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Background: Uveal melanoma is the most common primary ocular malignancy in adults in the USA and Europe. The optimal treatment of large uveal melanoma is still under debate. Radiation therapy has its limitation due its eye-threatening secondary complications and is therefore often combined with surgical excision of the tumor., Methods: In a retrospective interventional review, we evaluated in total 242 patients with uveal melanoma that underwent transscleral tumor resection with a predefined protocol, either with adjuvant ruthenium brachytherapy (Ru-106 group, n 136,), or with neoadjuvant proton beam therapy (PBT group, n 106). Kaplan-Meier estimates with log-rank test were used to show survival curves and a multivariable Cox regression model was used to calculate adjusted rate ratios., Results: Local tumor recurrence rates after 3 and 5 years were 4% (95% CI 1.2-17.8%) and 9.1% (95% CI 2.9-27.3%), respectively, in the PBT group and 24.6% (95% CI 15.8-37.1%) and 27.5 (95% CI 17.8-41.1%), respectively, in the Ru-106 group. This leads to an overall recurrence rate almost 4 times higher in the Ru-106 group compared to the PBT group. After adjusting for the a priori confounders and the tumor distance to optic disc and ciliary body infiltration, the adjusted risk of tumor recurrence was 8 times (RR 7.69 (2.22-26.06), p < 0.001) higher in the Ru-106 group as compared to the PBT group. Three- and 5-year metastatic rates were 23.2% (95% CI 5.6-37.1%) and 31.8% (95% CI 20.7-46.8%), respectively, in the PBT group and 13.2% (95% CI 6.8-24.9%) and 30.3% (95% CI 18.3-47.5%), respectively, in the Ru-106 group. There was no statistically significant difference in the overall metastasis rate between the two groups even after adjusting for possible confounders., Conclusion: Transscleral resection of large uveal melanomas combined with neoadjuvant proton beam therapy leads to a lower local tumor recurrence rate compared to transscleral tumor resection with adjuvant ruthenium brachytherapy. There was no statistically significant difference in the occurrence of rubeosis iridis, neovascular glaucoma, and in the need for enucleation later on.

Purpose: This study aims to analyze the effect of salvage proton beam therapy for the treatment of recurrent iris melanoma., Method: In this clinical case series, we retrospectively analyzed the data of eight patients who underwent proton beam therapy of the whole anterior segment as salvage therapy between 2000 and 2016 for recurrent iris melanoma after resection, ruthenium brachytherapy, or sector proton beam therapy. Two patients received salvage proton beam therapy for repeated tumor relapse. All patients were observed and prepared for proton beam therapy at the Charité and irradiated at the Helmholtz-Zentrum Berlin where they received 50 cobalt Gray equivalents (CGE) in four daily fractions. We investigated survival rates and ocular outcome., Results: Median follow-up after salvage proton beam therapy was 39 months. No local recurrence was detected during follow-up. One patient died from hepatic metastases 5.5 years after salvage therapy. Secondary glaucoma occurred in seven out of eight patients during follow-up. Two patients had chronic corneal erosion and two other patients presented with corneal decompensation, necessitating Descemet membrane endothelial keratoplasty (DMEK), and perforating keratoplasty. Median visual acuity was 0.2 logMAR before salvage proton beam therapy and 0.7 logMAR at the end of follow-up., Conclusion: Whole anterior segment salvage proton beam therapy has effectively controlled recurrent iris melanoma in our patients, but has been associated with a high incidence of radiation-induced corneal impairment and secondary glaucoma requiring extensive secondary treatment.

Purpose: To analyze the risk factors for the development of neovascular glaucoma (NVG) of patients with choroidal melanoma after proton beam therapy (PBT)., Method: Clinical case series, retrospective study. We evaluated 629 consecutive patients receiving proton beam therapy for the treatment of a choroidal melanoma at the oncology service at Charité, Berlin and Helmholtz-Zentrum, Berlin between 05/1998 and 11/2008 regarding the development and risk factors of NVG. Patients with tumor resection, salvage proton beam therapy for recurrent disease and known glaucoma of other origin were excluded from the cohort., Results: Of the 629 patients matching the inclusion criteria, 20.8% developed neovascularization of the iris after a mean time of 2.0 years (range 0.45 to 8.4 years) after PBT. Forty-seven percent of the patients with a neovascularization of the iris developed NVG after a mean time of 2.0 years after PBT, ranging from 5 months to 11.6 years. Univariate analysis revealed tumor height [p < 0.001, hazard ratio (HR): 2.71, 95% confidence interval (CI): 1.36-5.35 for tumors >6 mm ≤9 mm and 11.32 (4.03-31.73) for tumors >9 mm], distance of the tumor to the optic disc (p < 0.001, HR: 0.43, 95% CI: 0.24-0.77 for >0 mm ≤3 mm and HR: 0.13, 95% CI: 0.04-0.37 for >3 mm), dose to the ciliary body (p < 0.001, HR: 9.21, 95% CI: 5.08-16.71 (21-40 cobalt gray equivalents (CGE), HR 27.23, 95% CI: 6.33-116.97 (41-60 CGE)), dose to the optic disc (p < 0.001, HR: 3.53, 95% CI: 1.11-11.27 (21-40CGE), HR: 5.37, 95% CI: 2.72-10.63 (41-60CGE)), the irradiated length of the optic nerve (p < 0.001, HR: 4.48, 95% CI: 2.47-8.13) and diabetes mellitus (p < 0.05, HR: 2.53, 95% CI: 1.4-4.5) were found to be risk factors for the development of NVG. Multivariate regression analysis identified the dose to the ciliary body [p < 0.001, HR: 4.39, 95% CI: 2.28-8.44 (21-40 CGE), HR: 11.04, 95% CI: 1.97-61.69 (41-60 CGE)], the irradiated length of the optic nerve (p < 0.001, HR: 3.88, 95% CI: 2.11-7.16), the existence of diabetes mellitus (p < 0.01, HR: 1.28, 95% CI: 1.24-4.21) and tumor height [p < 0.05, HR: 2.28, 95% CI: 1.17-4.83 (>6 mm ≤9 mm), HR: 3.74, 95% CI: 1.05-13.23, (>9 mm)] to be independent risk factors for the development of NVG., Conclusions: In the present analysis we found tumor height, dose to the ciliary body, irradiated length of the optic nerve and diabetes mellitus to be risk factors for the development of NVG. Whenever possible, critical structures of the anterior and posterior segment should be spared by beam shaping or changing of the beam entry angle.

Purpose: This study was performed in order to evaluate the incidence of radiation retinopathy and optic neuropathy occurring after proton beam therapy for uveal melanoma., Methods: Included in this study were all patients who had been treated with primary proton beam therapy for uveal melanoma at the oncology service between May 1998 and June 2014 with a minimum follow-up of 12 months. Excluded were all patients who underwent re-irradiation, or vitrectomy due to exudative retinal detachment or for tumor-resection., Results: During this period, 1127 patients matched the inclusion criteria, of whom 768 (68.1 %) and 463 (41.0 %) developed radiation retinopathy and optic neuropathy after a median time of 18.9 months (2.0-99.84 months) and 19.8 months (0.2-170.4 months), respectively. Mean follow-up was 53.4 months (12-170.4 months). Included were 558 men (49.5 %) and 569 women (50.5 %). Mean age was 61 years (16-89 years). Visual acuity slightly decreased from initial levels of 0.3 logMAR-0.4 logMAR in patients without developing any radiation-induced complication but severely decreased to 1.0 logMAR or 1.5 logMAR in the case of developing radiation retinopathy only or optic neuropathy, respectively. Independent risk factors for radiation retinopathy were a centrally (<2.5 mm from sensitive structures) located tumor or a thick tumor located more than 2.5 mm from sensitive structures, while those for radiation optic neuropathy comprised a short distance and applied dose to the optic disk., Conclusion: The risk for radiation retinopathy is higher in central uveal melanoma. Mid-/peripheral tumors are at high risk for radiation retinopathy and maculopathy if presenting with increased thickness.

Purpose: To evaluate the incidence, risk factors, and dosages of proton beam therapy associated with cataract development, and long-term visual outcomes after treatment of uveal melanoma., Methods: All patients receiving primary proton beam therapy for uveal melanoma between 1998 and 2008 with no signs of cataract before irradiation were included. A minimum follow-up of 12 months was determined. Exclusion criteria included all applied adjuvant therapies such as intravitreal injections, laser photocoagulation, tumor resections, or re-irradiation. For subgroup analysis, we included all patients who underwent brachytherapy between 1998 and 2008 for uveal melanoma, considering the above mentioned inclusion and exclusion criteria., Results: Two hundred and fifty-eight patients matched our inclusion criteria. Median follow-up was 72.6 months (12.0-167.4 months). Of these 258 patients, 71 patients (66.3 %) presented with cataract after 31.3 months (0.7-142.4 months), of whom 35 (20.4 %) required surgery after 24.2 (0.7-111.1 months) to ensure funduscopic tumor control. Kaplan-Meier estimates calculated a risk for cataract of 74.3 % after 5 years. There was no increase in metastasis or local recurrence in these patients. Patient's age was the sole independent statistically significant risk factor for cataract development. The probability of cataract occurrence significantly increased with doses to lens exceeding 15-20 CGE. Neither the appearance of cataract nor cataract surgery influenced long-term visual outcome., Conclusion: Cataract formation is the most frequent complication after irradiation. There is no benefit vis-a-vis brachytherapy with regard to cataract development. Data indicate a dose-effect threshold of 0.5 CGE for cataractogenesis, with significantly increasing risk above a dose of 15 CGE. Furthermore, cataract surgery can be performed without an increased risk for metastasis.

Background: Retrospective evaluation of intraocular pressure, use of topical and systemic anti-glaucoma medication, secondary complications, local tumor control and survival in patients treated with trabeculectomy for the regulation of the intraocular pressure (IOP) after proton beam therapy for uveal melanoma., Methods: In this retrospective clinical case series we evaluated the follow-up of 15 patients receiving a trabeculectomy as surgical treatment if the IOP could not be lowered adequately by medications or laser surgery. All patients had received proton beam therapy for uveal melanoma at the Helmholtz-Zentrum Berlin between 1998 and 2010., Results: The median IOP decreased significantly from 35 mmHg ± 8.8 before TE to 16 mmHg ± 8.2 (=52.3 %) six months after TE (Wilcoxon-Mann-Whitney-U Test, p<0.01). None of the patients needed any glaucoma medication six months after trabeculectomy. Two patients developed local recurrence during follow-up, which were independent of the trabeculectomy. One patient had to be enucleated due to intractable pain and suspected remaining tumor activity. One patient died due to metastasis., Conclusions: Trabeculectomy is an option in intractable glaucoma in patients with uveal melanoma after proton beam therapy in single cases. Secondary interventions are common. Inoculation metastases are possible. Secure local tumor control must be a prerequisite for filtrating operations.

Background: The aim of this retrospective study was to determine the efficacy of proton beam irradiation in choroidal hemangioma in a long-term follow-up., Patients and Methods: A total dose of 20 Cobalt Gray equivalent (CGE) was administered to 50 eyes of 50 patients from September 1998 to September 2010. All treated patients presented with a symptomatic tumor. Nine patients were pre-treated by photodynamic therapy (PDT). Visual outcome, tumor regression, and complications resulting from radiation were investigated., Results: The mean follow-up was 55.4 months (range 13-132). Tumor thickness decreased in all patients. Retinal re-attachment was achieved without evidence of tumor leakage. Visual acuity improved by two lines after one year in 43.4 % of patients and after two years in 36.8 % of patients. During the 55.4 months of long-term follow-up the visual acuity improved from 6/15 to 6/12 after proton therapy. Twenty-three patients (46.0 %) developed radiation retinopathy. According to the Finger classification of 2004, 21 patients (42.0 %) showed a stage 1 or 2 (functionally not relevant) retinopathy, and two patients (4.0 %) presented a stage 3 or 4 (functionally relevant) retinopathy. Further complications included sicca syndrome in nine cases, cataract formation in 10 cases, and radiation optic neuropathy in four cases., Conclusion: Proton therapy with 20 CGE is an efficient primary therapy in choroidal hemangioma and is very effective as a secondary treatment after PDT.