Radiotherapy for age-related macular degeneration: no more pilot studies please

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Age-related macular degeneration (AMD) is a major health problem for the United Kingdom. Currently, AMD accounts for the majority of the 124 000 blind registrations in the over 65 age group. This demonstrates that AMD is also an immensely frustrating condition for patients and their doctors as current treatments are extremely limited both for the atrophic form and for choroidal neovascularization (CNV). CNV while accounting for 10% of the disease, disproportionately causes up to 88% of the legal blindness associated with AMD. Conventional laser treatments for CNV improve vision in only 5% of cases and are suitable only for a minority of patients. Therefore, there is a pressing need for novel and effective therapies. Investment in research makes sense financially as well, as the considerable costs to the NHS in managing visually impaired patients could be significantly reduced with better treatments for CNV. One possible novel therapy for the treatment of CNV associated with AMD is ionising radiation. Radiotherapy seems rational because of its known ability to inactivate rapidly proliferating cells such as the capillary endothelium of CNV. Such cells typically manifest impaired radiation damage repair relative to adjoining slowly proliferating cells. A differential survival response might therefore be exploited with CNV destroyed through DNA breaks that normal tissues have time to repair before undergoing cell division. Although radiation dose fractionation with multiple small treatments over many days is commonly used to reduce normal tissue complications in the treatment of malignancies, since CNV is not a true neoplasm, arguments have been made that there may be no therapeutic advantage to dose fractionation, especially if the volume irradiated can be restricted to the region of macula (it is an axiom of radiotherapy that the probability of complications is proportional to the size of the target volume). In the journal this month, however, a radiotherapy trial is reported which shows no benefit in AMD. Should we therefore abandon this treatment in AMD? The short answer is no, because of the theoretical rationale for why radiotherapy may work and a series of studies which have given enticing hints that it may still be of benefit in AMD. Research into radiotherapy as a treatment modality for AMD started in earnest 10 years ago after Chakravarthy et al demonstrated significant regression in (CNV) following external beam radiotherapy in an animal model and later in a phase I study. Since then a multitude of small pilot studies using standard fractions of 2–3 Gy with a total dose of 10–20 Gy have been published, some showing better maintenance of visual acuity in treated eyes, while others failed to show any benefit. Overall, prior to the study by Hoeller et al there have been 10 randomised control trials (RCT), three nonrandomised trials and eight case series each with over 100 people in the study (see Table 1). Among the above RCTs, three studies demonstrated a significant reduction in visual loss when comparing radiotherapy to very lowdose (effectively sham) radiotherapy or observation. The National Institute for Clinical Excellence recognises the modest benefits from radiotherapy while justifying its restricted usage within ethically approved quality clinical trials in the UK. Part of the challenge with radiotherapy is in finding an appropriate radiation regimen. The difficulty lies in the many different ways and dosage schedules by which ionising radiation can be applied to the eye. The biologically Received: 1 September 2004 Accepted: 1 September 2004 Published online: 22 October 2004 University of Southampton, UK