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 Table of Contents  
ORIGINAL ARTICLE
Year : 2013  |  Volume : 3  |  Issue : 3  |  Page : 91-94

Clinical outcomes of orbital radiotherapy combined with systemic glucocorticoids for patients with Graves' ophthalmopathy refractory to steroid therapy☆


1 Department of Ophthalmology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan
2 Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan
3 Department of Ophthalmology, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan

Date of Web Publication22-Aug-2013

Correspondence Address:
Chieh-Chih Tsai
Department of Ophthalmology, Taipei Veterans General Hospital, Number 201, Section 2, Shih-Pai Road, Taipei
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.1016/j.tjo.2013.04.008

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  Abstract 


Purpose: To investigate the clinical outcomes of combined orbital radiotherapy and systemic glucocor-ticoids for patients with refractory Graves’ ophthalmopathy (GO).
Materials and methods: The records were retrospectively reviewed of six patients with active moderate-to-severe GO who had been refractory to steroid therapy alone and treated with combined orbital radiotherapy and systemic glucocorticoids. All patients had already received one or more trial of steroid therapy prior to radiotherapy. Two patients had recurrence after steroid cessation, and four were unable to taper corticosteroids partially or completely. Two patients experienced relapse compressive optic neuropathy during tapering of glucocorticoids. The radiation dose was 20 Gy at 2 Gy/fraction. Presenting signs especially for disease activity and severity, treatment outcomes, and side effects were assessed.
Results: After combined therapy, complete cessation of corticosteroid therapy and stabilization of disease without recurrence was achieved in all patients. The clinical activity score decreased from 6.0 to 2.5 (p = 0.04). The ophthalmopathy index decreased from 8.2 to 5.7 (p = 0.05), with significant improvement in soft tissue sign (p = 0.03) and extraocular muscle movement (p = 0.03). Both patients with relapse dysthyroid optic neuropathy regained their vision. Side effects of radiotherapy included posterior subcapsular cataract formation in one patient.
Conclusion: Combined orbital radiotherapy and systemic corticosteroids can help to achieve stable disease and cessation of corticosteroid without recurrence in patients with refractory GO. This technique achieves greater improvement in clinical activity, soft tissue inflammation, and ocular motility.

Keywords: Graves’ ophthalmopathy, radiotherapy, steroid


How to cite this article:
Huang SK, Yen SH, Tsai CC, Kau HC, Kao SC, Lee FL. Clinical outcomes of orbital radiotherapy combined with systemic glucocorticoids for patients with Graves' ophthalmopathy refractory to steroid therapy☆. Taiwan J Ophthalmol 2013;3:91-4

How to cite this URL:
Huang SK, Yen SH, Tsai CC, Kau HC, Kao SC, Lee FL. Clinical outcomes of orbital radiotherapy combined with systemic glucocorticoids for patients with Graves' ophthalmopathy refractory to steroid therapy☆. Taiwan J Ophthalmol [serial online] 2013 [cited 2022 Aug 16];3:91-4. Available from: https://www.e-tjo.org/text.asp?2013/3/3/91/203881




  1. Introduction Top


Graves’ ophthalmopathy (GO), the most common and important extrathyroidal manifestation of Graves’ disease, is thought to be an inflammatorydisorderofautoimmune background.[1] Although most GO patients have a mild and nonprogressive clinical course, it may lead to functional disability (diplopia, exposure keratitis, and vision impairment) and social disturbance (disFigureuring features), which profoundly influence the quality of life of affected individuals.[2] The clear and indisputable mechanism of the pathogenesis of GO remains to be elucidated, and it may represent a result of a complex interplay between endogenous and environmental factors.[3],[4] Systemic corticosteroid and orbital radiotherapy (OR) remains the mainstay treatment for GO. Systemic glucocorticoids (GCs) are often effective, but flare-up of ocular symptoms is commonwhen the dose of GCs is tapered or withdrawn. In some randomized clinical trials, OR was reported to be as effective as oral GCs [5] and the combined treatment with ORand oral GCs was more effective than either ORor oral GCs alone.[6],[7],[8] However, the efficacy of combination of OR and GCs for patients with GO refractory to GCs therapy remains to be determined. Here we investigate the clinical outcome of combined treatment with OR and intravenous GCs in patients with relapse GO when GCs are tapered or withdrawn.


  2. Materials and methods Top


2.1. Patients

The medical records were retrospectively reviewed of all active moderate-to-severe GO patients who were treated for refractory GO with combination of OR and GCs at a tertiary medical center between 2009 and 2012. All patients who had persistent or recurrent GO, even after one or more trials of GCs therapy, were enrolled for this study. Exclusion criteria were any ocular diseases other than GO; regular drug ingestion, or antioxidant use; pregnancy; and age < 35 or > 80 years. Individuals who had been receiving radiotherapy or surgical decompression for GO were also excluded. This study was performed in accordance with the Declaration of Helsinki, and informed consent was obtained from the patients.

2.2. Treatment with combination of OR and GCs

All patients initially received intravenous methylprednisolone 250 mg every 6 hours for 3 consecutive days, follow by oral pred-nisolone (0.7 mg/kg/day) for 4 weeks. Oral prednisolone was then tapered slowly to discontinuation in 3–4 months in all patients. OR was started after intravenous methylprednisolone therapy and all patients were treated bilaterally. A total of 20 Gy was delivered to each eye in 10 fractionated doses over a period of 2 weeks.

2.3. Ophthalmologic examinations

All participants received ophthalmologic evaluation by the same ophthalmologist (C.C. Tsai) prior to and after combination treatment. The patients were followed-up every 2 weeks for the first 2 months, and then every 1–2 months. Baseline characteristics of the patients, their presenting symptoms, biochemical data, outcome, and side effects after combined OR and systemic GCs were collected. Ophthalmological investigations including best-corrected visual acuity, intraocular pressure, funduscopic examination, and especially the disease activity and severity of GO were assessed prior to and after combined treatment. The clinical activity of GO was scored according to Mourits et al,[9] and the subsequent revision of an ad hoc international committee using the seven-point clinical activity score (CAS).[10] It is based on seven signs of inflammation of the orbit (spontaneous retrobulbar pain, pain on attempted eye movements, conjunctival hyperemia, eyelid redness, chemosis, swelling of the caruncle, and swelling of the eyelids). One point is given for any manifestation, and the score may range from 0 (no activity) to 7 (high activity). The patients with a CAS ≥ 3 were considered as having active GO. The severity of the ophthalmop-athy was scored according to the ophthalmopathy index (OI), based on the NOSPECS (No signs or symptoms; Only signs; Soft tissue; Proptosis; Extraocular muscle; Cornea; Sight loss) classification ranging from 0 points to 15 points (0–3 points were given for 5 clinical parameters of the disease based on the severity of soft tissue involvement, proptosis, extraocular muscle involvement, corneal involvement, and sight loss, respectively).[8] The definition of proptosis mentioned above was adjusted according to racial variation, and the mean value of exophthalmos in normal Taiwanese adults is 13.91 ± 2.33 mm.[11] Modified grading for ophthalmopathy index score is shown in [Table 1]. According to the consensus statement of the European Group on Graves’ Orbitopathy on management of GO, patients having any one or more of the following were considered as moderate-to-severe GO: lid retractions ≥ 2 mm, moderate or severe soft tissue involvement, exophthalmos ≥ 3 mm above normal for race and gender; and inconstant or constant diplopia.[12]
Table 1: Modified grading for ophthalmic index: the SPECS score.

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2.4. Statistical analysis

Statistical analysis was performed using GNU PSPP software version 0.7.9-gf00c84 (http://pspp.awardspace.com/). The data obtained are expressed as mean values ± standard deviation. Comparisons of CAS and OI difference between pretreatment and post-treatment were performed with the Wilcoxon Signed Rank test. A p value < 0.05 was considered statistically significant.


  3. Results Top


Seven patients met the inclusion criteria; however, one patient was lost to follow-up soon after treatment. Therefore six patients (1 man and 5 women) with a mean age of 56.7 years (range, 51–67 years) were analyzed. Two patients had recurrence GO after GCs cessation, and four was unable to taper GCs partially or completely. Two patients who refused decompression surgery and experienced relapse dysthyroid optic neuropathy (DON) during tapering of GCs were included. The mean follow-up time was 24.1 months (range 12–34 months).

[Table 2] shows the change of clinical parameters of six patients after treatment with combined OR and systemic GCs. The mean CAS of patients decreased significantly from 6.0 prior to combined therapy to 2.5 (p = 0.04). The mean OI of patients decreased from 8.2 prior to therapy to 5.7 (p = 0.05). Subgroup analysis on five parameters of OI showed significant improvement on soft tissue sign (p = 0.03) and extraocular muscle movement (p = 0.03), whereas no significant differences occurred in proptosis, corneal involvement, or sight loss. However both patients with DON regained and improved their best corrected visual acuities (worst eye) from 6/60 to 6/6.7 and from 6/10 to 6/6, respectively, even after GC cessation. None required surgical intervention to preserve their vision or restore binocular vision. During the follow-up period, none of the patients experienced any severe late complications such as radiation-induced retinopathy, corneal ulceration, or perforation. However, one patient developed posterior subcapsular cataract at 22 months after adjunctive OR and underwent cataract surgery.
Table 2: Change in clinical parameters of six patients after treatment with combined orbital radiotherapy and systemic glucocorticoids.

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  4. Discussion Top


Intravenous GC is the recommended first-line treatment for moderate to severe and active GO by the European Group on Graves’ Orbitopathy.[12] However, medical treatments for patients with recurrent or persistent GO after systemic GCs still represent a major clinical and therapeutic challenge. Many patients may eventually require rehabilitative surgery for functional or cosmetic morbidity. Our study showed that a combination of OR and intravenous GCs is effective particularly on clinical activity, ocular motility, and soft tissue inflammation for patients with GO refractory to steroid therapy.

OR has been used to treat GO for several decades and is often thought to be a safe second-line treatment. The rationale for using low-dose radiotherapy on GO is related to the anti-inflammatory effect, in particular the modulation of cytokines and adhesion molecules expression on activated leukocytes.[13] In addition, OR may reduce the synthesis and secretion of glycosaminoglycans by orbital fibroblasts.[14] Two randomized clinical trials (RCTs) confirmed that OR is effective on ocular motility in patients with either mild GO or moderate-to-severe GO,[5],[15] and two other RCTs addressed the combination effect of oral GCs and OR is more effective than either treatment alone.[7],[8] However, one RCT from the Mayo Clinic failed to find a clinically significant benefit of OR on GO, as compared to sham irradiation.[16] Three recent systematic literature reviews on OR alone in GO have reached different conclusions about its efficacy; one was positive[17] and two negative.[18],[19] These controversial findings may be due to selection bias, especially whether patients had longer or shorter duration of disease, variable severity and activity of GO, and different prior treatment. Other factors implicated in the variable response to OR include issues regarding different outcome measures, varied stage of the disease, and the use of adjunct corticosteroid therapy. There is agreement that OR alone is less effective on exophthalmos, long-standing or inactive GO, and those failing to respond to GCs.[20]

Although some underscore the role of OR alone on GO, most studies address that OR combined with GCs is more effective than monotherapy in reducing global indices of GO,[7],[8],[19] suggesting a synergistic effect of the combined treatment. Both OR and GCs are reported to reduce inflammatory processes, with GCs acting within days, whereas the response from OR may take weeks or months, but lasts longer. A preliminary study further reported that combination of orbital irradiation and systemic steroids (intravenous followed by oral steroid) is more effective than steroids alone in the treatment of active moderate-to-severe GO.[21] In addition, the combined therapy using the intravenous glucocorticoids was more effective than the combined treatment using the oral glucocorticoids (responders, 87.8% vs. 63.4%; p < 0.02) and better tolerated.[6] Therefore, we choose combined OR and intravenous GCs for patients who had active moderate-to-severe GO and failed to respond to one or more prior systemic steroid. Our current findings reveal that the efficacy of combined treatment is more pronounced on clinical activity score, soft tissue changes, and ocular motility, and much less impressive on proptosis, exposure keratopathy, and vision change. Two cases with DON did regain their vision after combined treatment, even though there was no significant vision change among all patients after treatment. This may be partially due to most patients (4 of 6 cases) in our study having no vision impairment prior to treatment.

Complete cessation of corticosteroid therapy and stabilization of GO without recurrence was obtained after combined treatment in all patients, including two cases with relapse DON. The ability to discontinue GCs shortly after adjunct OR has been reported.[22],[23] Sight-threatening GO usually occurs in the context of DON. DON can be treated by systemic GCs, surgery, or both. Relapse of DON may occur when systemic GCs are withdrawn and often require decompression surgery.[12] Our current findings showed that OR in combination with systemic GCs may have some benefit for relapse DON. Guy et al and Bartalena et al have documented benefit using radiotherapy in conjunction with systemic steroids for treatment of DON.[24],[25] Another study by Kazim et al found that radiotherapy was more effective than high-dose GCs in relieving compressive optic neuropathy.[26] Dolman et al suggest combined radiotherapy (20 Gy over 2 weeks) with systemic GCs may be effective and delay or avoid surgery in cases of DON with incomplete or short-lived visual improvement after intravenous GCs.[27] They also noted that postoperative (orbital decompression) OR had the extra benefitto prevent and control relapses in DON in cases with progressive muscle expansion.[27]

Potential complications of OR include cataract development, retinopathy, and tumor formation. The most common late effect observed was cataract development, which occurred more frequently in older patients. In the current study, cataract developed in one 67-year-old patient (16.7%), and was reversible with cataract surgery. Radiation retinopathy after OR for GO was relatively rare and had been reported in cases that were accidentally treated with an excessive radiotherapy dose.[28] Retinal microvascular changes may develop in diabetic patients treated with radiotherapy. The risk of radiation-induced cancer is extremely low, Snijders-Keilholz et al calculated a cumulative probable risk of tumor induction after retro-orbital irradiation for GO over a lifetime of up to 1.2%.[29] For that reason, radiotherapy in GO is commonly restricted to patients older than 35 years and lifelong surveillance is advised.

Most previous study aimed to discuss the efficacy of combined treatment as an initial treatment for GO patients or they often included both groups of patients as initial treatment and those with poor response or intolerance to systemic steroids,[6],[7],[8],[15],[21] whereas we have investigated the clinical outcomes of combined treatment for refractory cases only. However, because of limited cases in this study, more studies are warranted to provide additional information about the precise effect of adjunctive OR on the refractory GO.

In conclusion, adjunctive OR with systemic GCs provides an alternative treatment choice for patients with active moderate-to-severe GO refractory to steroid therapy alone.



 
  References Top

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Abstract
1. Introduction
2. Materials and...
3. Results
4. Discussion
References
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