# Radiation Oncology/Eye/Graves

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials

## Etiology

* Inflammatory condition of extraocular muscles and tissues; thought to be autoimmune
* Frequently associated with hyperthyroidism, but also described in euthyroid and hypothyroid patients
* Histology shows widespread lymphocytic infiltrates, and interstitial edema
* Edema can lead to compression of the optic nerve, decreased visual acuity, reduction in visual fields, and ultimately blindness
* Fibrosis develops over course of 2-5 years, so treatment (including RT) ought to start early

## Treatment Overview

* Permanent control of hyperthyroidism when present is recommended
* First line: high dose glucocorticoids, with favorable response in up to 60% patients
* Surgery (orbital decompression) or RT can be effective second line therapies

## Systematic Review

* Israel; 2009 PMID 19491222 -- "Treatment Modalities for Graves' Ophthalmopathy - Systematic Review and Meta-Analysis." (Stiebel-Kalish H, J Clin Endocrinol Metab. 2009 Jun 2.)
** Meta-analysis. 33 trials, 1367 patients.
** Meds: Corticosteroids: Intravenous pulsed better than oral. Somatostatin analogs: minor but statistically significant advantage over placebo
** RT: No benefit for orbital RT over sham on clinical activity, superior for diplopial (OR 4.9, SS). Combination corticosteroids + RT significantly better than either treatment alone

## Radiation

* May be offered to those who are symptomatic and who failed high dose steroids, or are contraindicated for steroids (optic neuropathy or corneal ulceration)
* Most common dose: 20 Gy in 10 fractions, although one study showed better results with 10 Gy in 1 Gy/fx, and even 20 Gy in 1 Gy/week x 20 weeks
* Fields: lateral fields with posterior angulation, and lens sparing
* RT may initially increase edema and thus symptoms; patients can be maintained on steroids early in the treatment
* Best benefit of RT is concurrently with corticosteroids
* Side effects (commonly 6 months - 3 years): cataracts, radiation retinopathy, radiation optic neuropathy
* Relative contraindication: Diabetes, and particularly diabetes with HTN due to high rate of retinopathy

### Randomized

* Amsterdam
** 2004 PMID 14715820 -- "A randomized controlled trial of orbital radiotherapy versus sham irradiation in patients with mild Graves' ophthalmopathy." (Prummel MF, J Clin Endocrinol Metab. 2004 Jan;89(1):15-20.)
*** Randomized, double-blind. 88 patients (44 orbital RT, 44 sham)
*** Outcome: RT 52% vs. 27% at 12 months (SS) in improving eye muscle motility and decreasing diplopial. RT group less need for further treatment (SS). But, QOL improvement similar in both groups. Worsening ophthalmopathy similar (~15%)
*** Conclusion: RT effective in mild ophthalmopathy, but no improved QOL or treatment costs
** 1993 PMID 8105213 -- "Randomized double-blind trial of prednisone versus radiotherapy in Graves' ophthalmopathy." (Prummel MF, Lancet. 1993 Oct 16;342(8877):949-54.)
*** Randomized double-blind. 56 patients with moderaly severe GO. Treated with 1) 3-month oral prednisone + sham RT vs. 2) RT 20 Gy + placebo capsules
*** Conclusion: RT and oral prednisone equally effective, but RT better tolerated
* Mayo, 2001 PMID 11535445 -- "A prospective, randomized, double-blind, placebo-controlled study of orbital radiotherapy for Graves' ophthalmopathy." (Gorman CA, Ophthalmology. 2001 Sep;108(9):1523-34.)
** Randomized, double-blind. 42 patients. Moderate, symptomatic Graves ophthalmopathy. Orbit treated with 20 Gy, sham therapy to other side; 6 months later therapy reversed.
** Outcome: No difference at 6 month cross-over. Slight improvement in muscle volume and proptosis in first treated eye at 12 months.
* Mainz, 2000 (Germany) PMID 10634372 -- "Low- versus high-dose radiotherapy for Graves' ophthalmopathy: a randomized, single blind trial." (Kahaly GJ, J Clin Endocrinol Metab. 2000 Jan;85(1):102-8.)
** Randomized. Euthyroid patients with moderately severe GO. Treated with 1) 20 Gy @ 1 Gy/week over 20 weeks, 2) 10 Gy @ 1 Gy/fx over 2 weeks, or 3) 20 Gy @ 2 Gy/fx over 2 weeks
** Outcomes: response to therapy 67% vs. 59% vs. 55% (SS)
** Conjunctivitis: none vs. 18% vs. 36%
** Conclusion: similar response rates, but 1 Gy/week protocol more effective and better tolerated
* Utrecht, 2000 (Holland) PMID 10801172 -- "Radiotherapy for Graves' orbitopathy: randomised placebo-controlled study." (Mourits MP, Lancet. 2000 Apr 29;355(9214):1505-9.)
** Randomised double-blind. 60 patients. Moderately severe GO. Treated with 1) RT 20/10 or 2) sham RT
** Outcome: success in 60% RT vs. 31% sham (SS). Improvement in diplopia grade, but no reduction in proptosis or eyelid swelling. Also significant improvement in elevation, but no other variables. But only 25% of RT patients spared from additional strabismus surgery
** Conclusion: RT should be used only for motility impairment

### Retrospective

* Amsterdam, 2004 (Holland) PMID 15288988 (1982-1993) -- "Orbital irradiation for Graves' ophthalmopathy: Is it safe? A long-term follow-up study." (Wakelkamp IM, Ophthalmology. 2004 Aug;111(8):1557-62.)
** Retrospective. 157/245 patients treated with 20/10 and/or oral glucocorticoids. Probable retinopathy defined as 1-5 hemorrhages, definite retinopathy >5 lesions. Mean F/U 11 years
** Mortality similar, none from intracranial tumor.
** Retinopathy: possible 15%, definite 3%. Of 23 possible, 22 received RT, 1 steroids. Of 5 definite, all received RT. Diabetes highly associated with retinopathy (RR 21)
** Cataracts: similar ~30%
** Conclusion: orbital irradiation safe, except possibly for diabetic patients
* Pisa, 2003 (Italy) PMID 12915636 (1972-1996) -- "Long-term safety of orbital radiotherapy for Graves' ophthalmopathy." (Marcocci C, J Clin Endocrinol Metab. 2003 Aug;88(8):3561-6.)
** Retrospective. 204 patients. Median f/u 11 years
** Cataracts: 10%. No tumors.
** Retinopathy: mild in 14% with diabetes and HTN, 3% with HTN alone, none with DM alone
** Conclusion: Safe, HTN with DM may be a relative contraindication
* Sapporo, 2003 (Japan) PMID 12614743 -- "Effect of steroid pulse therapy with and without orbital radiotherapy on Graves' ophthalmopathy." (Ohtsuka K, Am J Ophthalmol. 2003 Mar;135(3):285-90.)
** Prospective, nonrandomized. 39 patients, high dose steroids +/- RT 24 Gy
** No difference between groups. Both significan improvement in EOM hypertrophy
* Mayo, 2002 PMID 12414422 -- "The aftermath of orbital radiotherapy for graves' ophthalmopathy." (Gorman CA, Ophthalmology. 2002 Nov;109(11):2100-7.)
** Retrospective. 42 patients. All RT, ~half also decompressed later. 3 year F/U
** If RT only, slight improvement in outcome.
** Conclusion: Limited evidence for RT benefit in mild-moderate ophthalmopathy
* Muenster, 2002 1963-78 (Germany) PMID 11777638 -- "A long-term follow-up study after retro-orbital irradiation for Graves' ophthalmopathy." (Schaefer U, Int J Radiat Oncol Biol Phys. 2002 Jan 1;52(1):192-7.)
** Retrospective. 250 patients bilateral ocular RT. Median F/U 31 years
** OS (10 year, 20 year, 30 year): 89%, 68%, 49%; Normal popluation: 92%, 76%, 52%; Cancer specific OS: 98%, 92%, 88%. No radiation-induced cancer deaths evident
** Conclusion: long-term results satisfactory, in a small cohort
* Meinz, 2002 (Germany)(1981-1997) PMID 12548473 -- "[Retrobulbar irradiation for Graves' ophthalmopathy -- long-term results][Article in German]" (Pitz S, Klin Monatsbl Augenheilkd. 2002 Dec;219(12):876-82.)
** Retrospective. 104 patients, 29 RT only, 75 RT + steroids. Mean F/U 40 months
** Clinically no improvement in proptosis, lid signs, and intraocular pressure. Retrobulbar pain improved in 75%; improved motilty in 25%. Surgical decompression in 25% at 1 year
** Conclusion: No treatment-related side effect. Improvement in ocular motility. RT shortens duration of disease, allowing earlier rehabilitative surgery
* Stanford, 2001 PMID 11697323 -- "Long-term results of irradiation for patients with progressive Graves' ophthalmopathy." (Marquez SD, Int J Radiat Oncol Biol Phys. 2001 Nov 1;51(3):766-74.)
** Retrospective. 197 patients. RT 20 Gy. Min F/U 1 year, max 29 years
** Outcome: improved soft-tissue 89%, proptosis 70%, EOM dysfunction 85%, corneal abnormalities 96%, sight improved 67%. Time to response >6 months
** Side effects: 12% cataracts (median 11 years)
** Conclusion: safe and effective for progressive Graves