Radiation Therapy Complications in Choroidal Melanoma and Strategies for Their Management

Introduction. Organ-preserving modalities are the current standard of care in the management of choroidal melanoma (CM), with radiation therapy playing a pivotal role. Despite its high efficacy, radiation exposure is associated with a broad spectrum of post-radiation complications, which may compromise treatment outcomes and, in some cases, necessitate secondary enucleation.

The objective of the work is to summarize current evidence on the use of radiation therapy in CM, analyze the range and incidence of post-radiation complications, identify associated risk factors, and evaluate strategies for prevention and management depending on the treatment modality.

Materials and methods. A literature search and analysis of scientific publications in Russian and English was conducted using relevant keywords. Inclusion criteria: original studies (randomized and non-randomized clinical trials), reviews (meta-analyses and systematic reviews) relevant to the topic.

Results and discussion. This review encompasses modern methods of radiation therapy for CM, including brachytherapy, proton beam therapy, and stereotactic radiosurgery, with attention to their indications and clinical efficacy. The types, frequency, and specific features of post-radiation complications are analyzed, including damage to the eyelid and periocular skin, cornea, lens, macula, optic nerve, secondary glaucoma, among others. Risk factors for such complications are discussed, along with available preventive and therapeutic approaches.

Conclusion. Although different radiation modalities for CM share a similar spectrum of complications, their frequency and predominance vary considerably depending on the chosen technique. Most complications are manageable; however, neovascular glaucoma, scleromalacia, and persistent trophic corneal ulcers may require secondary enucleation. These outcomes highlight the need for improved prevention, early detection of complications, and clear patient selection criteria for organ-preserving treatment of choroidal melanoma.

1. Gill V, Herrspiegel C, Sabazade S, Fili M, Bergman L, Damato B, et al. Trends in uveal melanoma presentation and survival during five decades: A nationwide survey of 3898 Swedish patients. Frontiers in Medicine. 2022;9:926034. DOI: https://doi.org/10.3389/fmed.2022.926034.

2. Collaborative Ocular Melanoma Study Group. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: V. Twelve-year mortality rates and prognostic factors: COMS report No. 28. Archives of Ophthalmology. 2006;124(12):1684–1693. DOI: https://doi.org/10.1001/archopht.124.12.1684.

3. Naumenko LV, Zhyliayeva KP, Evmenenko AA, Zherka IY, Krasny SA. Eighteen-year results of treatment of uveal melanoma using Ruthenium-106 + Rhodium-106 brachytherapy. Proceedings of the National Academy of Sciences of Belarus, Medical Series. 2021;18(3):284–291. (In Russ.). DOI: https://doi.org/10.29235/1814-6023-2021-18-3-284-291.

4. Brovkina AF. Local treatment of choroidal melanoma: Possibilities and limitations. Russian Annals of Ophthalmology. 2018;134(4):52–60. (In Russ.). DOI: https://doi.org/10.17116/oftalma201813404152.

5. Roelofsen CDM, Wierenga APA, van Duinen S, Verdijk RM, Bleeker J, Marinkovic M, et al. Five decades of enucleations for uveal melanoma in one center: More tumors with high risk factors, no improvement in survival over time. Ocular Oncology and Pathology. 2021;7(2):133–141. DOI: https://doi.org/10.1159/000509918.

6. Neroev VV, Saakyan SV, Amiryan AG, Valskiy VV. Clinico-ecographic factors of prediction of uveal melanoma brachytherapy efficiency. REJR. 2018;8(1):40–51. (In Russ.). DOI: https://doi.org/10.21569/2222-7415-2018-8-1-40-51.

7. Georgopoulos M, Zehetmayer M, Ruhswurm I, Toma-Bstaendig S, Ségur-Eltz N, Sacu S, et al. Tumour regression of uveal melanoma after ruthenium-106 brachytherapy or stereotactic radiotherapy with gamma knife or linear accelerator. Ophthalmologica. 2003;217(5):315–319. DOI: https://doi.org/10.1159/000071345.

8. Samkovich EV, Panova IE, Boyko EV, Svistunova EM, Bykhovskii AA. Photodynamic therapy in the combined treatment of choroidal melanoma. Fyodorov Journal of Ophthalmic Surgery. 2024;(2):99–108. (In Russ.). DOI: https://doi.org/10.25276/0235-4160-2024-2-99-108.

9. Yarovoy AA, Magaramov DA, Bulgakova ES. Results of 10-year use of complex treatment of choroidal melanoma stage T2 with brachytherapy and transpupillary thermotherapy. Russian Annals of Ophthalmology. 2011;127(1):38–42. (In Russ.). EDN: https://elibrary.ru/NDJUKT.

10. Brovkina AF. Current aspects of treatment for choroidal melanomas: Problems, controversial questions. Russian Annals of Ophthalmology. 2006;122(1):13–16. (In Russ.). PMID: https://pubmed.gov/16550680.

11. Zherka IY, Dziameshka PD, Naumenko LV, Hizemava VA. Radiation therapy of choroidal melanoma: Comparative evaluation of the treatment results. Vitebsk Medical Journal. 2023;22(1):83–93. EDN: https://elibrary.ru/TKNVRR.

12. Wilson RR. Radiological use of fast protons. Radiology. 1946;47(5):487–491. DOI: https://doi.org/10.1148/47.5.487.

13. Gragoudas ES, Seddon JM, Egan K, Glynn R, Munzenrider J, Austin-Seymour M, et al. Long-term results of proton beam irradiated uveal melanomas. Ophthalmology. 1987;94(4):349–353. DOI: https://doi.org/10.1016/s0161-6420(87)33456-6.

14. Hrbacek J, Kacperek A, Beenakker JWM, Mortimer L, Denker A, Mazal A, et al. PTCOG ocular statement: Expert summary of current practices and future developments in ocular proton therapy. International Journal of Radiation Oncology, Biology, Physics. 2024;120(5):1307–1325. DOI: https://doi.org/10.1016/j.ijrobp.2024.06.017.

15. Miao Y, Zheng T, Zhang Q, Li M, Lei Q, Liu Q, et al. Efficacy and safety of proton radiotherapy in treating choroidal melanoma: A systematic review and meta-analysis. Radiation Oncology. 2025;20(1):7. DOI: https://doi.org/10.1186/s13014-024-02580-w.

16. Saakyan SV, Borodin JI, Shirina TV. Estimate of the treatment efficiency and survival of patients with uveal melanoma after treatment with a narrow medical proton beam. Radiology — Practice. 2012:49–53. (In Russ.). EDN: https://elibrary.ru/PUYYXX.

17. Desjardins L, Lumbroso-Le Rouic L, Levy-Gabriel C, Cassoux N, Dendale R, Mazal A, et al. Treatment of uveal melanoma by accelerated proton beam. In: Desjardins L, Kivelä T, Damato BE, Jager MJ (eds.). Current concepts in uveal melanoma. Basel: Karger; 2012. P. 41–57. DOI: https://doi.org/10.1159/000328257.

18. Hussain RN, Chiu A, Pittam B, Taktak A, Damato BE, Kacperek A, et al. Proton beam radiotherapy for choroidal and ciliary body melanoma in the UK — national audit of referral patterns of 1 084 cases. Eye. 2023; 37(5):1033–1036. DOI: https://doi.org/10.1038/s41433-022-02178-0.

19. Fakiris AJ, Lo SS, Henderson MA, Witt TC, Worth RM, Danis RP, et al. Gamma-knife-based stereotactic radiosurgery for uveal melanoma. Stereotactic and Functional Neurosurgery. 2007;85(2–3):106–112. DOI: https://doi.org/10.1159/000098525.

20. Zherkо IYu, Dziameshkо PD, Naumenko LV, Minailо II, Zhyliayeva EP, Hizemava OA, et al. The immediate results of choroidal melanoma treatment using stereotactic radiosurgery. Diagnostic Radiology and Radiotherapy. 2022;13(1):95–102. (In Russ.). DOI: https://doi.org/10.22328/2079-5343-2022-13-1-95-102.

21. Du K, Luo W. Efficacy and safety of robotic Cyberknife radiotherapy in uveal melanoma: A systematic review and meta-analysis. Eye. 2025;39(3):548–555. DOI: https://doi.org/10.1038/s41433-024-03582-4.

22. Liegl R, Schmelter V, Fuerweger C, Ehret F, Priglinger S, Muacevic A, et al. Robotic CyberKnife radiosurgery for the treatment of choroidal and ciliary body melanoma. American Journal of Ophthalmology. 2023;250:177–185. DOI: https://doi.org/10.1016/j.ajo.2022.12.021.

23. Weber DC, Bogner J, Verwey J, Georg D, Dieckmann K, Escudé L, et al. Proton beam radiotherapy versus fractionated stereotactic radiotherapy for uveal melanomas: A comparative study. International Journal of Radiation Oncology, Biology, Physics. 2005;63(2):373–384. DOI: https://doi.org/10.1016/j.ijrobp.2005.01.057.

24. Nathan P, Cohen V, Coupland S, Curtis K, Damato B, Evans J, et al.; United Kingdom Uveal Melanoma Guideline Development Working Group. Uveal melanoma UK National Guidelines. European Journal of Cancer. 2015;51(16):2404–2412. DOI: https://doi.org/10.1016/j.ejca.2015.07.013.

25. Gerard A, Peyrichon ML, Vidal M, Barnel C, Sauerwein W, Carnicer A, et al. Ocular proton therapy, pencil beam scanning high energy proton therapy or stereotactic radiotherapy for uveal melanoma; an in silico study. Cancer/Radiothérapie. 2022;26(8):1027–1033. DOI: https://doi.org/10.1016/j.canrad.2022.03.003.

26. Zemba M, Dumitrescu OM, Gheorghe AG, Radu M, Ionescu MA, Vatafu A, et al. Ocular complications of radiotherapy in uveal melanoma. Cancers. 2023;15(2):333. DOI: https://doi.org/10.3390/cancers15020333.

27. Tseng VL, Coleman AL, Zhang ZF, McCannel TA. Complications from plaque versus proton beam therapy for choroidal melanoma: A qualitative systematic review. Journal of Cancer Therapy. 2016;7(3):169–184. DOI: https://doi.org/10.4236/jct.2016.73018.

28. Neroev VV, Saakyan SV, Amiryan AG, Valsky VV. Radiation complications after brachytherapy of uveal melanoma: Their relationship with clinical, echographic, hemodynamic characteristics, and the degree of tumor resorption. REJR. 2018;8(2):8–23. (In Russ). DOI: https://doi.org/10.21569/2222-7415-2018-8-2-8-23.

29. Mishra K, Daftari I, Weinberg V, Cole T, Quivey J, Castro J, et al. Risk factors for neovascular glaucoma after proton beam therapy of uveal melanoma: A detailed analysis of tumor and dose-volume parameters. International Journal of Radiation Oncology, Biology, Physics. 2013;87(2):330–336. DOI: https://doi.org/10.1016/j.ijrobp.2013.05.051.

30. Foss A, Whelehan I, Hungerford J, Anderson D, Errington R, Kacperek A, et al. Predictive factors for the development of rubeosis following proton beam radiotherapy for uveal melanoma. British Journal of Ophthalmology. 1997;81(9):748–754. DOI: https://doi.org/10.1136/bjo.81.9.748.

31. Zherka IY, Dziameshka PD, Naumenko LV, Zhyliayeva KP, Hizemava VA, Polyakov SL. Predictive factors for the development of secondary glaucoma after stereotactic radiosurgery for choroidal melanoma. Journal of the Grodno State Medical University. 2022;20(3):335–342. (In Russ). DOI: https://doi.org/10.25298/2221-8785-2022-20-3-335-342.

32. Modorati GM, Dagan R, Mikkelsen LH, Andreasen S, Ferlito A, Bandello F. Gamma knife radiosurgery for uveal melanoma: A retrospective review of clinical complications in a tertiary referral center. Ocular Oncology and Pathology. 2020;6(2):115–122. DOI: https://doi.org/10.1159/000501971.

33. Jeganathan VS, Wirth A, MacManus MP. Ocular risks from orbital and periorbital radiation therapy: A critical review. International Journal of Radiation Oncology, Biology, Physics. 2011;79(3):650–659. DOI: https://doi.org/10.1016/j.ijrobp.2010.09.056.

34. Servodidio CA, Abramson DH. Acute and long-term effects of radiation therapy to the eye in children. Cancer Nursing. 1993;16(5):371–381. PMID: https://pubmed.gov/8261386.

35. Durkin SR, Roos D, Higgs B, Casson RJ, Selva D. Ophthalmic and adnexal complications of radiotherapy. Acta Ophthalmologica Scandinavica. 2007;85(3):240–250. DOI: https://doi.org/10.1111/j.1600-0420.2006.00822.x.

36. Hamilton CS, Denham JW, O’Brien M, Ostwald P, Kron T, Wright S, et al. Underprediction of human skin erythema at low doses per fraction by the linear quadratic model. Radiotherapy and Oncology. 1996; 40(1):23–30. DOI: https://doi.org/10.1016/0167-8140(96)01764-1.

37. Akagunduz OO, Yilmaz SG, Tavlayan E, Baris ME, Afrashi F, Esassolak M. Radiation-induced ocular surface disorders and retinopathy: Ocular structures and radiation dose-volume effect. Cancer Research and Treatment. 2022;54(2):417–423. DOI: https://doi.org/10.4143/crt.2021.575.

38. Parsons JT, Bova FJ, Mendenhall WM, Million RR, Fitzgerald CR. Response of the normal eye to high dose radiotherapy. Oncology. 1996;10(6):837–851. PMID: https://pubmed.gov/8823799.

39. Parsons JT, Bova FJ, Fitzgerald CR, Mendenhall WM, Million RR. Severe dry-eye syndrome following external beam irradiation. International Journal of Radiation Oncology, Biology, Physics. 1994;30(4):775–780. DOI: https://doi.org/10.1016/0360-3016(94)90348-4.

40. Kennerdell JS, Flores NE, Hartsock RJ. Low-dose radiotherapy for lymphoid lesions of the orbit and ocular adnexa. Ophthalmic Plastic and Reconstructive Surgery. 1999;15(2):129–133. DOI: https://doi.org/10.1097/00002341-199903000-00012.

41. Borodin YI, Valsky VV. Alteration in visual acuity in the patients with malignant tumors of eye adnexa after proton beam therapy. Ophthalmosurgery. 2010;(1):34–48. (In Russ.). EDN: https://elibrary.ru/PXQZPZ.

42. Ozkaya Akagunduz O, Guven Yilmaz S, Yalman D, Yuce B, Demirkilinc Biler E, Afrashi F, et al. Evaluation of the radiation dose-volume effects of optic nerves and chiasm by psychophysical, electrophysiologic tests, and optical coherence tomography in nasopharyngeal carcinoma. Technology in Cancer Research & Treatment. 2017;16(6):969–977. DOI: https://doi.org/10.1177/1533034617711613.

43. Foti PV, Travali M, Farina R, Palmucci S, Spatola C, Liardo RLE, et al. Diagnostic methods and therapeutic options of uveal melanoma with emphasis on MR imaging — part II: Treatment indications and complications. Insights into Imaging. 2021;12(1):67. DOI: https://doi.org/10.1186/s13244-021-01001-w.

44. Riekki R, Jukkola A, Oikarinen A, Kallioinen M. Radiation therapy induces tenascin expression and angiogenesis in human skin. Acta Dermato-Venereologica. 2001;81(5):329–333. DOI: https://doi.org/10.1080/000155501317140025.

45. Behroozian T, Goldshtein D, Ryan Wolf J, van den Hurk C, Finkelstein S, Lam H, et al.; Multinational Association of Supportive Care in Cancer (MASCC) Oncodermatology Study Group Radiation Dermatitis Guidelines Working Group. MASCC clinical practice guidelines for the prevention and management of acute radiation dermatitis: Part 1) systematic review. EClinicalMedicine. 2023;58:101886. DOI: https://doi.org/10.1016/j.eclinm.2023.101886.

46. Khanna NR, Kumar DP, Laskar SG, Laskar S. Radiation dermatitis: An overview. Indian Journal of Burns. 2013;21(1):24–31. DOI: https://doi.org/10.4103/0971-653X.121877.

47. Roth J, Brown N, Catterall M, Beal A. Effects of fast neutrons on the eye. The British Journal of Ophthalmology. 1976;60(4):236–244. DOI: https://doi.org/10.1136/bjo.60.4.236.

48. Akpek EK, Amescua G, Farid M, Garcia-Ferrer FJ, Lin A, Rhee MK, et al.; American Academy of Ophthalmology Preferred Practice Pattern Cornea and External Disease Panel. Dry eye syndrome preferred practice pattern. Ophthalmology. 2019;126(1):286–334. DOI: https://doi.org/10.1016/j.ophtha.2018.10.023.

49. El-Sawy T, Ali R, Nasser QJ, Esmaeli B. Outcomes of dacryocystorhinostomy in patients with head and neck cancer treated with high-dose radiation therapy. Ophthalmic Plastic and Reconstructive Surgery. 2012; 28(3):196–198. DOI: https://doi.org/10.1097/IOP.0b013e31824c11df.

50. Diba R, Saadati H, Esmaeli B. Outcomes of dacryocystorhinostomy in patients with head and neck tumors. Head & Neck. 2005;27(1):72–75. DOI: https://doi.org/10.1002/hed.20079.

51. Valsky VV, Saakyan SV, Borodin YI. Complications after proton beam irradiation therapy of uveal melanoma: Treatment and prophylaxis. Russian Ophthalmological Journal. 2013;6(3):12–15 (In Russ.). EDN: https://elibrary.ru/QIWMBF.

52. Passarin O, Zografos L, Schalenbourg A, Moulin A, Hospital JE. Scleritis after proton therapy in uveal melanoma. Klinische Monatsblatter fur Augenheilkunde. 2012;229(4):395–398. DOI: https://doi.org/10.1055/s-0031-1299184.

53. Saakyan SV, Amiryan AG, Valskiy VV, Mironova IS, Iomdina EN, Markosyan GA. Scleral necrosis after brachytherapy of uveal melanoma and methods of its elimination. Russian Ophthalmological Journal. 2017; 10(1):43–48. (In Russ.). EDN: https://elibrary.ru/YFQCGB.

54. Groenewald C, Konstantinidis L, Damato B. Effects of radiotherapy on uveal melanomas and adjacent tissues. Eye. 2013;27(2):163–171. DOI: https://doi.org/10.1038/eye.2012.249.

55. Wen JC, Oliver SC, McCannel TA. Ocular complications following I-125 brachytherapy for choroidal melanoma. Eye. 2009;23(6):1254–1268. DOI: https://doi.org/10.1038/eye.2009.43.

56. Panova IE, Svistunova EM, Vorobyov NA, Samkovich EV, Martynova NI, Bykhovsky AA. Neovascular glaucoma as a complication of proton therapy for uveal melanoma. Russian Journal of Clinical Ophthalmology. 2024;24(4):185–192. (In Russ.). DOI: https://doi.org/10.32364/2311-7729-2024-24-4-4.

57. Stadigh AE, Puska PM, Kivelä TT. Incidence and risk factors for secondary glaucoma in eyes with uveal melanoma. Ophthalmology Glaucoma. 2023;6(1):29–41. DOI: https://doi.org/10.1016/j.ogla.2022.08.002.

58. Brovkina AF, Khionidi YN, Nechesnyuk Syu. Mechanism of secondary glaucoma development after local destruction of choroidal melanoma. Glaukoma. 2010;(1):52–55. (In Russ.). EDN: https://elibrary.ru/MBRFZT.

59. Siedlecki J, Reiterer V, Leicht S, Foerster P, Kortüm K, Schaller U, et al. Incidence of secondary glaucoma after treatment of uveal melanoma with robotic radiosurgery versus brachytherapy. Acta Ophthalmologica. 2017;95(8):e734–e739. DOI: https://doi.org/10.1111/aos.13418.

60. Camp DA, Yadav P, Dalvin LA, Shields CL. Glaucoma secondary to intraocular tumors: Mechanisms and management. Current Opinion in Ophthalmology. 2019;30(2):71–81. DOI: https://doi.org/10.1097/icu.0000000000000550.

61. Mahdjoubi A, Najean M, Lemaitre S, Dureau S, Dendale R, Levy C, et al. Intravitreal bevacizumab for neovascular glaucoma in uveal melanoma treated by proton beam therapy. Graefe’s Archive for Clinical and Experimental Ophthalmology. 2018;256(2):411–420. DOI: https://doi.org/10.1007/s00417-017-3834-3.

62. Brovkina AF, Stoyukhina AS, Chesalin IP. Choroidal melanoma brachyterapy and secondary enucleation. Ophthalmology Reports. 2014;7(2):69–77. (In Russ.). DOI: https://doi.org/10.17816/OV2014269-77.

63. Foti PV, Inì C, Travali M, Farina R, Palmucci S, Spatola C, et al. MR imaging–pathologic correlation of uveal melanomas undergoing secondary enucleation after proton beam radiotherapy. Applied Sciences. 2021; 11(9):4310. DOI: https://doi.org/10.3390/app11094310.

64. Fabian ID, Tomkins-Netzer O, Stoker I, Arora AK, Sagoo MS, Cohen VM. Secondary enucleations for uveal melanoma: A 7-year retrospective analysis. American Journal of Ophthalmology. 2015;160(6):1104–1110.e1. DOI: https://doi.org/10.1016/j.ajo.2015.08.034.

65. Banou L, Tsani Z, Arvanitogiannis K, Pavlaki M, Dastiridou A, Androudi S. Radiotherapy in uveal melanoma: A review of ocular complications. Current Oncology. 2023;30(7):6374–6396. DOI: https://doi.org/10.3390/curroncol30070470.

66. Horgan N, Shields CL, Mashayekhi A, Shields JA. Classification and treatment of radiation maculopathy. Current Opinion in Ophthalmology. 2010;21(3):233–238. DOI: https://doi.org/10.1097/ICU.0b013e3283386687.

67. Wong AJ, Schefler AC, Teh BS. Overview of late complications of radiation therapy in uveal melanoma. Chinese Clinical Oncology. 2023;12(3):29–29. DOI: https://doi.org/10.21037/cco-22-88.

68. Panova IE, Bikhovsky AA, Samkovich EV, Svistunova EM. Glucocorticosteroids and postradiation macular edema: Rationale for choice of therapy and efficacy of use. Ophthalmology in Russia. 2024;21(3):533–539. (In Russ.). DOI: https://doi.org/10.18008/1816-5095-2024-3-533-539.

69. Bykhovsky AA, Panova IE, Samkovich EV. Post-radiation macular edema after brachytherapy for choroidal melanoma (Ru/Rh106): Risk factors and correction possibilities. P. A. Herzen Journal of Oncology. 2023; 12(6):19–23. (In Russ.). DOI: https://doi.org/10.17116/onkolog20231206119.

70. Tomkins-Netzer O, Lightman S, Drye L, Kempen J, Holland GN, Rao NA, et al.; Multicenter Uveitis Steroid Treatment Trial Research Group. Outcome of treatment of uveitic macular edema: The multicenter uveitis steroid treatment trial 2-year results. Ophthalmology. 2015;122(11):2351–2359. DOI: https://doi.org/10.1016/j.ophtha.2015.07.036.

71. Kline LB, Kim JY, Ceballos R. Radiation optic neuropathy. Ophthalmology. 1985;92(8):1118–1126. DOI: https://doi.org/10.1016/s0161-6420(85)33898-8.

72. Beykin G, Pe’er J, Hemo Y, Frenkel S, Chowers I. Pars plana vitrectomy to repair retinal detachment following brachytherapy for uveal melanoma. British Journal of Ophthalmology. 2013;97(12):1534–1537. DOI: https://doi.org/10.1136/bjophthalmol-2013-303331.