Elsevier

The Lancet

Volume 355, Issue 9214, 29 April 2000, Pages 1505-1509
The Lancet

Articles
Radiotherapy for Graves' orbitopathy: randomised placebo-controlled study

https://doi.org/10.1016/S0140-6736(00)02165-6Get rights and content

Summary

Background

The best treatment (steroids, irradiation, or both) for moderately severe Graves' orbitopathy, a self-limiting disease is not known. We tested the efficacy of extemal beam irradiation compared with sham-irradiation.

Methods

In a double-blind randomised clinical trial, 30 patients with moderately severe Graves' orbitopathy had radiotherapy (20 Gy in ten fractions), and 30 were assigned sham-irradiation (ten fractions of O Gy). Treatment outcome was measured qualitatively by changes in major and minor criteria and quantitatively in several ophthalmic and other variables, such as eyelid aperture, proptosis, eye movements, subjective eye score, and clinical-activity score at 24 weeks.

Findings

The qualitative treatment outcome was successful in 18 of 30 (60%) irradiated patients versus nine of 29 (31%) sham-irradiated patients at week 24 (relative risk [RR]=1·9 [95% Cl 1·0–3·6], p=0·04). This difference was caused by improvements in diplopia grade, but not by reduction of proptosis, nor of eyelid swelling. Quantitatively, elevation improved significantly in the radiotherapy group, whereas all other variables remained unchanged. The field of binocular single vision was enlarged in 11 of 17 patients after irradiation compared with two of 15 after sham-irradiation. Nevertheless, only 25% of the irradiated patients were spared from additional strabismus surgery.

Interpretation

In these patients with moderately severe Graves' orbitopathy, radiotherapy should be used only to treat motility impairment.

Introduction

Graves' orbitopathy can be classified as mild, moderately severe, and vision-threatening. In mild orbitopathy, local measures such as lubricants, sunglasses, and prisms are sufficient while awaiting spontaneous recovery. In vision-threatening orbitopathy, treatment is either by prednisone pulse therapy or by immediate surgical orbital decompression.1 In moderately severe orbitopathy, however, what to do is not clear. Patients may be disabled considerably by painful, watering eyes and double vision, and feel socially embarrassed because of eyelid swelling and proptosis.2 As a result, the quality of their lives is greatly decreased3 and the demand for treatment is strong.

Graves' orbitopathy is thought to be an autoimmune disease characterised by an inflammatory phase followed by fibrosis.4 Surgery to correct eyelid swelling, proptosis, and diplopia is effective, but cannot be done until the inflammatory phase has passed.5 To arrest the inflammatory phase, several types of immunosuppressive treatments have been investigated. Oral steroids are effective, but have many and frequent side-effects.6 Ciclosporin, used as single-drug treatment has shown to be of little value, but in combination with corticosteroids it could be of benefit because it allows lowering of the dose of steroids required.6 Plasmapheresis has only a temporary effect.7 Intravenously administered high-dose immunoglobulin8 and octreotide9 seem effective, but are expensive.

Fibroblasts, which are thought to have a key role in the development of initial oedema and consequent fibrosis are highly sensitive to small doses of irradiation. Irradiation, therefore, could be a way to arrest the immune process and has been applied since the 1930s. Reports on the efficacy of radiotherapy for Graves' orbitopathy, however, are conflicting because of their retrospective nature and the fact that radiotherapy was often given in combination with steroids.10, 11 Previously, in a controlled clinical trial, we have shown that oral prednisone and orbital irradiation are equally effective in the treatment of the disease.11 Because radiotherapy lacks the many side-effects of corticosteroids, it would be the first choice in patients with an active, moderately severe form of the disease. Graves' disease, however, is judged as being self-limiting and the improvements seen in our study could also be explained as part of the natural course of the disease. Controlled data of spontaneous improvements or worsening of Graves' eye disease are scarce. Therefore, we designed a double-blind, randomised, clinical trial to assess whether retrobulbar irradiation lessens the severity of Graves' orbitopathy more than sham-irradiation.

Section snippets

Patients

We included consecutive patients with moderately severe Graves' orbitopathy. The diagnosis of disease was based on the presence of typical clinical features of the disease, such as eyelid retraction and swelling, proptosis, impaired motility, an increase of intraocular pressure in upward gaze, together with one or more enlarged extraocular eye muscles, and increased intraorbital fat on a coronal computed-tomography scan of the orbits.6, 12 Patients were judged to have moderately severe Graves'

Patients

Between December, 1993 and February, 1997, 368 patients with Graves' eye disease were referred to our department. 91 were eligible for participation in the trial, but 31 patients refused because of: a lack of faith in this treatment (n=three); fear of treatment (two); a wish to receive nothing but radiotherapy (13); a wish to have nothing but surgery (three); or the difficulty of visiting hospital at least ten more times (ten). The patients who refused to participate in the trial had similar

Discussion

Reports differ about the efficacy of radiotherapy for Graves' orbitopathy. Several studies10, 11, 12, 14 showed overall success of about 60%, but the reported effects on individual items such as soft-tissue involvement, proptosis, eye motility, and optic neuropathy are conflicting. The frequently referred to study of Donaldson and colleagues10 was not controlled, and biased because six of their 23 patients received more than one treatment (radiotherapy plus corticosteroids) at the same time,

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