Breakdown of the blood-eye barrier in choroidal melanoma after proton beam radiotherapy

  • Annette Hager
  • Friederike Meissner
  • Aline–Isabel Riechardt
  • Theresa Bonaventura
  • Julia Löwen
  • Jens HeufelderEmail author
  • Antonia M. Joussen



Irradiation of choroidal melanoma is a safe and globe preserving procedure. Chronic inflammatory processes and ischemia are the main reasons for secondary enucleation in the long run. The aim of this study was to determine whether intraocular inflammation and especially inflammatory response after proton beam therapy (PBT) is related to primary tumor characteristics such as height, tumor volume, and initial flare values.


Twenty-six patients treated for uveal melanoma using PBT were included. All patients were examined for signs of inflammation using laser flare photometry (LFP). Each examination included assessment of the melanoma and fellow eye (which acted as the control) and imaging of the melanoma.


Significant differences of flare values between melanoma eyes and control group were found both at baseline (median 17.65 ph/ms (min 4, max 37.10), 7.45 ph/ms (min 0.80, max 16.40), respectively) and during follow-up (median 21.45 ph/ms (min 4.5, max 70.90); 6.05 ph/ms (min 2.40, max 16.40), respectively) (p < 0.001, Wilcoxon test). Flare values in melanoma eyes increased significantly after PBT (p = 0.005, Wilcoxon test) and after a follow-up of 94 days (median, 7–420 days). Flare values of the control group did not change (p = 0.946, Wilcoxon test). The increase of flare values correlated significantly with maximum tumor height and volume (Spearman-Rho 0.633, p = 0.001 and 0.519, p = 0.007, respectively).


LFP has proven to show significantly higher flare values in melanoma eyes as compared with the control group and provides data on the course of the inflammatory response after treatment. It may ease treatment planning both at baseline and during follow-up.


Choroidal melanoma Proton beam radiotherapy Inflammatory response Breakdown blood-aqueous barrier Flare meter 


Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical approval and informed consent

IRB approval was obtained. All procedures performed in studies involving human participants were in accordance with the ethical standards of the IRB Charité–Universitätsmedizin Berlin (EA4/095/15) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent from all patients was obtained.


  1. 1.
    Collaborative Ocular Melanoma Study Group (2006) The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: V. Twelve-year mortality rates and prognostic factors: COMS report No. 28. Arch Ophthalmol 124:1684–1693CrossRefGoogle Scholar
  2. 2.
    Seibel I, Cordini D, Rehak M et al (2015) Local recurrence after primary proton beam therapy in uveal melanoma: risk factors, retreatment approaches, and outcome. Am J Ophthalmol 160:628–636CrossRefGoogle Scholar
  3. 3.
    Seibel I, Riechardt AI, Heufelder J et al (2017) Adjuvant ab interno tumor treatment after proton beam irradiation. Am J Ophthalmol.
  4. 4.
    Seibel I, Cordini D, Willerding G et al (2015) Endodrainage, tumor photocoagulation, and silicone oil tamponade for primary exudative retinal detachment due to choroidal melanoma persisting after proton beam therapy. Ocul Oncol Pathol 1:24–33CrossRefGoogle Scholar
  5. 5.
    Riechardt AI, Cordini D, Rehak M et al (2016) Trabeculectomy in patients with uveal melanoma after proton beam therapy. Graefes Arch Clin Exp Ophthalmol 254:1379–1385CrossRefGoogle Scholar
  6. 6.
    Lumbroso L, Desjardins L, Levy C et al (2001) Intraocular inflammation after proton beam irradiation for uveal melanoma. Br J Ophthalmol 85:1305–1308CrossRefGoogle Scholar
  7. 7.
    Sawa M (2017) Laser flare-cell photometer: principle and significance in clinical and basic ophthalmology. Jpn J Ophthalmol 61:21–42CrossRefGoogle Scholar
  8. 8.
    Dobler B, Bendl R (2002) Precise modelling of the eye for proton therapy of intraocular tumours. Phys Med Biol 47:593–613CrossRefGoogle Scholar
  9. 9.
    Pfeiffer K, Bendl R (2001) Real-time dose calculation and visualization for the proton therapy of ocular tumours. Phys Med Biol 46:671–686CrossRefGoogle Scholar
  10. 10.
    Groenewald C, Konstanidis L, Damato B (2013) Effects of radiotherapy on uveal melanomas and adjacent tissues. Eye 27:163–171CrossRefGoogle Scholar
  11. 11.
    Mashayekhi A, Schönbach E, Shields CL, Shields JA (2015) Early subclinical macular edema in eyes with uveal melanoma: association with future cystoid macular edema. Ophthalmology 122:1023–1029CrossRefGoogle Scholar
  12. 12.
    Missotten GS, Notting IC, Schlingemann RO et al (2006) Vascular endothelial growth factor a in eyes with uveal melanoma. Arch Ophthalmol 124:1428–1434CrossRefGoogle Scholar
  13. 13.
    Nagarkatti-Gude N, Bronkhorst IHG, van Duinen SG et al (2012) Cytokines and chemokines in the vitreous fluid of eyes with uveal melanoma. Invest Ophthalmol Vis Sci 53:6748–6755CrossRefGoogle Scholar
  14. 14.
    Mashayekhi A, Tuncer S, Shields CL, Shields JA (2013) Tumor-related lipid exudation and associated tumor-related complications after plaque radiotherapy of posterior uveal melanoma. Eur J Ophthalmol 23:399–409CrossRefGoogle Scholar
  15. 15.
    Mashayekhi A, Tuncer S, Shields CL, Shields JA (2010) Tumor-related lipid exudation after plaque radiotherapy of choroidal melanoma: the role of Bruch’s membrane rupture. Ophthalmology 117:1013–1023CrossRefGoogle Scholar
  16. 16.
    Kivelä T, Eskelin S, Mäkitie T et al (2001) Exudative retinal detachment from malignant uveal melanoma: predictors and prognostic significance. Invest Ophthalmol Vis Sci 42:2085–2093Google Scholar
  17. 17.
    Malcles A, Nguyen AM, Mathis T et al (2017) Intravitreal dexamethasone implant (Ozurdex) for exudative retinal detachment after proton beam therapy for choroidal melanoma. Eur J Ophthalmol.
  18. 18.
    Konstantinidis L, Groenewald C, Coupland SE et al (2014) Trans-scleral local resection of toxic choroidal melanoma after proton beam radiotherapy. Br J Ophthalmol 98:775–779CrossRefGoogle Scholar
  19. 19.
    Char DH, Bove R, Phillips TL (2003) Laser and proton radiation to reduce uveal melanoma-associated exudative retinal detachment. Am J Ophthalmol 136:180–182CrossRefGoogle Scholar
  20. 20.
    Newman H, Finger PT, Chin KJ et al (2011) Systemic bevacizumab (Avastin) for exudative retinal detachment secondary to choroidal melanoma. Eur J Ophthalmol 21:796–801CrossRefGoogle Scholar
  21. 21.
    Fraser DJ, Font RL (1979) Ocular inflammation and hemorrhage as initial manifestations of uveal malignant melanoma. Arch Ophthalmol 97:1311–1314CrossRefGoogle Scholar
  22. 22.
    Nguyen NX, Küchle M, Naumann GOH (1992) Tumor growth of a choroidal malignant melanoma and aqueous flare. Ophthalmologica 213:194–196CrossRefGoogle Scholar
  23. 23.
    Küchle M, Nguyen NX, Naumann GO (1994) Quantitative assessment of the blood-aqueous barrier in human eyes with malignant or benign uveal tumors. Am J Ophthalmol 117:521–528CrossRefGoogle Scholar
  24. 24.
    Castella AP, Bercher L, Zografos L et al (1995) Study of the blood-aqueous barrier in choroidal melanoma. Br J Ophthalmol 90:354–357CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.AugenklinikCharité – Universitätsmedizin Berlin, Campus Benjamin FranklinBerlinGermany
  2. 2.BerlinProtonen am Helmholtz-Zentrum Berlin für Materialien und EnergieCharité – Universitätsmedizin BerlinBerlinGermany

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