Charlotte A. Espensen, Jens F. Kiilgaard, Kristian Klemp, Anita Gothelf, Ane L. Appelt, Lotte S. Fog
Current standard treatment procedures for Ruthenium-106 (Ru-106) brachytherapy for choroidal melanomas do not use 3D image-guided treatment planning. We evaluated the potential impact of introducing 3D treatment planning and quantified the theoretical clinical benefits in terms of tumour control probability (TCP) and normal tissue complication probability (NTCP).
Materials and methods
Treatment plans for thirty-two patients were optimized using 3D image-guided treatment planning and compared to the original 2D clinical plans. Optimization of plans was done in an image-based treatment planning system by optimizing the plaque position and treatment time such that the entire tumour received the prescribed dose of 100 Gy. TCP and NTCP for 2D clinical plans and optimized 3D image-guided plans were estimated from published outcome prediction models and compared within patients using Wilcoxon signed-rank test.
The median minimum tumour dose (D99%) for 2D clinical plans was 93 Gy (range: 23–158 Gy), corresponding to 5-year TCP of 75% (IQR 61–86%), while median tumour D99% for optimized 3D image-guided plans was 115 Gy (range 103–141 Gy), corresponding to TCP of 82% (IQR 80–84%). This was a statistically significant increase in estimated TCP (median increase in TCP 8% (IQR: −5–23, p = 0.006). While the dose to normal tissue increased somewhat, there was no significant change in NTCP.
3D treatment planning theoretically allows for improved tumour dose delivery for Ru-106 brachytherapy of choroidal melanomas, resulting in a significant increase in expected tumour control compared to traditional approaches using 2D calculations. The deliverability of optimized plans, and potential increased risk of late complications, will have to be confirmed in future clinical studies.
Rumana Hussain, Florian Moritz Heussen, Heinrich Heimann
Introduction Uveal melanoma is most commonly treated with radiotherapy, destroying the tumour cells with adequate safety margins and limiting collateral damage to surrounding structures to preserve maximal vision. We used optical coherence tomography (OCT) to study the effects of radiotherapy on the retina.
Methods Patients with posteriorly located choroidal melanoma treated with proton beam radiotherapy (PBR) and ruthenium-106 brachytherapy between January 2010 and June 2014 underwent spectral domain OCT.
Results Images of 32 patients following ruthenium-106 brachytherapy and 44 patients following proton beam teletherapy were analysed. Following plaque brachytherapy, an early marked disruption of the outer retinal layers could be observed in 30 cases (94%) with retinal atrophy evident in 26 cases (81%). In contrast, the images from patients who underwent PBR showed subtle outer retinal layer change with 16 cases (36%) showing some inner-outer segment junction disruption by 6 months and 63% by 24 months with minimal atrophy. In cases with tumours <2 mm from the fovea, the visual loss was significantly less at 6 and 12 months in the proton beam group.
Conclusion In comparison to ruthenium-106 plaque brachytherapy, PBR leads to more subtle and slower changes in the outer retinal layers enabling retention of visual function for longer. The difference in dosing regime and dose distribution across the tumour is likely to be causative for this structural differential.
Maria Filì, Eric Trocme, Christina Herrspiegel, Stefan Seregard, Gustav Stålhammar
Background Episcleral brachytherapy is the most common treatment for medium-sized choroidal melanomas. Although controversial, inadequate brachytherapy dose and dose rates have at least a hypothetical implication on patient survival.
Methods All patients who received ruthenium-106 or iodine-125 brachytherapy for choroidal melanoma at St. Erik Eye Hospital 1996 to 2016 were included (n=1238). Cox regression hazard ratios for melanoma-related mortality across deciles, quartiles and individual integers of apex radiation doses (Gy) and dose rates (Gy/hour) were calculated, adjusted for tumour size and location.
Results The average radiation dose at the tumour apex ranged from 73.0 Gy in the first decile to 108.6 Gy in the tenth. Decreasing apex dose by 1 Gy increments or by decile or quartile group was not associated with melanoma-related mortality (p>0.2) The average radiation dose rate at the tumour apex ranged from 0.5 Gy/hour in the first decile to 2.8 Gy/hour in the tenth. Similarly, decreasing apex dose rate by 1 Gy/hour increments or by decile or quartile groups was not associated with melanoma-related mortality (p>0.5).
Conclusion There are no increased hazards for choroidal melanoma-related mortality after brachytherapy with decreasing doses between 108.6 and 73.0 Gy, or with decreasing dose rates between 2.8 and 0.5 Gy/hour.
Zaragoza F.J. · Eichmann M. · Flühs D. · Timmermann B. · Brualla L.
Background/Aims:The aim of this work is to compare Monte Carlo simulated absorbed dose distributions obtained from 106Ru eye plaques, whose heterogeneous emitter distribution is known, with the common homogeneous approximation. The effect of these heterogeneities on segmented structures at risk is analyzed using an anthropomorphic phantom. Methods:The generic CCA and CCB, with a homogeneous emitter map, and the specific CCA1364 and CCB1256 106Ru eye plaques are modeled with the Monte Carlo code PENELOPE. To compare the effect of the heterogeneities in the segmented volumes, cumulative dose-volume histograms are calculated for different rotations of the aforementioned plaques. Results:For the cornea, the CCA with the equatorial placement yields the lowest absorbed dose rate while for the CCA1364 in the same placement the absorbed dose rate is 33% higher. The CCB1256 with the hot spot oriented towards the cornea yields the maximum dose rate per unit of activity while it is 44% lower for the CCB. Conclusions:Dose calculations based on a homogeneous distribution of the emitter substance yield the lowest absorbed dose in the analyzed structures for all plaque placements. Treatment planning based on such calculations may result in an overdose of the structures at risk.
Maria Filì, Eric Trocme, Louise Bergman, Thonnie Rose Ong See, Helder André, Katarina Bartuma, Leonard Girnita, Charlotta All-Eriksson, Stefan Seregard, Gustav Stålhammar
Background Episcleral brachytherapy is the most common eye-preserving treatment for medium-sized choroidal melanomas. γ-emitting iodine-125 (125I) and β-emitting ruthenium-106 (106Ru) are widely used. The latter is however generally reserved for thinner tumours (<6 mm). In this study, we compare ocular and patient survival in thicker tumours treated with the respective radioisotope.
Methods All patients with ≥5.5 mm thick choroidal melanomas who were treated with plaque brachytherapy at a single institution between 1 November 1979 and 31 December 2015 were included (n=571). Size-controlled Cox regression HRs for postbrachytherapy enucleation, repeated brachytherapy and melanoma-related mortality were calculated, as well as Kaplan-Meier disease-specific survival and relative 10-year survival in matched subgroups.
Results 317 patients were treated with 106Ru and 254 with 125I. The rate of repeated brachytherapy was significantly higher among patients treated with 106Ru (8%) than with 125I (1%, p<0.001). Size-controlled Cox regression HRs for postbrachytherapy enucleation (125I vs 106Ru 0.7, p=0.083) and melanoma-related mortality were not significant (125I vs 106Ru 1.1, p=0.63). Similarly, Kaplan-Meier disease-specific and relative 10-year survival was comparable in matched groups of 5.5–7.4 mm (relative survival 106Ru 59%, 125I 56%) and ≥7.5 mm thick tumours (relative survival 106Ru 46%, 125I 44%).
Conclusions Rates of repeated brachytherapy were significantly higher among patients treated with 106Ru versus 125I for thick choroidal melanomas. There were, however, no significant differences in rates of enucleation or patient survival.
Matteo Fallico, Michele Reibaldi, Teresio Avitabile, Antonio Longo, Vincenza Bonfiglio, Argyrios Chronopoulos, Rosario Caltabiano, Corrado Spatola, Andrea Russo
To assess the efficacy of intravitreal aflibercept in patients suffering from post-radiation macular edema following plaque radiotherapy for choroidal melanoma.
This prospective, interventional case series included patients affected by radiation maculopathy (RM) with macular edema secondary to ruthenium-106 plaque brachytherapy for choroidal melanoma. The effect of intravitreal aflibercept on best-corrected visual acuity (BCVA), central foveal thickness (CFT) detected by spectral domain optical coherence tomography (sd-OCT), and Horgan’s grading scale of RM was evaluated throughout the 24-month follow-up. Intraocular pressure (IOP) and possible complications were also recorded.
Nine eyes of 9 patients were included. A mean of 4.4 ± 1.2 injections were given over the 24 months. At the end of follow-up, mean BCVA was significantly improved, from 0.9 ± 0.19 logMAR at baseline to 0.56 ± 0.3 logMAR (P = 0.028), and mean CFT was significantly decreased, from 546 ± 123 μm at baseline to 223 ± 34 μm (P < 0.001). Intravitreal aflibercept lowered baseline maculopathy stage as well. No significant change in IOP values and no complications, such as endophthalmitis, was recorded.
Intravitreal aflibercept is an effective treatment for patients with radiation-induced macular edema, allowing functional and anatomical improvements to be achieved with a relatively low number of injections.
Alexander Böker, Daniel Pilger, Dino Cordini, Ira Seibel, Aline I. Riechardt, Antonia M. Joussen, Nikolaos E. Bechrakis
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.
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.
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.
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.
Umiya Agraval, Manvi Sobti, Heather C Russell, David Lockington, Diana Ritchie, Paul Cauchi, Ewan G Kemp, Vikas Chadha
Purpose To analyse long-term outcomes of ruthenium-106 (106Ru) plaque brachytherapy for the treatment of iris melanoma.
Methods We retrospectively reviewed medical records of 19 consecutive patients with pure iris melanoma treated with 106Ru plaque brachytherapy between 1998 and 2016 at the Scottish Ophthalmic Oncology Service, Glasgow. The iris melanoma was treated with a ruthenium plaque placed on the corneal surface to deliver a surface dose of 555 Gy. We analysed vision preservation, local tumour control, radiation-related complications, eye retention rates, symptomatic metastasis and melanoma-related mortality.
Results The mean largest basal diameter of the lesions was 3.50±1.42 mm (range 1.6–6.5 mm), and the mean maximum height was 1.47±0.65 mm (range 0.7–2.8 mm). The tumour control and eye retention were 100% at a mean follow-up of 62 months (range 6–195 months). A 62% reduction in tumour height was observed on ultrasonography. Complications included cataract (68%), dry eye (47%), uveitis (37%) and scleral thinning (5%). At the final follow-up visit, the mean loss of Snellen visual acuity was 1.11±2.90 lines and vision of 6/9 or better was maintained in 53% of patients. None of the patients had evidence of symptomatic metastasis (non-imaged) or melanoma-related mortality.
Conclusions 106Ru plaque treatment for iris melanoma was highly effective a high tumour control, no tumour recurrences and a relatively a low complication rate.
Charlotte Alfast Espensen, Peter Koch Jensen, Lotte Stubkjær Fog, Ane Lindegaard Appelt, Kristian Klemp, Hans Callø Fledelius, Lena Specht, Jens Folke Kiilgaard
Background/aims To present a new method to determine dose depth and the distance from the concave side of the plaque to the tumour base in patients with uveal melanoma treated with ruthenium-106 based on ultrasonic mirror image.
Methods We used the mirror image associated with ultrasound during plaque brachytherapy to determine intraobserver reproducibility and interobserver agreement between two surgeons. 230 eyes with primary uveal melanoma were included in a retrospective analysis to determine the distance from the plaque to the tumour base using ultrasound. A phantom study was used to illustrate the effects on radiation dose to apex of the tumour when the dose depth was incorrectly determined. Doses to apex of the tumour were determined using Plaque Simulator.
Results The intraobserver variation in dose depth measurement with plaque was significantly lower than for measures without plaque (p<0.001). Agreement between the surgeons was better with a plaque in place. Distances from the plaque to the tumour base were distributed with mean=0.99 (median: 1, range: 0.1–2.9 mm). From the phantom study, it was clear that the tumour did not receive the prescribed 100 Gy if the dose depth was incorrectly determined.
Conclusions The dose depth in patients with uveal melanoma must be measured accurately for correct calculation of the radiation dose to the apex of the tumour. Repeated in vivo and in vitro ultrasound measurements of dose depth showed higher variance than measurements using the mirror image produced from a ruthenium plaque. Using the mirror image thus help to improve the dose calculation.