Radiation Oncology/Eye/Graves

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 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 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 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 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) 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) 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) 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) 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) 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 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) 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) 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 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