Mourits M, van Kempen-Harteveld M, Garci M, Koppeschaar H, Tick L, Terwee C. Radiotherapy for Graves' orbitopathy: randomized placebo-controlled study. Lancet 2000;355:1505–1509.
Original study reprint requests: M. P. Mourits, Donders Institute of Ophthalmology, University Medical Centre, Utrecht, Heidelberglaan 100, 3584 CX Utrecht, Netherlands.
To test the efficacy of external beam irradiation compared with sham irradiation.
Double-blind randomized clinical trial.
Donders Institute of Ophthalmology, Utrecht, Netherlands, Departments of Radiotherapy and Endocrinology, UMCU; and Clinical Epidemiology and Biostatistics, Academic Medical Centre, Amsterdam, Netherlands.
In a double-blind randomized clinical trial, 30 patients with moderately severe Graves orbitopathy had radiotherapy (20 Gy in 10 fractions), and 30 were assigned sham irradiation (10 fractions of 0 Gy). Treatment outcome was measured qualitatively in several ophthalmic and other variables, such as eyelid aperture, proptosis, eye movements, subjective eye score, and clinical-activity score at 24 weeks.
Eyelid aperture, proptosis, eye movements, subjective eye score, and clinical-activity score at 24 weeks.
The qualitative treatment outcome was successful in 18 of 30 (60%) irradiated patients versus 9 of 29 (31%) sham-irradiated patients at week 24 (relative risk = 1.9; 95% CI: 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 2 of 15 after sham-irradiation. Nevertheless, only 25% if the patients treated with irradiation were spared from addition strabismus surgery.
In these patients with moderately severe Graves orbitopathy, radiotherapy should be used only to treat motility impairment.
Graves ophthalmology represents a frustrating disease both for the patient and clinician. The patients are highly distressed by the functional and cosmetic changes that they experience, and clinicians are frustrated by lack of efficacious treatment. Among the modalities that have been suggested include conservative, watchful waiting “for the disease to stabilize” with subsequent surgical reconstruction as necessary or radiation therapy or corticosteroid therapy. Corticosteroid therapy has a high morbidity and as such is generally recommended only for a short time to treat compressive optic neuropathy. Its use for congestive orbitopathy, proptosis, or strabismus is not recommended. “Watchful waiting” is necessary before surgical intervention in all cases, with the exception of those patients in whom acute exposure keratopathy or optic neuropathy threaten permanent visual loss. Otherwise, orbital decompression surgery, strabismus surgery, or eyelid surgery are not recommended until the underlying disease process is stabilized or plateaued, something that may take 1 year or more. Surgery is not recommended during the acute inflammatory phase because it is not advisable to operate on a “moving target.” Radiotherapy has enjoyed some favor over the years because it is something that can be administered “right away” and does not require a delay for the disease to “cool down.” In fact, radiotherapy has been thought to be most successful when used on the acute inflammatory phase of the condition.
Despite its historical acceptance, radiotherapy for Graves ophthalmopathy has not previously been rigorously evaluated in a randomized fashion. The article by Mourits et al. is a landmark study. In this controlled, double-blind, randomized clinical trial, the patients consisted of a group with moderately severe Graves orbitopathy who were rendered euthyroid by a “block and replace therapy” with an antithyroid drug levothyroxine. These patients were then randomized to receive either orbital irradiation with the midline dose of 20 Gy in 10 fractions during 12 days or sham irradiation. The surprising findings in these patients was that significant differences were not found between the radiotherapy and sham groups in either their need for subsequent surgeries or their subsequent degree of orbital inflammation. The authors found the only significant difference was that the range of extraocular motility in upgaze was statistically better in the irradiated group than in the sham-irradiated group. Interestingly, however, there was not a significant difference in ultimate need for extraocular muscle surgery because patients after irradiation, although improved, still required surgery at a similar rate to achieve single binocular vision in primary gaze. The authors specifically found no reduction in eyelid retraction, eyelid swelling, or proptosis after irradiation. The authors concluded that patients with moderately severe Graves orbitopathy should be treated with irradiation only for the treatment of motility impairment, and even then it was unlikely to allow the patients to avoid subsequent strabismus surgery.
These findings by Mourits et al. are not dissimilar to those reported by Gorman and Garrity and colleagues in the September issue of Ophthalmology. 1 In this group, the authors reported on 41 patients older than age 30 with moderately symptomatic Graves ophthalmopathy. One randomly selected orbit was treated with 20 Gy of external beam therapy, whereas sham therapy was given to the other side. Six months later the therapies were reversed. The authors looked for changes in extraocular muscle and fat, proptosis, range of extraocular muscle motion, area of diplopia fields, and lid fissure width to see whether irradiation therapy was effective in modifying one or more of these parameters. The authors were not able to demonstrate any beneficial therapeutic effect.
In light of both of these studies, we must conclude that orbital irradiation does not have a significant role in the treatment of patients with symptomatic Graves ophthalmopathy. It should be emphasized that neither of these studies was designed to look at the role of orbital irradiation in treating patients with compressive optic neuropathy ion patients with Graves orbitopathy generally occurs because of the enlargement of extraocular muscles, which can centrically “squeeze” the optic nerve at the orbital apex. The finding of Gorman and Garrity and colleagues that orbital irradiation did not decrease extraocular muscle size or proptosis, however, would strongly suggest that irradiation would be unlikely to have a beneficial effect on compressive optic neuropathy as well.
An accompanying editorial to Gorman and Garrity's article cautioned that there are variabilities in timing of therapy in these patients. Variability and multiplicity of clinical manifestations, and previous confounding therapies called for a “larger multi-center study using carefully defined clinical progression” before a definitive conclusion could be drawn. However, in the meantime, there is little clinical justification for recommending orbital irradiation for patients with Graves ophthalmopathy unless as part of such a larger randomized multicenter study.