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Radiotherapy for Graves’ Ophthalmopathy^b

Departments of Endocrinology/Metabolism (G.J.K.), Radiology (H.P.R.), Ophthalmology (S.P.), and Medical Statistics (F.K., G.H.) Gutenberg–University Hospital Mainz 55101, Germany

To the editor:

We would like to express our thanks for giving us the opportunity to respond to the letter of the Danish colleagues and to their constructive points of criticism. We have tried to comply with their points where possible and to answer facts that remained unclear. The therapeutic outcome of the randomized, single-blind trial comparing low- vs. high-dose orbital radiotherapy for patients with Graves’ ophthalmopathy (GO) was assessed according to predefined objective criteria, e.g. changes in lid fissure width, proptosis, diplopia, and changes in eye muscle area (1, 2, 3). A detailed NO SPECS classification showing the changes in these classes and their degrees both before and after radiotherapy among all groups has been documented. The clinical activity score for GO (4) and a subjective evaluation by the patients (satisfaction rate at the end of the trial) have been added. All patients were euthyroid before and during therapy. With the exception of subjects with optic neuropathy, this series included consecutive patients with previously untreated and congestive GO. Because one group of patients was treated with a protracted protocol during 20 weeks, subjects with optic neuropathy were excluded from the study and were treated either with high doses of steroids iv or decompressed surgically. All investigations were performed 24 weeks after starting radiotherapy, and neither the radiologist nor the ophthalmologist was informed with respect to the exact study protocol.

In group A (protracted protocol with a single dose of 1 Gray (Gy) per week for a therapy period of 20 weeks), 3 of 21 patients dropped out within 4 weeks after starting treatment. They lived more than 100 km from the university hospital and were no longer willing to drive so far once weekly for retrobulbar irradiation. For these 3 subjects, baseline values only were available. Because both ophthalmic data and valuable information regarding further follow-up were missing, we did not include these patients in the definitive analysis. Even if the 3 excluded patients were considered in the evaluation of the results, similar outcome would be registered between the short 20-Gy regimens and the protracted protocol. Nevertheless, the objective ophthalmic parameters, the findings of the imaging techniques [e.g. magnetic resonance imaging (5, 6), the further follow-up after radiotherapy, the lower rate of subsequent orbital surgery, and especially both the markedly higher satisfaction rate and the minimal side effects] led to a differentiated evaluation of this new therapy regimen and to the conclusions that the protracted protocol seemed to be at least as effective and far better tolerated than the short-arm regimens. We are not drawing false conclusions, because even if the recovery rate in the protracted radiotherapy group should have been calculated as 12 of 21 patients corresponding to 57%, this would give us a similar success rate as in the other two groups. The somehow misleading P value was based on the comparison of basic data between the two groups. Statistical analysis was performed with the help of all obtained values both within as well as between the three different radiotherapy groups. Therefore, we do think that the A protocol might be presented as one aim of the study, namely protracting the treatment scheme and giving antiphlogistic low doses once a week only in subjects with an orbital inflammatory disease, led to markedly different results in comparison with the standard daily regimens. Nevertheless, to further underline the potential advantages of this protocol, we definitely recommend to increase the number of GO patients treated with this new regimen. With this purpose in mind, a European randomized, double-blind, multicenter trial comparing a low-dose short-arm radiotherapy regimen and a protracted protocol will start in the near future.

The conclusion of the primary study aim is the absence of statistical differences, with respect to clinical ophthalmic signs, between low and high doses of orbital radiotherapy. Recent data from our institution have failed to show any beneficial differences for the high-dose treatment (7). To evaluate the long-term efficacy and tolerability of radiotherapy for GO patients, as well as to determine the risk of radiation-induced retinopathy, data of 125 GO subjects irradiated between 1982 and 1998 have been examined retrospectively. Total doses of 20 or 10 Gy (2 or 1 Gy/day) were administered. Median follow-up was 5 yr (0.5–17 yr). No significant differences were registered between the two treatment groups. After irradiation, median decrease of the objective parameters at the latest ophthalmic investigation prior to orbital decompression or squint surgery were as follows: for proptosis -2 mm in both groups; lid fissure width -2.5 vs. -2 mm (10 vs. 20 Gy), and intraocular pressure in up gaze -3 vs. -4.5 mm Hg. Constant diplopia was present in 43 vs. 37% (10 vs. 20 Gy) of the GO subjects before and in 26 vs. 24% after radiotherapy. Decompression and squint surgery were necessary in 28 (10 Gy) vs. 33% (20 Gy) and in 36 vs. 44%, respectively. No retinopathy occurred up to 17 yr after 10 Gy, whereas nonproliferate vascular changes (focal capillary occlusions with microaneurysms) were noted in 4 diabetics and in 1 hypertensive subject (4%) 7–11 yr after 20 Gy. Thus, in the long run, efficacy of 10 and 20 Gy seems similar, whereas side effects may occur after high-dose radiotherapy.

Footnotes

^b Received February 6, 2001. Address correspondence to: Prof. George J. Kahaly, M.D., Department of Endocrinology and Metabolism, University Hospital, Building 303, Mainz 55101, Germany.

References

1. Kahaly GJ, Rösler HP, Pitz S, Hommel G. 2000 Low- vs. high-dose radiotherapy for Graves’ ophthalmopathy–a randomized, single-blind trial. J Clin Endocrinol Metab. 85:102–108.[Abstract/Free Full Text]
2. Kahaly GJ, Gorman CA, Kal KB, et al. 2000 Radiotherapy for Graves’ ophthalmopathy. In: Prummel MF, ed. Recent developments in Graves’ ophthalmopathy. Boston: Kluwer Publishers; 115–131.
3. Gorman CA. 1998 The measurement of change in Graves’ ophthalmopathy. Thyroid. 8:539–543.[Medline]
4. Anonymous. 1992 Classification of eye changes of Graves’ disease. Thyroid. 2:235–236.[Medline]
5. Just M, Kahaly GJ, Higer HP, et al. 1991 Graves’ ophthalmopathy: role of MR imaging in radiation therapy. Radiology. 179:187–190.[Abstract/Free Full Text]
6. Müller-Forell W, Pitz S, Mann W, Kahaly GJ. 1999 Neuroradiological diagnosis of thyroid-associated orbitopathy. Exp Clin Endocrinol Diabetes. 107:177–183.[Medline]
7. Kahaly GJ, Rösler HP, Pitz S, Krummenauer F. 1999 Longterm follow-up of low- and high-dose radiotherapy for Graves’ ophthalmopathy. Thyroid suppl. 72nd Annual Meeting of the American Thyroid Association, Palm Beach, FL, 1999, p 29 (Abstract).

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