Controversy grows over use of orbital radiotherapy in treatment of thyroid eye disease

By Sean Henahan

While recent reports in journals call into question the role of radiotherapy in the treatment of thyroid eye disease, the approach should not be abandoned in all cases, according to some clinicians.

Researchers at the Mayo Clinic published a controversial negative study on orbital radiotherapy in the treatment of Graves ophthalmopathy in a recent issue of Ophthalmology (2001; 108: 1523-34). The Minnesota study evaluated the effect of radiotherapy in an unusual protocol in which 42 patients with Graves ophthalmopathy were treated first in one eye, and then six months later in the other eye.
Surprisingly, the researchers noted no difference in proptosis, muscle volume, range of motion or width of the lid fissure between treated and untreated eyes at six months. Additional follow-up after 12 months also revealed no differences in the first or second treated eyes.

“Because this treatment is still in wide use, is expensive and is not without risk, it is our belief that it should not be used for patients with mild or moderately severe ophthalmopathy,” said lead author Colum Gorman MD, Mayo Clinic, Rochester, Minnesota.

Dr Gorman noted that while the treatment has been used for 80 years, its effectiveness has never been convincingly demonstrated. He suggested there might have been a perception that the treatment was effective because of the tendency of Grave’s disease to remit naturally over time.

All participants in the study had symptoms of mild to moderate Grave’s ophthalmopathy. Symptoms included eye pain, lacrimation and photophobia.
The protocol additionally required that patients have at least three of the following symptoms: conjunctival or eyelid edema; lid retraction; staring or bulging eyes; proptosis of at least 20 mm; and decreased eye movement. Computed tomography confirmed muscle enlargement in all patients prior to treatment.

External radiation treatment consisted of 20 Gy delivered in 10 fractions to one eye chosen at random. The other eye received sham radiation, with the radiation beam blocked at the source. The control eyes never received more than 2 Gy of radiation.
Six months later the process was reversed, with active treatment of the second eye and sham treatment of the first. The study protocol excluded patients with optic neuropathy and more severe disease. The current results should not be extrapolated to those patient groups, the researchers stressed.

“Even though the study appeared in a leading journal from a leading institution, I think there are some flaws with it. Some would say those included in the study would not have been good candidates anyway. That is why there was no significant difference.
“We still use radiation therapy and feel there are appropriate indications, such as optic neuropathy and orbital inflammation,” Don Kikkawa MD, Director of the Orbital and Oculoplastic Service at the Shiley Eye Center, La Jolla, California, told EuroTimes.

Second study also negative
Another recent study, published in the April 2002 issue of the Journal of the American Academy of Paediatric Ophthalmology and Strabismus, arrived at a conclusion similar to the Mayo Clinic study.

John D Ferris FRCOphth and colleagues in the Department of Ophthalmology, Cheltenham General Hospital, England looked at the effect of orbital radiotherapy on the field of binocular single vision. The retrospective review of all cases treated between 1992 and 1998 indicated that orbital radiotherapy was ineffective in treating restrictive thyroid myopathy and improving binocular function in patients with thyroid eye disease.

The debate goes on
A debate is now developing in the ophthalmology community on what, if any, the role of orbital radiotherapy should be in the treatment of thyroid eye disease.

“The authors can be faulted for not providing more information about the patients, but they argue persuasively that it would be difficult to claim benefit for a treatment that does not alter the fundamental causes of the clinical manifestations of Graves ophthalmopathy, which are enlargement of the extraocular muscles and retroorbital fat and impairment of muscle function,” noted Robert D Utiger MD, Professor of Medicine at Harvard Medical School, in the journal Clinical Thyroidology.

The issue was also chosen for debate in the Controversies in Ophthalmology section of a recent issue of the British Journal of Ophthalmology (2002;86:102-107).
Arguing in favour of radiotherapy, Dr Kimberley P Cockerham and Dr John S Kennerdell, Allegheny General Hospital, Pittsburgh, PA, maintain that radiotherapy has a key role in the management of moderate to severe inflammatory symptoms and is effective treatment for optic nerve compromise.

They assert that external beam radiation can help to arrest the underlying immune process that produces orbital inflammation. They also cite clinical studies suggesting that radiation can improve motility during the active inflammatory phase, noting that it is ineffective against fibrotic extraocular muscle restriction. They also concur that proptosis does not respond to external beam radiation.
Maarten Mourits MD, Department of Ophthalmology, University Hospital Utrecht, took an opposing view. Echoing the comments of Dr Gorman, he noted that it is very difficult to evaluate treatments of orbitopathy because of the variable natural course of the disease.

He referred to his own research, a controlled randomised clinical trial comparing radiotherapy to sham irradiation in patients with moderately severe orbitopathy (Lancet 2000;355:1505–9). That study did not demonstrate any treatment-associated improvement in soft tissue signs, proptosis or ocular motility.

He notes that radiotherapy, or corticosteroids, may have the potential to reduce the period of disease activity in thyroid orbitopathy. This will be difficult to prove because of disagreement about reliable parameters for the assessment of disease activity. He said that in his study, which used the clinical activity score as the index of disease activity, patients showed a more rapid fall of disease activity after radiotherapy than after sham irradiation.

Scepticism replaces enthusiasm
“With the introduction of more advanced, evidence-based clinical trials, the initial enthusiasm about the efficacy of radiation for thyroid orbitopathy has been replaced by scepticism. At present, orbital radiotherapy remains useful in the treatment of a select number of patients with thyroid orbitopathy, but overall its place in management is uncertain,” he said in his commentary.

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