Orbital Radiotherapy for Graves’ Ophthalmopathy

Luigi Bartalena, Claudio Marcocci and Aldo Pinchera

Departments of Endocrinology, University of Insubria (L.B.), Varese, Italy, and University of Pisa (C.M., A.P.), Pisa, Italy

Address all correspondence and requests for reprints to: Prof. Luigi Bartalena, M.D., University of Insubria, Division of Endocrinology, Ospedale di Circolo, Viale Borri, 57, 21100 Varese, Italy. E-mail: l.bartalena{at}libero.it or luigi.bartalena{at}uninsubria.it.

Management of Graves’ ophthalmopathy (GO) is a major therapeutic challenge, and the therapeutic outcome is often unsatisfactory (1). Although novel treatments such as somatostatin analogs, cytokine antagonists, and antioxidants are currently being or will shortly be evaluated in randomized controlled trials, after several decades of investigations the mainstays of GO management are still high-dose glucocorticoids, orbital radiotherapy, and orbital decompression, but results obtained with these treatments are often unsatisfactory (1). Whereas orbital surgery is aimed at expanding the available space for the increased orbital content, glucocorticoids and irradiation are aimed at decreasing orbital content in view of nonspecific antiinflammatory actions and specific immunological effects.

Orbital radiotherapy has been used for over 60 yr in the treatment of GO and is currently performed by supervoltage apparatus, mostly linear accelerators (2). A review of papers published between 1973 (first study in which a linear accelerator was used) and 2000 showed that positive results were obtained in 59% of 624 cumulative patients (2). It should be mentioned that most studies were either retrospective or nonrandomized and/or uncontrolled. The last 3 yr have witnessed important discussions on the role of orbital radiotherapy, in particular questioning its effectiveness and safety (3, 4, 5, 6, 7, 8, 9). Most authors agree that orbital radiotherapy is a safe procedure. If the technique of irradiation is correct, there seems to be no increased risk of cataract and only a remote risk of retinopathy, with the exception of patients with diabetic and, possibly, hypertensive retinopathy (10, 11). The two latter conditions, especially if associated, should be considered as relative contraindications to orbital radiotherapy, in particular when signs of retinopathy are present before irradiation. It is worth noting that, even after a very long follow-up, orbital radiotherapy does not seem to bear a risk of radiation-induced tumors (10, 12, 13).

Thus, whereas safety of orbital radiotherapy is not a major matter of argument, substantially more controversy exists as to its real effectiveness. The debate has been revitalized by a recent randomized, placebo-controlled, double-blind study from the Mayo Clinic (14). In the original experimental design of this study, only one orbit of 42 patients with moderately severe GO was irradiated, whereas the contralateral orbit served as internal control. A detailed analysis of objective measures was provided, leading the authors to conclude that orbital radiotherapy is ineffective (14) and should, therefore, not be offered to GO patients (3). Although Gorman and co-workers are to be congratulated on the major effort they made, this study was criticized for several reasons, including the fact that many patients had a long-standing ophthalmopathy and had been treated, likely without success, by systemic glucocorticoids (5, 15). Patients who do not respond to glucocorticoids are unlikely to show any benefit from orbital radiotherapy. In addition, the observation that the untreated orbit did not show any improvement or worsening during the 6-month period of observation further suggests that enrolled patients had stable, nonprogressive, i.e. inactive ("burnt-out") eye disease.

What did the other few available randomized, controlled trials tell us about the efficacy of orbital radiotherapy for GO? In 1993, a randomized double-blind trial of prednisone vs. orbital radiotherapy in patients with moderately severe GO (16) demonstrated that the proportion of responders in prednisone-treated (14 of 28, 50%) and irradiated (13 of 28, 46%) patients (18%) was similar. Because all agree that glucocorticoids are an effective treatment for GO, this study provided good, albeit indirect, evidence that orbital radiotherapy is also effective. In addition, the above study also demonstrated a decrease in eye muscle volume, as assessed by the eye muscle score (16). In a randomized, single-blind study, Kahaly et al. (17) evaluated the outcome of orbital radiotherapy using different radiation doses. Irrespective of small differences observed using low-dose vs. high-dose radiotherapy, beneficial effects of radiotherapy were observed in all three groups of patients in 55 to 67% of cases. In a double-blind randomized study, 60 patients with moderately severe GO were submitted to either orbital radiotherapy or sham-irradiation (18). The qualitative treatment outcome was successful in 60% of irradiated patients and in only 31% of sham-irradiated patients, the latter being representative of the natural history of the disease (18). Improvement was mainly confined to eye movements, but do not forget that diplopia is one of the most disturbing changes observed in GO; it should also be noted that 25% of irradiated patients were saved from additional strabismus surgery (18).

The paper by Prummel et al. (19) in this issue of JCEM provides new important information about the use of orbital radiotherapy for GO. This double-blind, randomized clinical trial is the first to address the question of whether orbital radiotherapy has a place in the management of nonsevere GO. Based on the evaluation of changes in prespecified major and minor criteria, primary therapeutic outcome was successful in 52% of irradiated patients and in only 27% of sham-irradiated patients (19), with an improvement in eye muscle function and diplopia and a reduction, albeit modest, in the need of follow-up treatments in the irradiated group. It should, however, be noted that orbital radiotherapy was not associated with a greater improvement of quality of life, compared with sham-irradiation (19). Additionally important, although negative, information is that orbital radiotherapy did not prevent progression to more severe expressions in about 15% of patients in both groups. The reason why severe forms of GO develop is presently unclear, but it seems that environmental factors play a decisive role in this progression (20). Thus, if the study by Prummel et al. (19) lends further support to the concept that orbital radiotherapy is in general an effective treatment for GO, it also suggests that the commonly adopted policy of "wait-and-see" in cases of mild GO should be maintained, also in view of cost/benefit considerations.

In summary, what is the message that can be conveyed to the reader, based on the present and previous studies? We believe that orbital radiotherapy still has an important role in the management of GO. Although many studies available in the literature may have a limited impact owing to selection bias, retrospective and uncontrolled features, and lack of appropriate ophthalmological assessment, in times of evidence-based medicine it cannot be denied that four of five randomized and (with one exception) controlled studies (14, 16, 17, 18, 19) showed that orbital radiotherapy is effective on GO, especially on extraocular muscle involvement. Orbital radiotherapy, by burning out eye disease, can also make eye muscle and/or eyelid corrective surgery possible at an earlier stage. The effectiveness of orbital radiotherapy can be increased by the synergistic interaction with glucocorticoids (2). Accordingly, we believe that orbital radiotherapy should still be offered as a valid therapeutic option to patients with moderate to severe GO. Needless to say, selection of patients is fundamental, because patients with inactive ("burnt-out") GO are unlikely to respond to irradiation (as well as to glucocorticoids). In this regard, the use of orbital radiotherapy in the early stage of disease (possibly less than 1 yr from the onset) is recommended. Finally, owing to current controversies, the final word on the efficacy of orbital radiotherapy should come, as both detractors and supporters of radiotherapy agree, from well-designed, multicenter, randomized and controlled studies enrolling a large number of patients. The recently established European Group of Graves’ Orbitopathy (EUGOGO) is a good example of a structure in which such studies can be designed and carried out.

Footnotes

This work was supported in part by grants from the University of Insubria (Fondi d’Ateneo per la Ricerca, Varese, Italy) and from the Ministero dell’Istruzione, Università e Ricerca (Rome, Italy) (to L.B.).

Abbreviation: GO, Graves’ ophthalmopathy.

Received October 9, 2003.

Accepted October 15, 2003.

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