Comparative analysis of dosimetric parameters of three different radiation techniques for patients with Graves’ ophthalmopathy treated with retro-orbital irradiation
© Lee et al.; licensee BioMed Central Ltd. 2012
Received: 22 April 2012
Accepted: 10 November 2012
Published: 26 November 2012
We would like to investigate the if IMRT produced better target coverage and dose sparing to adjacent normal structures as compared with 3-dimensional conformal radiotherapy (3DCRT) and lateral opposing fields (LOF) for patients with Graves’ ophthalmopathy treated with retro-orbital irradiation.
Ten consecutive patients diagnosed with Graves’ ophthalmopathy were prospectively recruited into this study. An individual IMRT, 3DCRT and LOF plan was created for each patient. Conformity index (CI), homogeneity index (HI) and other dosimetric parameters of the targets and organs-at-risk (OAR) generated by IMRT were compared with the other two techniques.
Mann–Whitney U test demonstrated that CI generated by IMRT was superior to that produced by 3DCRT and LOF (p=0.005 for both respectively). Similarly HI with IMRT was proven better than 3DCRT (p=0.007) and LOF (p=0.005). IMRT gave rise to better dose sparing to some OARs including globes, lenses and optic nerves as compared with 3DCRT but not with LOF.
IMRT, as compared with 3DCRT and LOF, was found to have a better target coverage, conformity and homogeneity and dose sparing to some surrounding structures, despite a slight increase but clinically negligible dose to other structures. Dosimetrically it might be a preferred treatment technique and a longer follow up is warranted to establish its role in routine clinical use.
KeywordsIntensity-modulated radiation therapy Graves’ ophthalmopathy Retro-orbital irradiation
Graves’ ophthalmopathy is an orbital inflammatory pathology associated with an underlying autoimmune thyroid disease particularly Graves’ disease[1, 2]. Radiotherapy has long been used for this pathology, besides decompressive and corrective surgery as well as systemic steroids[1, 3–5]. Traditionally a pair of lateral opposing fields (LOF) directed to the orbital structures has been adopted for decades in virtue of its easy set-up and prompt delivery. The beams are either blocked anteriorly or tilted 5 degrees posteriorly to minimize dose to the lenses. However, this will inevitably lead to inadequate dose to parts of the orbital structures especially the insertions of the extra-ocular muscles and the anterior portions of the retro-orbital fat. More advanced technique including 3-dimensional conformal radiotherapy (3DCRT), intensity modulated radiation therapy (IMRT) and robotic stereotactic radiotherapy are increasingly gaining popularity, due to their superior target coverage, dose escalation to the targets and better radiation sparing of normal structures[6–12]. In this study, we would like to investigate if IMRT provides a better target coverage as well as superior dose sparing to the normal structures as compared with 3DCRT and LOF for patients treated with orbital irradiation for their Graves’ ophthalmopathy.
CI, HI and other dosimetric parameters generated by IMRT as mentioned above were compared with the other two techniques by Mann–Whitney U tests. A two-tailed p-value less than 0.05 was considered statistically significant. All statistical analyses were performed by Statistical Packages for Social Sciences (SPSS) version 19.
Date of diagnosis of Graves’ disease
Date of diagnosis of Graves’ ophthalmopathy
Prior use of systemic steroid
Prior corrective eye operation
Prior radio- iodine therapy
Time between diagnosis to radiotherapy (months)
Use of systemic steroid during radiotherapy
Use of anti-thyroid drugs during radiotherapy
CI and HI
Mean CI generated by IMRT was 1.24 (range: 1.15-1.30) while those for 3DCRT and LOF were 1.74 (range: 1.42-1.90) and 3.11 (range: 2.42-4.27) respectively. When IMRT was compared with 3DCRT, a superior CI was observed in IMRT (p=0.005). Likewise when IMRT was compared with LOF, IMRT definitely resulted in a better CI (p=0.005). Mean HI generated by IMRT, 3DCRT and LOF were 1.05 (1.03-1.08), 1.08 (1.05-1.14), 1.60 (1.06-4.60) respectively, with significant statistical difference in favor of IMRT when compared with 3DCRT (p=0.007) and LOF (p=0.005).
Comparison of dosimetric parameters of targets (Table2)
IMRT versus 3DCRT
Dosimetric parameters of GTV and PTV planned by three different treatment techniques
Parameters (mean[range], Gy)
IMRT versus LOF
The GTV of both eyes, when considered individually, received a higher minimum (left: p=0.005; right p=0.005) and a mean dose (left: p=0.008; right: p=0.005) with IMRT. When added together to form single GTV of both eyes, IMRT was able to give a higher minimum and mean dose (p=0.005 for both respectively).
IMRT versus 3DCRT
When dividing PTV according to individual eye, both the left and right eyes had a higher minimum (p=0.005 for both eyes) and mean dose (left: p=0.007; right: p=0.005) with IMRT. When they were combined together to be a single PTV, a higher minimum (p<0.001), maximum (p=0.022) and mean dose (p=0.007) could be achieved by IMRT.
IMRT versus LOF
When PTV was considered individually, both the left and right eyes received a higher minimum (p=0.005 for both eyes) and mean dose (left: p=0.007; right: p=0.005) with IMRT. Apart from that, the right eyes also received a higher median dose (p=0.005). When they were combined together to become a single PTV, a higher minimum and mean dose (p=0.005 for both) could be observed when planned with IMRT.
Comparison of dosimetric parameters of OARs (Table3)
IMRT vs 3DCRT
Dosimetric parameters of OARs planned by three radiation treatment techniques
Parameters (mean[range], Gy)
Left optic nerve
Right optic nerve
Left lacrimal gland
Right lacrimal gland
IMRT vs LOF
There was no statistical difference in all dosimetric parameters for both globes when comparing IMRT versus LOF. It was originally thought that LOF, as compared with IMRT, would contribute less radiation to the globes as their anterior portions were not within the radiation portals of LOF, it was not demonstrated in our study however. The reason was that the anterior thirds of the globes still received some dose owing to radiation falloff and scattered radiation in LOF. This gave rise to the result that, despite lower value of parameters generated by LOF, they were not statistically different from those generated by IMRT.
IMRT versus 3DCRT
Similar to the globes, IMRT definitely produced better sparing to the both lenses compared with 3DCRT, with a reduced minimum (p=0.005 both lenses), maximum (left: p=0.009; right: p=0.013), mean (left: p=0.005; right: p=0.007), median (left: p=0.005; right: p=0.007), D05 (p=0.013 for both lenses) and D01 (left: p=0.009; right: p=0.017).
IMRT versus LOF
There was no difference in all dosimetric parameters for both lenses between IMRT and LOF. Similar to the globes, though the lenses were not included in the radiation portals of LOF, they still received certain radiation due to falloff and scattered radiation. This resulted in numerically lower values of the parameters achieved by LOF, but statistical differences were not found when compared with IMRT.
IMRT versus 3DCRT
IMRT produced some dose sparing to both the left and right optic nerves. The median dose (p=0.028) and D05 (p=0.038) of left optic nerve was slightly reduced and the mean (p=0.037) and median dose (p=0.021) of the right optic nerve was also slightly improved when planned by IMRT.
IMRT versus LOF
IMRT produced a slightly higher minimum dose to the optic nerves (left: p=0.022; right: p=0.110) when compared with LOF, simply because the optic nerves were totally encompassed by the PTV. The improved coverage of PTV inevitably led to an increased minimum dose to the optic nerves. However weightings were given to the optic nerves during IMRT optimization so that hot spots did not fall within them. It was reflected by a lower maximum dose (p=0.038), D05 (p=0.011) and D01 (p=0.028) to the left optic nerve and a lower median dose (p=0.037) and D05 (p=0.047) to the right optic nerve.
IMRT versus 3DCRT
There were no significant statistical differences in the dosimetric parameters of the optic chiasm between IMRT and 3DCRT, though they were all slightly higher when planned by IMRT.
IMRT versus LOF
IMRT produced a higher minimum (p=0.005), mean (p=0.007), median (p=0.007), D05 (p=0.022) to the optic chiasm as compared with LOF. This was because the IMRT beams directed from posterior to anterior contributed to the increased dose to the optic chiasm in contrast to the steep drop of radiation dose in that region delivered by LOF.
IMRT versus 3DCRT
There were no significant statistical differences in the dosimetric parameters of the both lacrimal glands between IMRT and 3DCRT, though again they were all slightly higher when planned by IMRT.
IMRT versus LOF
IMRT produced a higher minimum (p=0.017), maximum (p=0.013), mean (p=0.022) and median dose (p=0.047) as well as D05 (p=0.047) and D01 (p=0.047) to the left lacrimal glands. Similarly, D05 (p=0.047) and D01 (p=0.041) of the right lacrimal glands were also higher with IMRT. The lacrimal glands, as situated anteriorly in the globe at the upper outer quadrants of the conjunctiva, were not within the radiation portals when planned by LOF. As the most anterior portions of the globes were blocked from radiation in LOF, the lacrimal glands, as a result, were also blocked from radiation as well. The dose to the lacrimal glands was thus lower with LOF.
Planning time, treatment time and monitor units
The average planning time for an IMRT plan by our experienced physicists and dosimetrists was around 2 hours, as compared with 1.5 hours and 30 minutes for a 3DCRT and LOF plan respectively. Similarly treatment time of each fraction for IMRT was also longer (26 minutes) than that delivered for a 3DCRT (16 minutes) and LOF (10 minutes). Average monitor units (MU) consumed was greater for IMRT (773 MU), in contrast to that for 3DCRT (252 MU) and LOF (197 MU).
Radiation-induced cataract based on NTCP model
The lenses are the only potential critical organs which might suffer from radiotherapy-induced complications like cataract, since we only delivered a low dose of radiation to the orbits. We calculated their normal tissue complication probability (NTCP) after treatment with each radiation technique, based on the equivalent uniform dose (EUD) and the following formula:, where TD 50 is the tolerance dose for a 50% complication rate at a specific time interval when the whole organ of interest is homogeneously irradiated and γ50 is a model parameter that is specific to the normal tissue and describes the slope of the dose response curve[19–21]. Ranges of values NTCP of the left lens contributed by LOF, 3DCRT and IMRT were 0.003-3.194, 0.213-0.429 and 0.010-0.280 respectively. Similarly NTCP for the right lens contributed by LOF, 3DCRT and IMRT were 0.001-2.942, 0.188-0.480 and 0.009-0.236 respectively. Statistical comparison demonstrated that NTCP contributed by IMRT was higher than that contributed 3DCRT (left: p=0.001; right: p=0.013) but not higher than that by LOF (left: p=0.096; right: p=0.257), revealing the risk of radiation-induced cataract might be higher for IMRT as compared 3DCRT but not with LOF.
Graves’ ophthalmopathy is the commonest extrathryoidal manifestation of Graves’ disease[1, 2, 22]. Clinical presentations include proptosis, eyelid swelling and retraction, chemosis, compressive optic neuropathy and papilloedema. The underlying pathogenesis is believed to be autoimmune-related leading to excessive infiltration of lymphocytes and excessive production of hydrophilic glycosaminoglycans and subsequently expansion of retro-orbital tissues and enlargement of extraocular muscles. Treatment options include steroid therapy, corrective/decompressive surgery, radiation therapy or combination of these approaches[3–5, 23]. Orbital irradiation has been practiced for more than 60 years. It is usually reserved for cases with moderate and severe degree of exophthalmos or compressive optic neuropathy when decompressive surgery is not immediately available or if patients are medically contraindicated for surgery. Though producing conflicting and controversial results as demonstrated in several double-blind randomized-controlled trials and numerous non-randomized trials with a small potential risk of long-term adverse events, orbital irradiation is still an acceptable treatment option for such disease[24–29]. There are also disputes on the optimal dose of orbital irradiation[30, 31]. For studies in favor of orbital irradiation, they used delivered 20Gy in 10 fractions over 2 weeks as the standard dose while more recent studies demonstrated that a lower dose was also equally effective. A randomized study revealed treatment with 20Gy of 1Gy-fraction weekly over 20 weeks was more effective and better tolerated than treatment with 20Gy of 2Gy-fraction over 2 weeks and 10Gy of 1Gy-fraction over 2 weeks. The dose prescription in our study was based on this study after taking the balance between the total dose and the total treatment duration into consideration. LOF technique has been employed by radiation oncologists for many decades in virtue of its simple and swift set-up procedures. However the obvious drawbacks of this technique are insufficient dose to the insertions of the extraocular muscles and the most anterior portion of the retro-orbital fat which are commonly involved in Graves’ ophthalmopathy, as well as inhomogeneous dose distribution within the target, since the anterior portion of the globes are usually blocked from the radiation portals of LOF in order to reduce the dose to the lenses. 3DCRT and IMRT, widely adopted for more than 10 years, were regarded as the current standard radiation treatment technique for head and neck and orbital tumors[6–10]. However there has been so far no study regarding the use of IMRT as the treatment technique for Graves’ ophthalmopathy and only a few studies of using IMRT for other orbital diseases[6, 11, 12].
IMRT is an acceptable radiation treatment technique for Graves’ ophthalmopathy in virtue of its superior target coverage, better CI and HI, despite an increase in treatment planning and delivery time, consumption of monitor units and a slightly increased but clinically negligible dose to some surrounding structures. It might supersede the other two older radiation techniques when orbital irradiation is contemplated.
- Burch HB, Wartofsky L: Graves’ ophthalmopathy: current concepts regarding pathogenesis and management. Endocr Rev 1993, 14: 747-793.PubMedGoogle Scholar
- Bahn RS, Heufelder AE: Pathogenesis of graves’ ophathlmopathy. N Eng J Med 1993, 329: 1468-1474. 10.1056/NEJM199311113292007View ArticleGoogle Scholar
- Prummel MF, Mourits MP, Blank L, et al.: Randomized double-blind trial of prednisone versus radiotherapy in graves’ ophthalmopathy. Lancet 1993, 342: 949-954. 10.1016/0140-6736(93)92001-AView ArticlePubMedGoogle Scholar
- Trokel S, Kazin M, Moore S: Orbital fat removal. Decompression for graves’ orbitopathy. Ophthalmol 1993, 100: 674-682.View ArticleGoogle Scholar
- Hallin ES, Feldon SE, Lutrell J: Graves’ ophthalmopathy: effect of transantral orbital decompression on optic neuropathy. J Ophthalmol 1988, 72: 683-687.Google Scholar
- Goyal S, Cohler A, Camporeale J, et al.: Intensity-modulated radiation therapy for orbital lymphoma. Radiat Med 2008,26(10):573-581. 10.1007/s11604-008-0276-1View ArticlePubMedGoogle Scholar
- Chao KS, Deasy JO, Markman J, et al.: A prospective study of salivary function sparing in patients with head-and-neck cancers receiving intensity-modulated or three-dimensional radiation therapy: initial results. Int J Radiat Oncol Biol Phys 2001, 49: 907-916. 10.1016/S0360-3016(00)01441-3View ArticlePubMedGoogle Scholar
- Eisbruch A, Ship JA, Dawson LA, et al.: Salivary gland sparing and improved target irradiation by conformal and intensity modulated irradiation of head-and-neck cancer. World J Surg 2003, 27: 832-837. 10.1007/s00268-003-7105-6View ArticlePubMedGoogle Scholar
- Nutting CM, Morden JP, Harrington KJ, et al.: Parotid- sparing intensity modulated versus conventional radiotherapy in head-and-neck cancer (PARSPORT): a phase 3 multicentre randomized controlled trial. Lancet Oncol 2011, 12: 127-136. 10.1016/S1470-2045(10)70290-4PubMed CentralView ArticlePubMedGoogle Scholar
- Eisbruch A, Schwartz M, Rasch C, et al.: Dysphagia and aspiration after chemoradiotherapy for head-and-neck cancer: which anatomic structures are affected and can they be spared by IMRT? Int J Radiat Oncol Biol Phys 2004, 60: 1425-1439. 10.1016/j.ijrobp.2004.05.050View ArticlePubMedGoogle Scholar
- Al-Wassia R, Dal Pra A, Shun K, et al.: Stereotactic fractionated radiotherapy in the treatment of juxtapapillary choroidal melanoma: the McGill university experience. Int J Radiat Oncol Biol Phys 2011,81(4):e455-e462. 10.1016/j.ijrobp.2011.05.012View ArticlePubMedGoogle Scholar
- Hirschbein MJ, Collins S, Jean WC, et al.: Treatment of intra-orbital lesions using the accuray CyberKnife system. Orbit 2008,27(2):97-105. 10.1080/01676830601177471View ArticlePubMedGoogle Scholar
- Ulmer W, Pyyry J, Kaissl W: A 3D photon superposition/convolution algorithm and its foundation on results of Monte Carlo calculations. Phys Med Biol 2005, 50: 1767-1790. 10.1088/0031-9155/50/8/010View ArticlePubMedGoogle Scholar
- Bragg CM, Wingate K, Conway J: Clinical implications of the anisotropic analytical algorithm for IMRT treatment planning and verification. Radiother Oncol 2008,86(2):276-284. 10.1016/j.radonc.2008.01.011View ArticlePubMedGoogle Scholar
- ICRU: Prescribing, recording and reporting photon beam therapy (supplement to ICRU report 50). Bethesda, MD: International Commission of Radiation Units and Measurements: ICRU 62; 1999.Google Scholar
- Paddick I: A simple scoring ratio to index the conformity of plans. J Neurosurg 2000,93(Suppl. 3):219-222.PubMedGoogle Scholar
- Sheng K, Molloy JA, Larner JM, Read PW: A dosimetric comparison of non-coplanar IMRT versus Helical Tomotherapy for nasal cavity and paranasal sinus cancer. Radiother Oncol 2007, 82: 174-178. 10.1016/j.radonc.2007.01.008View ArticlePubMedGoogle Scholar
- Wang X, Zhang X, Dong L, et al.: Effectiveness of noncoplanar IMRT planning using a parallelized multiresolution beam angle optimization method for paranasal sinus carcinoma. Int J Radiat Oncol Biol Phys 2005, 63: 594-601. 10.1016/j.ijrobp.2005.06.006View ArticlePubMedGoogle Scholar
- Niemierko A: Radiobiological models of tissue response to radiation in treatment planning systems. Tumori 1998,84(2):140-143.PubMedGoogle Scholar
- Niemierko A: Reporting and analyzing dose distributions: a concept of equivalent uniform dose. Med Phys 1997,24(1):103-110. 10.1118/1.598063View ArticlePubMedGoogle Scholar
- Emami B, Lyman J, Brown A, et al.: Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991,21(1):109-122. 10.1016/0360-3016(91)90171-YView ArticlePubMedGoogle Scholar
- Bartalena L, Marcocci C, Tanda ML, et al.: Cigarette smoking and treatment outcomes in graves ophthalmopathy. Ann Intern Med 1998,129(8):632-635.View ArticlePubMedGoogle Scholar
- Ohtsuka K, Sato A, Kawaguchi S, et al.: Effect of pulse steroid therapy with and without orbital radiotherapy on graves’ ophthalmopathy. Am J Ophthalmol 2003,135(3):285-290. 10.1016/S0002-9394(02)01970-0View ArticlePubMedGoogle Scholar
- Gorman CA, Garrity JA, Fatourechi V, et al.: The aftermath of orbital radiotherapy for graves’ ophthalmopathy. Ophthalmology 2002,109(11):2100-2107. 10.1016/S0161-6420(02)01293-9View ArticlePubMedGoogle Scholar
- Mourits MP, van Kempen-Harteveld ML, Garcia MB, et al.: Radiotherapy for graves’ orbitopathy: randomized placebo-controlled study. Lancet 2000,355(9214):1505-1509. 10.1016/S0140-6736(00)02165-6View ArticlePubMedGoogle Scholar
- Marquez SD, Lum BL, McDougall IR, et al.: Long-term results of irradiation for patients with progressive graves’ ophthalmopathy. Int J Radiat Oncol Biol Phys 2001,51(3):766-774. 10.1016/S0360-3016(01)01699-6View ArticlePubMedGoogle Scholar
- Prummel MF, Terwee CB, Gerding MN, et al.: A randomized controlled trial of orbital radiotherapy versus sham irradiation in patients with mild graves’ ophthalmopathy. J Clin Endocrinol Metab 2004,89(1):15-20. 10.1210/jc.2003-030809View ArticlePubMedGoogle Scholar
- Wakelkamp IM, Tan H, Saeed P, et al.: Orbital irradiation for graves’ disease. Is it safe? a long-term follow-up study. Ophthalmology 2004,111(8):1557-1562. 10.1016/j.ophtha.2003.12.054View ArticlePubMedGoogle Scholar
- Akmansu M, Dirican B, Bora H, et al.: The risk of radiation-induced carcinogenesis after external beam radiotherapy of graves’ orbitopathy. Ophthalmic Res 2003, 35: 150-153. 10.1159/000070050View ArticlePubMedGoogle Scholar
- Kahaly GJ, Rosler H, Pitz S, et al.: Low- versus high-dose radiotherapy for graves’ ophthalmopathy: a randomized, single blind trial. J Clin Endocrinol Metab 2000,85(1):102-108. 10.1210/jc.85.1.102PubMedGoogle Scholar
- Gerling J, Kommerell G, Henne K, et al.: Retrobular irradiation for thyroid-associated orbitopathy-double blind comparison between 2.4 and 16Gy. Int J Radiat Oncol Biol Phys 2003,55(1):582-589.View ArticleGoogle Scholar
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