Original research study - OA Publishing London · Original research study Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY) Competing interests: none

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Original research study

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

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For citation purposes: Kouloulias V, Kouvaris J, Zygogianni A, Mosa E, Georgakopoulos J, Theodosiadis P, Antypas C, Platoni K, Tolia M, Beli I, Alonistiotis D, Dilvoi M, Patatoukas G, Asimakopoulos C, Efstathopoulos E, Kelekis N. Efficacy and toxicity of radiotherapy for Graves’ ophthalmopathy: the University of Athens experience. Head Neck Oncol. 2013 Feb 06;5(2):12.

Efficacy and toxicity of radiotherapy for Graves’ ophthalmopathy: the University of Athens experience

V Kouloulias1*, J Kouvaris2, A Zygogianni2, E Mosa1, J Georgakopoulos1, P Theodosiadis3, C Antypas2, K Platoni1, M Tolia2, I Beli1, D Alonistiotis3, M Dilvoi1, G Patatoukas1, C Asimakopoulos1, E Efstathopoulos1, N Kelekis1

AbstractAimTo evaluate the efficacy, the feasibility as well as the acute and late toxicity of orbital radiotherapy in patients with Graves’ ophthalmopathy.Materials and methodsBetween 2002 and 2011, we retrospec-tively evaluated 17 patients (7 males, 10 females) diagnosed with Graves’ orbitopathy that were treated with external three-dimensional conformal radiotherapy. The median age of the patients was 58 years. Patient symp-toms included pain (17/17), propto-sis (14/17), redness of the eyelid (17/17) and extraocular muscle dys-function with decreased eye move-ments (16/17). The mean clinical activity score (CAS) was 8.65 ± 1.87. Corticosteroids were used in all the patients. A dose of 20 Gy in 10 daily fractions was prescribed. The primary endpoints were the assessment of the therapeutic impact, the safety of the treatment and the acute toxicity of irradiation.ResultsThe median follow-up was 15 months. Stabilization of the disease without recurrence was achieved in 12/17 patients. At the end of radiotherapy,

the CAS regressed to 4.82 ± 2.24 (P < 0.001, Wilcoxon test). However, in smokers, the CAS decreased signifi-cantly slower and to a lower extent than that in non-smokers (P = 0.008, log-rank test). Extraocular motility and pain behind the globe were improved in 14/17 and 16/17 patients, respec-tively. Five patients developed recur-rent signs and symptoms and they underwent surgical decompression, all of them being smokers. However, mortality was not reported. None of the patients developed retinopathy, while cataract and chronic dry eyes were observed in 2/17 and 6/17 patients, respectively.ConclusionOrbital radiotherapy for Graves’ dis-ease is a well-established treatment option, even if patients have failed previously with other treatment modalities such as corticosteroids and surgical decompression.

IntroductionThyroid opthalmopathy is usually the main sign of Graves’ disease, but can also arise in association with Hashimoto’s thyreoiditis or myxoedema without previous thyreotoxicosis. It rarely occurs in patients without a history of thyroid dysfunction. It refers to an inflammatory fibrosing disease of the predominantly retro-orbital contents. Graves’ orbitopathy (GO) is consid-ered an autoimmune disease due to the T-cell predominant lymphocytic infiltration of orbital tissues and the appearance of glycosaminoglycans in periorbital fat and extraocular muscles1,2.

The symptomatic presentation of GO is a direct result of the inflammatory

and fibrotic reactions in the retro-orbit space and can occur as exoph-thalmos, impaired muscle involvement, diplopia, blurred vision, periorbital oedema, chemosis, lid retraction and compressive optic neuropathy. Typical presentation symptoms may include proptosis, pain, tearing, visual impair-ment and rarely blindness.

Management of Graves’ ophthal-mopathy is a challenging procedure, based on individualized data after thorough evaluation of each patient and which also requires a multidisci-plinary approach from a team of physicians including endocrinolo-gists, ophthalmologists, radiologists, radiation oncologists and orbital surgeons3.

There are several important vari-ables that should always be consid-ered when making a treatment plan for GO. First, thyroid function should be taken into account, since euthyroism is necessary when treating GO. Second, severity classification of GO is of major importance. The European Group of Graves’ Orbitopathy (EUGOGO) classi-fies GO severity based on subjective symptoms and objective signs into three categories: mild, moderate to severe and sight-threatening4. The last cate-gory is of major importance as these patients are at a risk of vision loss.

Patients of sight-threatening GO appear to have dysthyroid optic neuropathy or corneal breakdown and need immediate intervention4. On the other hand, the activity of GO refers to the presence of inflammatory signs. It can be measured through the clinical activity score (CAS) based on the classical features of inflammation. In this way, one point is given for each of

* Corresponding authorEmail: [email protected] 2nd Radiology Department, Radiotherapy

Unit, ATTIKO University Hospital, Medical School, National Kapodistrian University of Athens, Greece

2 1st Radiology Department, Radiotherapy Unit, Aretaieio University Hospital, Medical School, National Kapodistrian University of Athens, Greece

3 2nd Opthalmological Clinic, ATTIKO University Hospital, Medical School, National Kapodistrian University of Athens, Greece

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the following features: spontaneous retrobular pain, pain of attempted up- or down gaze, conjuctival redness, redness of the eyelid, swelling of the caruncle or plica, swelling of the eyelid and chemosis. A score ≥3 rep-resents active GO5. Orbital radiother-apy (RT) for GO is a well-established treatment modality for patients, as a sole therapy or in combination with glucocorticosteroids6,7.

The aims of this study, in terms of primary endpoints, was to report in a retrospective manner the efficacy and the acute as well as the late toxicity of an irradiated scheme of 20 Gy admin-istered in 10 fractions of 2 Gy per fraction. The secondary endpoint was the impact of smoking on the treat-ment outcome of orbitary irradiation. In general, the manuscript reports on the experience of the two University Radiotherapy Units of the Medical School of Athens.

Methods and materialsPatient characteristicsBetween 2002 and 2011, 17 patients with bilateral GO were enrolled into this retrospective study. Of these, 7 were males and 10 were females. The median age at the time of enrolment was 58 years (range: 45–74). All patients were evaluated before initia-tion of treatment by a multidisciplinary team of physicians including endocri-nologists, ophthalmologists, radiolo-gists, radiation oncologists and orbital surgeons.

According to the EUGOGO criteria, patients were categorized in three categories4. Patients with mild GO only had a minor impact on daily life, insufficient to justify immunosup-pressive or surgical treatment. They presented with one or more of the fol-lowing: minor lid retraction (<2 mm), mild soft tissue involvement, exoph-thalmos <3 mm above normal for race and gender, transient or no diplopia and corneal exposure responsive to lubricants. Patients with moderate-to-severe GO suffered from eye dis-ease with sufficient impact on daily

life, justifying the risks of immuno-suppression (if active) or surgical intervention (if inactive), and they usually presented with one or more of the following: lid retraction ≥2 mm, moderate or severe soft tissue involve-ment, exophthalmos ≥3 mm above normal for race and gender and inconstant or constant diplopia.

The complete pre-treatment evalu-ation at presentation apart from the physical examination included pathol-ogy review, laboratory studies with complete blood count, chemistries and thyroid function tests, radiologi-cal imaging with computed tomog-raphy (CT) and/or magnetic resonance imaging (MRI) of the orbits and meas-urement of proptosis with Hertel exophthalmometer.

If GO was estimated as mild or stable and there was no threat of impeding vision loss, the aim of the treatment was to correct the underlying thyroid disorder. If GO was moderately symp-tomatic with signs of progression and refractory symptoms the treatment strategy included orbital RT with systemic immunosuppressive agents, especially IV corticosteroids and oral steroids. In this case, the RT scheme comprised 20 Gy in 10 fractions in 2 weeks’ time. When vision loss was diagnosed, decompressive surgery was the standard of care8. Patients included in the present study were those diagnosed with moderate-to-severe and sight-threatening GO, according to the EUGOGO criteria, and with a CAS ≥4. Patients with mild thyroid-associated ophthalmopathy (TAO) (CAS <4), psychological disor-ders or those who were very elderly and unfit for immobilization during RT were excluded. Patients were also excluded if they had history of previ-ous RT for GO and if they had suffered from diabetes mellitus and hyperten-sion9. All patients were subjected to treatment with glucocorticoids. Patient characteristics are summarized in Table 1.

Patients were referred either to ATTIKO University Hospital of Athens

or Aretaieio University Hospital to undergo radical RT as a treatment for GO. All patients were required to sign an informed consent form, concern-ing the side effects of irradiation.

RT treatment and radiobiological assessmentsCT scan images (3-mm slice thickness) were acquired and transferred to the treatment planning system. Patients were treated in a neutral supine posi-tion, while being immobilized with a thermoplastic head mask. Pretreat-ment planning included orbital CT. Patients were instructed not to move during CT scan and simulation and during the complete treatment course. CT datasets were transferred either to the Prosoma® Virtual simulation or Plato® contouring system through a DICOM III network. Contouring of clinical target volume (CTV), planning target volume (PTV) and normal structures (organs at risk, OARs) was performed according to the Interna-tional Commission on Radiation Units and Measurements (ICRU) criteria10,11. Dose calculations were performed using either the treatment planning system Eclipse (Varian Associates, Palo Alto, CA) or PLATO (Nucletron, The Netherlands) to deliver the prescribed dose to the ICRU reference point10,11. Treatment planning consisted of three-dimensional (3D) conformal planning to the bilateral retro-orbital contents. Each patient’s globe, lens, extraocular muscles and brain were contoured. Anterior blocking shielded the anterior chamber and lens of the eye, whereas posterior and superior blocking shielded the brain, sella tur-nica and lacrimal gland. Each portal field was designed to cover all enlarged rectus muscles and retro-orbital tissues during treatment planning. When necessary, the beams were angled 5° posteriorly or they were shielded by a half-beam block of the anterior edge of the field to minimize the contralat-eral lens exit dose (Figure 1). Weighted beams and wedges were used as nec-essary to improve dose homogeneity.

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In general, the fields were placed iso-centrically. We kept the dose range between 95% and 107% of prescribed dose10. Wedge compensation was used to ensure uniform dose distribution throughout the target volume. To eval-uate the dose constraints for normal tissues, we used the QUANTEC trial12.

RT was delivered once daily with a 2 Gy dose per fraction, five times a

week for a period of 10 days. For the treatment technique, histograms were generated; a number of parameters—including mean, median and maximum dose—were evaluated. Patient set-up was monitored weekly using portal films obtained in the treatment posi-tion with therapeutic beam to confirm adequate coverage. Patients were treated with megavoltage equipment,

either on a VARIAN CLINAC 600 C Linac with 6 MV photons or on an ELECTA 6 MV Linac.

Follow-upAll patients were evaluated to deter-mine RT response and toxicity at the beginning of the treatment, once a week during treatment and at com-pletion of radiation course. Post-RT follow-up was performed by radiation oncologists and ophthalmologists monthly, bimonthly and biannually later on. Symptoms occurring in the intervals between the start of RT and 90 days after this time point were classified as “acute”. “Late” radiation complications were defined as those appearing 3 months from the end of the treatment. The evaluation of acute and late radiation-induced toxicity was done with the EORTC/RTOG toxicity criteria13. Median follow-up duration was 12 months (range, 10–15).

Statistical analysisThe response to treatment in terms of CAS regression and stabilization was presented via life table analysis according to Kaplan–Meier, while the differences between smokers and non- smokers were tested with the log-rank test 12 months post-RT. Failure after RT was considered an event when calculat-ing the response to treatment. Surgical control after RT was not considered in this study. Difference in the incidence of CAS before and after RT was evaluated using the Chi2 test. The significance in CAS regression after RT was assessed with the Wilcoxon non-parametric test. The significance level was set at 0.05. The analysis was performed with SPSS ver. 10 software (IL, USA).

ResultsAll patients completed the planned 3D- conformal RT (3DCRT) with none experiencing acute treatment reac-tions necessitating a break in the treatment. All patients completed the irradiation schedule with 20 Gy in 10 daily fractions. Stabilization of the disease without recurrence was

Table 1 Patient characteristics (n = 17)

Patients

Age median (range) 58 (45–74)

Male/female 7/10

Severity classification in GO (CAS)

Moderate-to-severe (CAS: 3–5) 2/17

Sight-threatening (CAS >5) 15/17

Smokers

Yes 11/17

No 6/17

Median duration of GT (range) in months 36 (13–60)

Median duration of TAO (range) in months 9 (3–12)

Figure 1: A 3D-conformal treatment planning with two oppose fields with shielding of the lenses.

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achieved in 12/17 patients. At the end of RT, the CAS regressed to 4.82 ± 2.24 (P < 0.001, Wilcoxon test). The CAS before and after RT is detailed in Table 2. As shown in Figure 2, the mean CAS regressed from 9.1 ± 1.3 to 6.0 ± 1.9 and 7.9 ± 2.0 to 3.1 ± 1.7,

respectively, for smokers and non-smokers. Moreover, in smokers, the CAS decreased significantly to a lower extent than that in non-smokers (P < 0.01). Time to response, together with smokers versus non-smokers, is shown in Figure 3. Response to

treatment was slower in smokers than in non-smokers (P = 0.008, log-rank test). Three patients failed to present a decrease of more than 2 in the CAS, all being smokers. Extraocular motility and pain behind the globe were improved in 14/17 and in 16/17 patients, respectively. In a time range of 5–7 months after the establishment of any response, five patients devel-oped recurrent signs and symptoms followed by surgical decompression, all of them being smokers. However, mortality was not reported. No patients developed retinopathy. Late toxicity was noted in 6/17 patients that devel-oped chronic dry eyes and in 2/17 that developed cataract. No patients experienced retinopathy, concerning the presence of ≥1 haemorrhages and/or microaneurysms on stand-ardized 50° red-free, black and white retina photographs.

DiscussionGO is an autoimmune disease charac-terized by an inflammatory swelling of

Table 2 CAS before RT and after the establishment of a stable response

Items Description Before RTN (%)

Post-RTN (%)

Pain Painful, oppressive feeling on or behind the globe during the last 4 weeks

17/17 1/17

Pain on attempted up, side or down gaze during the last 4 weeks

17/17 1/17

Redness Redness of the eyelid(s) 17/17 14/17

Diffuse redness of the conjunctiva, covering at least one quadrant

15/17 15/17

Swelling Swelling of the eyelid(s) 13/17 13/17

Chemosis 15/17 13/17

Swollen caruncle 15/17 12/17

Increase of proptosis of ≥2 mm during a period of 1–3 months

14/17 6/17

Impaired function Decrease of eye movements in any direction ≥5° during a period of 1–3 months

16/17 3/17

Decrease of visual acuity of 1 line(s) on the Snellen chart (using a pinhole) during a period of 1–3 months

8/17 4/17

Mean total CAS (±SD) The sum of all items scored by 1 each 8.65 ± 1.87 4.82 ± 2.24

GD, Graves’ hyperthyoidism; TAO, thyroid-associated ophthalmopathy.

Figure 2: Mean CAS before and after the establishment of a response to RT. Vertical lines represent standard deviation.

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orbital fat and extraocular muscles. The treatment of GO depends on its sever-ity and activity. The correction of the thyroids’ dysfunction and euthyroism is of major importance for the success of GO’s treatment. Patients with moder-ately severe or severe orbitopathy often require treatment with glucocorticos-teroids and retrobulbar irradiation, particularly in case of eye muscle involvement13. However, the usage of corticosteroids can provoke major side effects, especially when people suffer from diabetes mellitus, hypertension, cardiovascular disorders, obesity and gastrointestinal diseases. Additionally, chronic treatment with steroids can lead to acute liver damage (cytotoxic, autoimmune or viral), liver steatosis and autoimmune hepatitis-related autoantibodies14.

The advantage of RT over gluco-corticosteroids is that it is well toler-ated with usually no side effects15. The established RT schedule is 20 Gy in 10 daily fractions. However, there are

studies that suggest that doses <20 Gy are sufficient for patients with only soft tissue signs, without ocular dys-motility16. It is a fact that the duration of symptoms before RT has been found to be of great importance. Matthiesen et al.6 reported that patients treated for <6 months from the onset of symptoms had worse results than those treated in the 6–12 month duration of the pres-ence of orbitopathy. In our study, the median time of irradiation after the onset of GO was 9 months.

A correct management of GO should include adequate patient counselling, concerning therapy outcomes, risks related to treatments, timing and the need for a long lasting follow-up. Radiation-induced tumours have so far not been reported in follow-up stud-ies, even in the setting of reirradiation for GO6,17. On the contrary, radiation-induced retinopathy has been docu-mented in low quality in terms of technique treatments and with the coexistence of diabetes mellitus18.

Cataract as late radiation toxicity is rarely seen when lens receive <10% of the prescribed radiation dose19.

Table 3 summarizes the results from several controlled-randomized trials that have studied the efficacy of RT in the treatment of GO9,15,20–23. In all cases, a significant response to RT was noted, while the highest inci-dence of radiation-induced cataract was 27%. Our own study is in accord-ance with these results by means of treatment efficacy, while the acute and late toxicity were quite minimal. In general, RT improves extraocular motility. However, radiation-induced retinopathy, although rare, is a potential side effect of orbital RT. In our study, no patients presented with orbital retinopathy. It is worth mentioning that smoking is associated with an increased risk of GO develop-ment and/or progression, while at the same time, it may decrease the effec-tiveness of GO treatment, something which was profound in our study as the CAS was significantly better in non-smokers14,24–26 (Figures 2 and 3).

Last but not the least, all patients were thoroughly checked histologi-cally by pathologists in case of simul-taneous presence of thyroid carcinoma or mediastinal disease and other auto-immune diseases27. It is also important to mention that the follow-up of patients who have undergone orbitary RT should be as extended as much as possible. Retinopathy is a severe radiation-induced toxicity that is pre-sented as a late effect of RT and would be confirmed after a minimum of six months post-RT. Studies with more patients, more extended follow-ups and modern intensity-modulated RT techniques are required.

ConclusionsOur retrospective study shows that external RT with 3DCRT is a safe modal-ity for patients with ocular symptoma-tology derived from Graves’ thyroid eye disease. The majority of patients achieve clinical improvement, without progression. Our study is in complete

Figure 3: Decrease of CAS >2 by time (%) in a Kaplan–Meier curve for all patients together with smokers versus non-smokers (P = 0.008, log-rank test). Bold line represents all patients; slim line represents non-smokers and dotted line represents smokers.

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accordance with studies in the litera-ture, which suggest that a combination of 3DCRT and glucocorticosteroids is a well-established treatment modality that can be safely prescribed with good results for the treatment of GO.

References1. Bahn RS. Thyrotropin receptor expres-sion in orbital adipose/connective tissues from patients with thyroid-associated ophthalmopathy. Thyroid. 2002 Mar;12(3): 193–5.2. Kendlerr DL, Lippa J, Rootman J. The initial clinical characteristics of Graves’

orbitopathy vary with age and sex. Arch Ophthalmol. 1993 Feb;111(2):197–201.3. Wiersinga WM, Perros P, Kahaly GJ Mourits MP, Baldeschi L, Boboridis K, et al. Clinical assessment of patients with Graves’ orbitopathy recommendations to general-ists, specialists and clinical resarchers. Eur J Endocrinol. 2006 Sep;155(3):387–9.4. Bartalena L, Baldeschi L, Dickinson A, Eckstein A, Kendall-Taylor P, Marcocci C, et al. Consensus statement of the European Group on Graves’ orbitopathy. Eur J Endocrinol. 2008 Mar;158(3):273–85.5. Mourits MP, Prummel MF, Wiersinga WM, Koornneef L. Clinical activity score as a guide in the management of patients

with Graves’ ophthalmopathy. Clin Endo-crinol (Oxf). 1997 Jul;47(1):9–14.6. Matthiensen C, Thompson S, Thompson D, Farris B, Wilkes B, Ahmad S, et al. The efficacy of radiation therapy in the treatment of Graves’orbitopathy. Int J Radiat Oncol Biol Phys. 2012 Jan;82(1): 117–23.7. Bradley EA, Gower EW, Bradley DJ, Meyer DR, Cahill KV, Custer PL, et al. Orbital radiation for Graves’ ophthalmop-athy. A report by the American Academy of Ophthalmology. Ophthalmology. 2008 Feb;115(2):398–409.8. Kaprealian T, Mishra K, Wang-Chesebro A, et al. Malignant and benign diseases

Table 3 Randomized-controlled studies with irradiation for GO concerning the efficacy and toxicity of RT

Study, N (patients)

Intervention Severity/ Activity of GO

Age (median)

Primary study outcome

Radiation-induced toxicity

Follow-up(months)

Bartalena et al.20, N = 24

RT + prednisone vs. prednisone alone

Active GO 44 Mean decrease OI: 4.8,10/12 patients good response

None 19

Antonelli et al.21,N = 14

Orbital radiation IVIG vs.IVIG alone

OI > 4 46 Mean decrease OI: 3.2,4/12 good response

None 6

Prummel et al.15, N = 59

Sham RT + prednisonevs. OR (10 × 2 Gy) + placebo

Moderate 47 NOSPECTS:18.5° to 21.8° for RT (P = 0.003)

1 headache 6

Prummel et al.22, N = 88

Orbital RT (10 × 2 Gy) vs. sham RT

Mild motility impairment, mild or moderate lid swelling, proptosis ≤24

45 Major and minor criteria52% response in RT vs. 27% in sham RT

No significant changes in quality of life in both groups

12

Wakelkapm et al.9, N = 245

Orbital RT(10 × 2 Gy) + GC vs. GC

Active GO 48 Major and minor criteria

15% possible retinopathy,2% definitive retinopathy,RT: 29% cataract

132

Ng et al.23, N = 16

Orbital RT (10 × 2 Gy) + GC vs. GC alone

Moderate to severe

56 Change in NOSPECS

37% had mild exacerbation of periorbital swelling,37% had temporal hair loss

12

Current study Orbital RT (10 × 2 Gy) + GC

Moderate to severe

58 Mean decrease of CAS: 3.83

Cataract: 2/17,chronic dry eyes: 6/17

15

OI, Ophthalmopathy index as proposed by Donaldson et al.28; IVIG, Intravenous immunoglobulin; NOSPECTS, Classification of eye disease related to Graves’; GC, Glycol-corticosteroids.

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