decisions. Providers are expected to make treatment decisions based on their medical judgment. Blue Cross and Blue Shield of Montana recognizes the rapidly changing nature of technological development and welcomes provider feedback on all medical policies.

When using this policy to determine whether a service, supply or device will be covered please note that member contract language will take precedence over medical policy when there is a conflict.

ICD-9 Codes
Investigational for all diagnoses
ICD-10 Codes
H35.30, H35.31, H35.32, 08B43ZZ, 08B53ZZ, 08H031Z, 08H0X1Z, 08H131Z, 08H1X1Z 
Procedural Codes: 0190T, 67036
References
  1. A prospective, randomized, double-masked trial on radiation therapy for neovascular age-related macular degeneration (RAD Study). Radiation Therapy for Age-related Macular Degeneration. Ophthalmology 1999; 106(12):2239-47.
  2. Stevenson MR, Hart PM, Chakravarthy U et al. Visual functioning and quality of life in the SubFoveal Radiotherapy Study (SFRADS): SFRADS report 2. Br J Ophthalmol 2005; 89(8):1045-51.
  3. Chalam KV, Balaiya S, Malyappa RS et al. Evaluation of choroidal endothelial cell proliferation after exposure to varying doses of proton beam radiation. Retina 2011; 31(1):169-76.
  4. 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(2):157-69.
  5. Avila MP, Farah ME, Santos A et al. Twelve-month short-term 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(3):305-9.
  6. Avila MP, Farah ME, Santos A et al. Three-Year Safety and Visual Acuity Results of Epimacular 90strontium/90yttrium Brachytherapy with Bevacizumab for the Treatment of Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration. Retina 2012; 32(1):10-8.
  7. National Institute for Health and Clinical Excellence. IPG415 Epiretinal brachytherapy for wet age related macular degeneration: guidance. 2011. Available online at: http://guidance.nice.org.uk/IPG415/Guidance/pdf/English  Last accessed December 2011.
History
April 2012  New Policy for BCBSMT: Policy created with literature review; considered investigational
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Epiretinal Radiation Therapy for Age-Related Macular Degeneration