How effective is radiotherapy for treating wet age-related macular degeneration (AMD) (a degenerative eye condition)?

Why this question is important
AMD is a common condition of the eyes that may develop in people aged over 50. It affects the central area (macula) of the back of the eye (retina). First, yellow spots (drusen) develop under the retina. These can been seen by health professionals during examinations of the eyes. As AMD progresses, new blood vessels can grow in the macula. These vessels may bleed or cause scarring; this is called ‘neovascular’ or ‘wet’ AMD. Wet AMD can cause people to lose the central part of their vision.

There is no cure for wet AMD. However, there are treatments designed to stop vision from worsening. One such treatment is radiotherapy (using radiation to kill harmful cells). To find out how effective radiotherapy is for treating wet AMD and whether it causes unwanted effects, we reviewed the evidence from research studies.

How we identified and assessed the evidence
First, we searched for all relevant studies in the medical literature. We then compared the results, and summarized the evidence from all the studies. Finally, we assessed how certain the evidence was. We considered factors such as the way studies were conducted, study sizes, and consistency of findings across studies. Based on our assessments, we categorized the evidence as being of very low-, low-, moderate- or high-certainty.

What we found
We identified 18 relevant studies on a total of 2340 people with wet AMD. These studies mainly took place in Europe and North America, though two studies were from Japan and one study included sites in South America. Fifteen studies investigated external beam radiotherapy and three studies investigated internal radiotherapy (brachytherapy), where radioactive materials are placed on the surface of the eye.

Studies compared:

➩ radiotherapy alone with no radiotherapy or a sham treatment (14 studies,1223 people); or

➩ radiotherapy plus eye injections (of a medicine called anti-vascular endothelial growth factor (VEGF)) with eye injections only (four studies,1117 people); or

The studies showed that:

When radiotherapy was compared with no radiotherapy or a sham treatment, at 12-month follow-up

➩ There may be little difference in how likely people’s vision is to worsen by 3 lines or more on a vision chart (low-certainty).

➩ There may be a small difference in average visual sharpness (in the order of 1 line of a vision chart) favouring radiotherapy (low-certainty).

➩ People’s ability to distinguish between bright and dim parts of an image may be slightly better with radiotherapy (low-certainty).

➩ The evidence on growth of new blood vessels in the back of the eye was inconsistent (very low-certainty).

➩ There may be little difference in quality of life (low-certainty).

➩ Studies that recorded unwanted effects generally reported no radiation-associated damage to the retina or optical nerve. Other unwanted effects, such as cataracts, were uncommon. There was no consistent evidence that unwanted effects were more likely in the radiation group (low-certainty).

When radiotherapy combined with anti-VEGF was compared with anti-VEGF alone, 12 months follow-up

➩ People treated with radiotherapy plus anti-VEGF are probably twice as likely to lose 3 lines or more on a vision chart than people treated with anti-VEGF alone (moderate-certainty).

➩ Studies reported inconsistent results on average vision sharpness (low-certainty) and new vessel growth (very low-certainty evidence). Average vision sharpness may be worse with brachytherapy.

➩ No studies investigated the impact on people’s ability to distinguish between bright and dim parts of an image, or quality of life.

➩ Three out of four studies reported few unwanted effects and no radiation-associated damage to the retina or optical nerve. In one study, half of the people treated with brachytherapy reported unwanted effects (particularly cataracts) and there were some instances of damage to the retina caused by the brachytherapy (low-certainty).

➩ In three out of four studies, people treated with radiotherapy received fewer anti-VEGF injections (moderate-certainty).

Conclusion
It is uncertain whether radiotherapy on its own or with eye injections of anti-VEGF is effective for treating wet AMD.

How up-to-date is this review?
Cochrane researchers searched for studies that had been published up to 4 May 2020.  

Authors' conclusions: 

The evidence is uncertain regarding the use of radiotherapy for neovascular AMD. Most studies took place before the routine use of anti-VEGF, and before the development of modern radiotherapy techniques such as stereotactic radiotherapy. Visual outcomes with epimacular brachytherapy are likely to be worse, with an increased risk of adverse events,  probably related to vitrectomy. The role of stereotactic radiotherapy combined with anti-VEGF is currently uncertain. Further research on radiotherapy for neovascular AMD may not be justified until current ongoing studies have reported their results.

Read the full abstract...
Background: 

Radiotherapy has been proposed as a treatment for new vessel growth in people with neovascular age-related macular degeneration (AMD).

Objectives: 

To examine the effects of radiotherapy on neovascular AMD.

Search strategy: 

We searched CENTRAL, MEDLINE, Embase, LILACS and three trials registers and checked references of included studies. We last searched the databases on 4 May 2020. 

Selection criteria: 

We included all randomised controlled trials in which radiotherapy was compared to another treatment, sham treatment, low dosage irradiation or no treatment in people with choroidal neovascularisation (CNV) secondary to AMD.

Data collection and analysis: 

We used standard procedures expected by Cochrane. We graded the certainty of the evidence using GRADE. We considered the following outcomes at 12 months: best-corrected visual acuity (BCVA) (loss of 3 or more lines, change in visual acuity), contrast sensitivity, new vessel growth, quality of life and adverse effects at any time point. 

Main results: 

We included 18 studies (n = 2430 people, 2432 eyes) of radiation therapy with dosages ranging from 7.5 to 24 Gy. These studies mainly took place in Europe and North America but two studies were from Japan and one multicentre study included sites in South America. Three of these studies investigated brachytherapy (plaque and epimacular), the rest were studies of external beam radiotherapy (EBM) including one trial of stereotactic radiotherapy. Four studies compared radiotherapy combined with anti-vascular endothelial growth factor (anti-VEGF) with anti-VEGF alone. Eleven studies gave no radiotherapy treatment to the control group; five studies used sham irradiation; and one study used very low-dose irradiation (1 Gy). One study used a mixture of sham irradiation and no treatment. Fifteen studies were judged to be at high risk of bias in one or more domains.

Radiotherapy versus no radiotherapy

There may be little or no difference in loss of 3 lines of vision at 12 months in eyes treated with radiotherapy compared with no radiotherapy (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.64 to 1.04, 811 eyes, 8 studies, I2 = 66%, low-certainty evidence). Low-certainty evidence suggests a small benefit in change in visual acuity (mean difference (MD) -0.10 logMAR, 95% CI -0.17 to -0.03; eyes = 883; studies = 10) and average contrast sensitivity at 12 months (MD 0.15 log units, 95% CI 0.05 to 0.25; eyes = 267; studies = 2). Growth of new vessels (largely change in CNV size) was variably reported and It was not possible to produce a summary estimate of this outcome. The studies were small with imprecise estimates and there was no consistent pattern to the study results (very low-certainty evidence). Quality of life was only reported in one study of 199 people; there was no clear difference between treatment and control groups (low-certainty evidence). Low-certainty evidence was available on adverse effects from eight of 14 studies. Seven studies reported on radiation retinopathy and/or neuropathy. Five of these studies reported no radiation-associated adverse effects. One study of 88 eyes reported one case of possible radiation retinopathy. One study of 74 eyes graded retinal abnormalities in some detail and found that 72% of participants who had radiation compared with 71% of participants in the control group had retinal abnormalities resembling radiation retinopathy or choroidopathy. Four studies reported cataract surgery or progression: events were generally few with no consistent evidence of any increased occurrence in the radiation group. One study noted transient disturbance of the precorneal tear film but there was no evidence from the other two studies that reported dry eye of any increased risk with radiation therapy. None of the participants received anti-VEGF injections.

Radiotherapy combined with anti-VEGF versus anti-VEGF alone

People receiving radiotherapy/anti-VEGF were probably more likely to lose 3 or more lines of BCVA at 12 months compared with anti-VEGF alone (RR 2.11, 95% CI 1.40 to 3.17, 1050 eyes, 3 studies, moderate-certainty). Most of the data for this outcome come from two studies of epimacular brachytherapy (114 events) compared with 20 events from the one trial of EBM. Data on change in BCVA were heterogenous (I2 = 82%). Individual study results ranged from a small difference of -0.03 logMAR in favour of radiotherapy/anti-VEGF to a difference of 0.13 logMAR in favour of anti-VEGF alone (low-certainty evidence). The effect differed depending on how the radiotherapy was delivered (test for interaction P = 0.0007). Epimacular brachytherapy was associated with worse visual outcomes (MD 0.10 logMAR, 95% CI 0.05 to 0.15, 820 eyes, 2 studies) compared with EBM (MD -0.03 logMAR, 95% CI -0.09 to 0.03, 252 eyes, 2 studies). None of the included studies reported contrast sensitivity or quality of life. Growth of new vessels (largely change in CNV size) was variably reported in three studies (803 eyes). It was not possible to produce a summary estimate and there was no consistent pattern to the study results (very low-certainty evidence). For adverse outcomes, variable results were reported in the four studies. In three studies reports of adverse events were low and no radiation-associated adverse events were reported. In one study of epimacular brachytherapy there was a higher proportion of ocular adverse events (54%) compared to the anti-VEGF alone (18%). The majority of these adverse events were cataract. Overall 5% of the treatment group had radiation device-related adverse events (17 cases); 10 of these cases were radiation retinopathy. There were differences in average number of injections given between the four studies (1072 eyes). In three of the four studies, the anti-VEGF alone group on average received more injections (moderate-certainty evidence).

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