Safety and efficacy of indigenously developed Ruthenium-106 eye plaque for brachytherapy of a spectrum of ocular tumors: A case series.

ABSTRACT: Various treatment modalities are available for treatment of ocular tumors, which include chemotherapy, laser, and radiotherapy (external beam radiation therapy or brachytherapy). Brachytherapy using plaque applicator is preferred over external beam radiation therapy when the tumor is well localized, as this therapy delivers radiation dose to the tumor with lower doses to normal tissues in the vicinity. However, plaque therapy is expensive and beyond the reach of many poor patients in India. The Bhabha Atomic Research Center (BARC) recently introduced an indigenous Ruthenium-106 plaque to make brachytherapy treatment available and affordable to all needy patients in India. In the present case series, we report our experience using the indigenous Ru-106 plaque for the treatment of a spectrum of ocular tumors.

Cytogenetic Analysis After Temporary Residence in the Area of the Uncontrolled Ruthenium-106 Release in Russia in September 2017.

In September and October 2017, elevated atmospheric ruthenium contamination was measured in several European countries. The most probable origin of this release of radionuclides was reconstructed to be the Southern Ural region. During that time, five workers from a German company stayed up to 2 wk about 120 km from the Chelyabinsk region in Ekaterinburg, Russia. No clinical symptoms were reported during or after the suspected radiation exposure, and no internal contamination was found in whole-body measurements. However, to investigate radiation protection issues and to clarify the workers' situation in order to reassure them, as they planned to continue working in Ekaterinburg, our laboratory was urgently requested by the company's occupational physician to perform biodosimetry using dicentric analysis to determine if the workers have been exposed to radiation by incorporation of radionuclides. The workers' dicentric yields have been compared to reference data of background frequencies in unexposed individuals, but, as it is not reasonable to quantify individual absorbed radiation doses from internalized beta emitters due to various confounding factors, individual dose estimation has not been performed. Dicentric frequencies for two workers differed significantly from the mean laboratory background level, which could have been induced by an exposure to incorporated radionuclides due to beta emissions by Ru or to gamma irradiation by the decay nuclide of Ru. However, the maximum absorbed radiation doses calculated for a resident in the Ru-contaminated area during that time does not correspond to the observed dicentric frequencies. It cannot be excluded that their dicentric frequencies were already elevated before September 2017, potentially induced by an earlier radiation exposure to diagnostic x rays or even by chance.

Pre and post operative radiation protection in Ru-106 brachytherapy ophthalmic plaque surgery and related material shielding properties.

Pre and post-operative exposure levels of medical staff and people from public in intra-operative Ru-106 ophthalmic brachytherapy are reported, together with attenuation properties of selected shielding materials. In particular radiation exposure of workers during plaque transportation and during medical assistance of implanted plaque patient was measured. Taking into account dose rates and considering standard assistance procedure of hospitalized patients, the exposure of medical staff and people of the public were evaluated for a given workload. In order to provide tools to optimize radiation protection, considering social and economic aspects due to possible hospital discharge or hospital stay, the attenuation properties of common shielding materials (lead, concrete, red brick, PMMA and gypsum) were measured, considering both narrow and broad beam setups. The eye was simulated using a water equivalent phantom and plaque was fixed on it. All measurements were performed with calibrated survey meters. Results were compared with numerical simulation of bremsstrahlung X-ray radiation spectra emitted from patient eye. Exposure levels measured at 1 m distance in front of the implanted eye are 0.05 µSv/h/MBq, at 10 cm from patient head, 0.44 µSv/h/MBq (plaque side), 0.4 µSv/h/MBq (front), 0.25 µSv/h/MBq (lateral, opposed to plaque), 0.2 µSv/h/MBq (back). Average exposure levels, under conservative assumptions, for medical staff is 17 µSv/patient and less than 23 µSv/patient for careers and comforters. TVLs in lead and concrete are about 1.6 cm and 11.5 cm respectively.

Retina dose as a predictor for visual acuity loss in 106Ru eye plaque brachytherapy of uveal melanomas.

BACKGROUND AND PURPOSE: To evaluate the retina dose as a risk factor associated with loss of visual acuity (VA) in 106Ru plaque brachytherapy. MATERIAL/METHODS: 45 patients receiving 106Ru plaques brachytherapy (median follow-up 29.5 months) were included in this study. An in-house developed treatment planning system with Monte Carlo based dose calculation was used to perform treatment planning and dose calculation. Risk factors associated with loss of VA were evaluated using the Cox proportional hazards models, Kaplan-Meier estimates and Pearson correlation coefficients. RESULTS: A significant correlation was found between VA loss and mean (r = 0.49, p = 0.001) and near maximum (r = 0.47, p = 0.001) retina dose D2% and tumor basal diameter (r = 0.50, p < 0.001). The Kaplan-Meier and Cox proportional hazards model yielded a significantly higher risk for VA loss (>0.3Snellen) for patients receiving a maximum dose of >500 Gy (p = 0.002). A Cox multivariate analysis including the macula dose (p = 0.237) and basal diameter (p = 0.791) showed that a high maximum retinal dose is the best risk factor (p = 0.013) for VA loss. CONCLUSION: The study showed that retina dose (D2% and Dmean) is a suitable predictor for VA loss.

Comparative outcomes and toxicities for ruthenium-106 versus palladium-103 in the treatment of choroidal melanoma.

For the treatment of choroidal melanoma, palladium-103 (Pd) and ruthenium-106 (Ru) plaque brachytherapy shows reduced toxicity compared with the historical standard iodine-125. No report has directly compared the clinical outcomes between Pd and Ru, and the reasons for the selection of one over the other remain purely theoretical. Patients with choroidal melanoma with apical tumor height up to 5 mm were included. Patients from Emory University were treated with Pd between 1993 and 2012. Patients from Cleveland Clinic were treated with Ru between 2005 and 2010. Medical records were retrospectively reviewed. We compared post-treatment visual acuity (VA), toxicity, and oncologic outcomes. Pd patients (n=124) and Ru patients (n=42) had a median follow-up of 4.2 and 5.0 years, respectively. Radiation retinopathy-free survival was similar for both radioisotopes, but Ru had lower grades of retinopathy (P=0.006). Pd was associated with worse VA preservation (≥20/40) by year 3 (odds ratio: 3.8; 95% confidence interval: 1.01-14.31, P=0.048). Pd was associated with higher distant metastases-free survival (DMFS) in multivariate analysis (hazard ratio: 0.10; 95% confidence interval: 0.02-0.38; P<0.001). Ru had lower grades of radiation retinopathy and improved long-term VA preservation, but also inferior DMFS, compared with Pd. Because of the inherent limitations of a retrospective analysis, the significance of the inferior DMFS for Ru remains unclear, although the suggestion of a slight inferiority in terms of DMFS for Ru is consistent with the other limited literature. On the basis of this study, we believe that both radioisotopes remain appropriate for the treatment of small choroidal melanomas up to 5 mm in apical height.

INTRAVITREAL DEXAMETHASONE IMPLANT FOR RADIATION MACULOPATHY SECONDARY TO PLAQUE BRACHYTHERAPY IN CHOROIDAL MELANOMA.

PURPOSE: To evaluate the efficacy of intravitreal dexamethasone implant 0.7 mg (Ozurdex) in radiation maculopathy secondary to plaque brachytherapy in choroidal melanoma. METHODS: Twelve eyes diagnosed of radiation maculopathy secondary to plaque brachytherapy and treated with intravitreal dexamethasone implant were included. Visual acuity, foveal thickness using spectral domain optical coherence tomography, and grade of macular edema, using Horgan classification, were evaluated. RESULTS: Mean age was 65.5 ± 28 years (range, 40-82 years). Mean follow-up was 8.2 ± 7.8 months (range, 2-28 months). Mean visual acuity before treatment was, in logarithm of the minimum angle of resolution scale, 1 ± 0.58 (range, 0.4-2) and mean final visual acuity 0.8 ± 0.58 (range, 0.2-2), showing a nonsignificant trend to improvement (P = 0.091; Wilcoxon's test). Foveal thickness before treatment was 416 ± 263 µm (range, 222-725 µm) and final foveal thickness 254 ± 170 µm (range, 145-750), showing a significant decrease (P = 0.016; Wilcoxon's test). Referring to Horgan classification, a significant reduction in grades before and after treatment was demonstrated (P = 0.007; Wilcoxon's test). CONCLUSION: Ozurdex is a useful treatment for radiation maculopathy associated to plaque brachytherapy for uveal melanoma, with a significant decrease in foveal thickness and a significant improvement in Horgan classification. This anatomical improvement was correlated with a moderate improvement in visual acuity.

A choice of radionuclide: Comparative outcomes and toxicity of ruthenium-106 and iodine-125 in the definitive treatment of uveal melanoma.

PURPOSE: Both iodine-125 ((125)I) Collaborative Ocular Melanoma Study and ruthenium-106 ((106)Ru) eye plaques can achieve excellent tumor control in patients diagnosed with uveal melanoma. We analyzed our single institutional experience in the management of ocular melanoma treated with either (125)I or (106)Ru plaque brachytherapy. METHODS AND MATERIALS: The records of 107 patients with uveal melanoma treated with either (106)Ru (n = 40) or (125)I (n = 67) plaque brachytherapy between 2000 and 2008 were retrospectively reviewed. Tumor control parameters and toxicity were assessed. RESULTS: Actuarial 5-year rates of local control, progression-free survival, and overall survival with (106)Ru were 97%, 94%, and 92%, respectively. For (125)I, these values were 83%, 65%, and 80%. In the subset of patients with tumor apex height ≤5 mm (36 (125)I and 40 (106)Ru), there was no difference in overall survival; however, progression-free survival was significantly improved with (106)Ru (P = .02). Enucleation-free survival was significantly different between the 2 subsets, with no enucleations in the (106)Ru cohort (P = .02). Patients treated with (106)Ru experienced reduced retinopathy (P = .03) and cataracts (P < .01). CONCLUSIONS: Both (125)I and (106)Ru eye plaque brachytherapy treatment result in encouraging tumor control for patients with uveal melanoma. We demonstrate that (106)Ru offers these benefits with reduced toxicity in patients treated for uveal melanomas ≤5 mm in apical height.

Disease control and toxicity outcomes using ruthenium eye plaque brachytherapy in the treatment of uveal melanoma.

PURPOSE: Ruthenium-106 ((106)Ru) eye plaques have the potential to achieve excellent tumor control with acceptable radiation toxicity. We evaluated our experience in the management of uveal melanoma treated with (106)Ru brachytherapy. METHODS AND MATERIALS: The records of 40 patients with uveal melanoma treated with brachytherapy using (106)Ru plaques from 2003 to 2007 at University of Texas MD Anderson Cancer Center were reviewed. Endpoints assessed included tumor control and toxicity. RESULTS: Median ophthalmologic follow-up was 67 months. Actuarial 5-year rates of local control (LC), progression-free survival (PFS), and overall survival (OS) were 97%, 94%, and 92%. There were 3 deaths, 2 related to melanoma. Fifteen patients experienced clinically significant visual loss; no patients were diagnosed with neovascular glaucoma, and 1 patient developed a clinically significant radiation-associated cataract. No patient required enucleation. CONCLUSIONS: We report the largest published US cohort of patients treated with (106)Ru plaque brachytherapy for uveal melanoma. Tumor control was excellent, and toxicity was acceptably low. These data support the reintroduction of (106)Ru into clinical practice for ocular melanoma.

Changes in the micromorphology of the corneal subbasal nerve plexus in patients after plaque brachytherapy.

BACKGROUND: To quantify the development of radiation neuropathy in corneal subbasal nerve plexus (SNP) after plaque brachytherapy, and the subsequent regeneration of SNP micromorphology and corneal sensation. METHODS: Nine eyes of 9 melanoma patients (ciliary body: 3, iris: 2, conjunctiva: 4) underwent brachytherapy (ruthenium-106 plaque, dose to tumour base: 523 ± 231 Gy). SNP micromorphology was assessed by in-vivo confocal microscopy. Using software developed in-house, pre-irradiation findings were compared with those obtained after 3 days, 1, 4 and 7 months, and related to radiation dose and corneal sensation. RESULTS: After 3 days nerve fibres were absent from the applicator zone and central cornea, and corneal sensation was abolished. The earliest regenerating fibres were seen at the one-month follow-up. By 4 months SNP structures had increased to one-third of pre-treatment status (based on nerve fibre density and nerve fibre count), and corneal sensation had returned to approximately two-thirds of pre-irradiation values. Regeneration of SNP and corneal sensation was nearly complete 7 months after plaque brachytherapy. CONCLUSIONS: The evaluation of SNP micromorphology and corneal sensation is a reliable and clinically useful method for assessing neuropathy after plaque brachytherapy. Radiation-induced neuropathy of corneal nerves develops quickly and is partly reversible within 7 months. The clinical impact of radiation-induced SNP damage is moderate.

Post-brachytherapy tumor endoresection for treatment of toxic maculopathy in choroidal melanoma.

PURPOSE: Toxic tumor syndrome may occur when the irradiated choroidal melanoma releases cytokines, by exudation from irradiated ischemic tissue. We report our experience and outcomes in a series of post-brachytherapy tumor endoresection to mediate radiation complications. METHODS: Patients who underwent endoresection of a choroidal melanoma treated with iodine-125 plaque brachytherapy were evaluated. Baseline patient and tumor parameters were tabulated. RESULTS: Five patients underwent post-brachytherapy tumor endoresection with intraocular gas or silicone oil tamponade. Three of the five patients underwent concomitant phacoemulsification with intraocular lens placement. Initial tumor height ranged from 2.03-8.91 mm (mean 5.81 mm). Time between brachytherapy and endoresection ranged from 13-62 months (mean 26.8 months), and total follow-up time from brachytherapy ranged from 2.5-9.75 years (mean 5.2 years). Vision post-brachytherapy and pre-endoresection ranged from 20/30 to 20/400. Final visual acuity ranged from 20/70 to no light perception. One patient developed neovascular glaucoma. Radiation maculopathy increased in all patients. One patient developed metastasis at last follow-up. No patient developed exudative retinal detachment, none had local treatment failure, and none required enucleation. CONCLUSION: Although tumor endoresection post-brachytherapy is a technically feasible procedure, all patients in our series experienced progressive radiation maculopathy with gradual visual decline.

Ruthenium-106 eye plaque brachytherapy in the conservative treatment of uveal melanoma: a mono-institutional experience.

BACKGROUND: Traditional treatment for uveal melanoma is the enucleation of the eye with outcomes cosmetically unacceptable and loss of useful vision. Plaque brachytherapy, compared to enucleation, had the advantage to preserve the eye with outcomes cosmetically acceptable and preservation of vision. PATIENTS AND METHODS: From July 1990 to December 2009 one hundred forty-two (142) patients (51 males and 91 females) with small to medium uveal melanoma were treated with 106Ru plaque brachytherapy. The patients underwent a complete staging before brachytherapy with indirect ophthalmoscopy and ultrasounds. Mean tumour thickness was 3.26 mm (1.6-6 mm). The dose scheduled was 80-100 Gy to the apex with a maximum dose of 800 Gy to the sclera. RESULTS: One hundred forty-two have been treated, nine patients had lost the follow-up and drop out; 133 patients were assessed. Mean follow-up was 7.7 years (6 months-18 years). The overall survival at 5, 10 and 15 years was 92%, 85% and 78% respectively. Cancer fee survival was 95%, 90% and 83%, respectively at 5, 10 and 15 year. Radiation-induced toxicity was represented in 47 patients with a 5 year actuarial survival rate free from complications of 54%. CONCLUSIONS: 106Ru plaque brachytherapy is a valid approach for treatment of uveal melanoma. This technique is efficacy and safe, with a low toxicity profile.

Ruthenium plaque radiation therapy for iris and iridociliary melanomas.

PURPOSE: To determine the long-term effects of ruthenium-106 plaque radiation therapy for iris and iridociliary melanomas in terms of tumour regression and complications. METHODS: Between 1 November 1997 and 31 December 2007, 36 patients with an iris or iridociliary melanoma were treated with Ruthenium-106 (Ru-106) ophthalmic plaque radiation therapy. The median follow-up was 6.5 years with a range of 2-11 years. The mean tumour apex dose was 151.5 Gy. Main outcome measures were local tumour control and radiation-related ocular complications. RESULTS: The mean age of the patients at the time of treatment was 54 years (range 14-82). The tumours had a median largest basal dimension of 4.8 mm (range 3-11) and a prominence of 2.3 mm (range 0.8-5), with a median involvement of three clock hours (range 1-6). The tumours were confined to the iris in 14 patients (39%), extended into the anterior ciliary body in 12 (33%), while the anterior ciliary body tumour extended into the iris in ten patients (28%). Tumours regressed in all patients (100%) with a mean regression of 80% of the original tumour size at 7 years of follow-up. Radiation-related complications included corneal erosions on the first postoperative day in nine patients (25%), cataract in four of 11 patients free of cataract before treatment (36%) and postradiation glaucoma in one patient (3%). Visual acuity of 20/200 or worse was present in one of 20 patients (5%) at 6 years of follow-up. Local recurrences occurred in two patients (5%), 2 and 5 years after the radiation therapy respectively, and both underwent enucleation. Distant metastases occurred in one of these enucleated patients (3%) 2 years after treatment. CONCLUSION: Ru-106 plaque radiation therapy for iris and iridociliary melanoma resulted in good local tumour control and preservation of visual acuity with few and treatable side-effects.

Treatment of radiation maculopathy with intravitreal injection of bevacizumab (Avastin).

PURPOSE: To evaluate the safety and efficacy of intravitreal injection of bevacizumab as a treatment option for radiation maculopathy secondary to plaque radiotherapy. METHODS: Interventional case series of five patients who developed radiation maculopathy complicating plaque radiotherapy with ruthenium 106 for choroidal melanoma. One to two intravitreal injections of bevacizumab (0.5 mL) were given, with an interval of 4 weeks between each injection. The main outcome measures were visual acuity and results of clinical ophthalmic examination and optical coherence tomography. RESULTS: Preinjection visual acuity ranged from hand movements to 20/25. The average preinjection central macular thickness measured by optical coherence tomography was 351 microm. Three of five patients had no improvement in macular edema after treatment with a single injection of bevacizumab at the 2-week follow-up (average postinjection central macular thickness, 287 microm). Maculopathy in these three patients was long-standing (3-5 years). Improvement in visual acuity occurred in two patients (from 20/30 to 20/25 and from 20/25 to 20/20). Maculopathy in these two patients was diagnosed 1 week before treatment was offered. Resolution of macular edema occurred after a single injection in Patient 4 and after two injections in Patient 5. Patient 4 did not receive direct radiation to the fovea. All but one patient (Patient 5; dose, 8,000 cGy) received a radiation dose of 10,000 cGy to the tumor apex. CONCLUSIONS: In this series, treatment of radiation maculopathy with intravitreal injection of bevacizumab was useful in two patients as measured by improvement in visual acuity due to resolution of macular edema. These patients were younger and had macular edema for a shorter duration. One patient did not receive direct radiation to the fovea, and the other had a lower dose of radiation.

Strabismus in adults with uveal melanoma following episcleral plaque brachytherapy.

PURPOSE: To ascertain the incidence of persistent strabismus in patients treated with plaque brachytherapy and its subsequent treatment. METHODS: A single center retrospective case note review of adult patients with persistent diplopia or strabismus following plaque brachytherapy for all types of intraocular tumors between 1996 and 2004. RESULTS: A total of 929 consecutive adults underwent plaque brachytherapy during the study period at a single center. Sixteen patients (1.7%) with treated uveal melanoma developed persistent diplopia or strabismus. In 11 patients (69%) the timing of onset was in the first year, in 2 (13%) in the second year, and one each (6% each) in years 5, 7, and 8. Two patients (13%) did not require any intervention. Fourteen patients (88%) required treatment: 7 (50%) were treated with prisms only, 3 (21%) underwent botulinum toxin (BTXA) injections, and 4 (29%) were treated with extraocular muscle surgery (3 required one operation and one required 2 procedures). CONCLUSIONS: The incidence of ocular motility disorders following plaque brachytherapy in our cohort was 1.7% over 8 years and we include this in the consent process for conservative treatment of intraocular tumors. Options for treatment for persistent diplopia or strabismus include prisms, botulinum toxin injection, or surgery.