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Retina dose as a predictor for visual acuity loss in 106Ru eye plaque brachytherapy of uveal melanomas
Radiotherapy and Oncology xxx (2018) xxx–xxx
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Retina dose as a predictor for visual acuity loss in brachytherapy of uveal melanomas
106
Ru eye plaque
Gerd Heilemann a,⇑, Lukas Fetty a, Matthias Blaickner b, Nicole Nesvacil a,c, Martin Zehetmayer d, Dietmar Georg a,c, Roman Dunavoelgyi d a Division Medical Radiation Physics, Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna/AKH Vienna; b Austrian Institute of Technology GmbH, Health & Environment Department Biomedical Systems, Vienna; c Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna; and d Department of Ophthalmology and Optometry, Medical University of Vienna/AKH Vienna, Austria
a r t i c l e
i n f o
Article history: Received 21 December 2016 Received in revised form 22 September 2017 Accepted 20 November 2017 Available online xxxx Keywords: Uveal melanoma Brachytherapy Eye plaque Ruthenium Visual acuity
a b s t r a c t 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 (>0.3 Snellen) 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. Ó 2017 The Authors. Published by Elsevier Ireland Ltd. Radiotherapy and Oncology xxx (2018) xxx–xxx This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).
The preservation of visual acuity is a major objective in conservative treatments of uveal melanoma, such as brachytherapy using either 106Ru or 125I plaques and external beam stereotactic radiotherapy with photons or charged particle therapy [1–10]. Among these techniques brachytherapy using 106Ru or 125I plaques achieves excellent local control while providing a treatment option that allows to preserve useful vision, good cosmetic and quality of life results [2,7,11]. However, the loss of visual acuity is a common side effect of these techniques and can be associated with different factors [11–14]. In 106Ru brachytherapy, mainly geometric characteristics of the tumor were identified to be associated with worse visual outcome in earlier studies [1,11,15]. Only recent publications were able to correlate the loss of visual acuity to dosimetric parameters such as the dose to the fovea [13]. Increased tumor height and basal diameters were both associated with a decreased visual acu⇑ Corresponding author at: Division Medical Radiation Physics, Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna/ AKH Vienna, Austria. E-mail address: [email protected] (G. Heilemann).
ity [13,15]. But while both parameters directly affect the overall dose to the retina, the retina dose itself was not found to be a risk factor for bad visual outcome in past studies [11]. The present study is focusing on the effect of retina dose on visual acuity and secondary toxicities after 106Ru plaque brachytherapy using a newly developed treatment planning system. Materials and methods Patient cohort and data collection In this retrospective study patients with choroidal and/or ciliary body melanoma were included who had been treated with 106Ru eye plaque brachytherapy at the Department of Ophthalmology and the Department of Radiotherapy, Medical University, Vienna, between 1995 and 2015. Patients were selected for 106Ru eye plaques according to common recommendations [16,17]. Patients were treated with 106Ru plaques unless tumor height was above 7 mm or in case of centrally located tumors (distance to macula and/or optic disk < 3 mm) – in these cases, patients were treated
https://doi.org/10.1016/j.radonc.2017.11.010 0167-8140/Ó 2017 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Heilemann G et al. Retina dose as a predictor for visual acuity loss in nomas. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2017.11.010
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using hypofractionated stereotactic photon radiotherapy [10,18]. The presence of metastatic disease was an exclusion criterion for this study. Of all these patients 45 patients could be used for dose recalculation. The remainder had to be excluded due to a lack of follow-up data. Standard A- and B-scan echography was performed to assess tumor dimensions. The tumor location was determined using A- and B-scan echography, ophthalmoscopy, funduscopy (using wide angle contact glasses if necessary) and diaphanoscopy. 106
R0 ð1 ekT Þ 2R0 k 1þ k ðl kÞða=bÞð1 ekT Þ 1 1 1 e2kT 1 eðlþkÞT 2k ðl þ kÞ
BED ¼
ð1Þ
Values for the tissue repair constant of sublethal damage l and a=b values were defined according to studies by Gagne et al. [23,24]. The implant duration T and initial dose rate R0 were derived from the recorded treatment parameters. Outcome measures and statistical methods
Ru plaque treatment protocol 106
All patients in this retrospective study were treated with Ru plaques manufactured by BEBIG (Eckert & Ziegler BEBIG GmbH, Berlin, Germany). Depending on tumor size and location one of two available plaque types (CCB, CCA) with diameters of 19.8 and 15.3 mm was chosen. Typically, tumors up to around 11 mm were treated with the CCA type plaque. Larger tumors were treated with the CCB type plaque. The treatment was aimed to deliver a minimum of 100 Gy to the tumor apex [19]. The required treatment time was calculated using the specification data provided by the manufacturer. The surgical implantation for all patients was done by the same physician. Treatment planning and dose calculation For this study, post-implantation treatment planning, dose calculation and the calculation of dose-volume metrics were performed using a novel treatment planning system that was described in a previous publication [20]. The underlying Monte Carlo generated dose lookup tables were benchmarked against experimental measurements [21]. Tumor size and location were used to recalculate dose distributions based on a standard 3D model of an eye. Typically, the plaque was centered on the tumor center. In some cases, in which a centered position would expose adjacent critical structures to higher doses, an eccentric plaque placement was chosen if the tumor diameter allowed for such a shift. Dose volume histograms were generated for the organs at risk (e.g. retina, lens, optic nerve, and macula). Doses were reported as near maximum (D2%) and mean doses (Dmean). The retina was assumed to be a finite layer with constant thickness of 400 mm, whereas the macula was rendered as a disk of 3 mm diameter and a height of 400 mm. The structures were interpolated from the 3D eye model onto the calculation grid with a voxel size of 200 200 200 mm3. Additionally to the physical dose, biologically equivalent doses (BED) to the OARs were calculated. The treatment planning software allowed to transform physical dose distributions into BED using an equation for temporary brachytherapy implants introduced by Dale and Jones [22]:
Visual acuity was documented using Snellen charts. The difference between the baseline visual acuity and visual acuity at the date of the last individual follow-up was considered as visual acuity lost or gained after 106Ru brachytherapy. Statistical analysis was first done for the entire patient cohort and in a second step for a subgroup of patients with more anteriorly located tumors with a minimum distance of 4 mm or more between tumor base and macula. Statistical calculations were performed using SPSS software (IBM SPSS Statistics version 21). Descriptive statistics were used to characterize the patient cohort (i.e. median and interquartile ranges (IQR) and mean plus standard deviation (SD) when data was normally distributed). To show differences between normally distributed data sets Student’s t-tests were performed as well as Pearson’s chi-squared tests for categorized samples. Risk factors were compared to loss of visual acuity by using Pearson correlation coefficients at the time of last follow-up. Predictors for visual acuity loss were evaluated using the Cox proportional hazards models and Kaplan–Meier estimations for loss of visual acuity at each follow-up. Statistical significance was defined to as p 0.05. Results Patient population and treatment characteristics The median follow-up time was 29.5 months (IQR 15.0–39.8) for all patients. The median apex dose was 131 Gy (IQR 113.0– 150.4). Median tumor height and tumor basal diameters were 4.6 mm (IQR 3.5–6.0), 10.8 mm (IQR 8.3–12.6) and 9.3 mm (IQR 7.9–11.4), respectively. The average distances to the optic nerve and macula were 5.0 mm (IQR 3.5–8.5) and 6.0 mm (IQR 4.0–9.5). Visual acuity outcome Visual acuity at baseline was 0.82 (±0.23) Snellen and declined to 0.59 (±0.28) at the last individual follow-up (p < 0.001). The results of the Pearson Correlation analysis and respective significance levels are listed in Table 1. A high net loss of visual acuity
Table 1 Summary of parameters associated with loss of visual acuity and worse post treatment visual acuity outcome obtained from Pearson correlation. Both physical (D2% and Dmean) and biological dose (BED2% and BEDmean) were evaluated. Factors
Loss of visual acuity in Snellen equivalent
Worse post treatment visual acuity in Snellen equivalent
Pearson correlation
p
Pearson correlation
p
Max retina dose D2%
D2% BED2%
0.472 0.381
0.001 0.010
0.538 0.414
<0.001 0.005
Mean retina dose
Dmean BEDmean
0.492 0.359
0.001 0.015
0.552 0.374
<0.001 0.011
Basal diameter
Largest Smallest
0.503 0.475
<0.001 <0.001
0.622 0.577
<0.001 <0.001
Max macula dose D2%
D2% BED2%
0.238 0.265
0.115 0.079
0.188 0.195
0.216 0.199
Please cite this article in press as: Heilemann G et al. Retina dose as a predictor for visual acuity loss in nomas. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2017.11.010
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between baseline VA and VA at last follow-up showed a significant correlation to tumor basal diameter and mean and maximum retina dose (physical and biological). Factors correlating with a worse post-treatment VA, meaning net VA at the last follow-up, were basal diameter, mean and maximum retina dose. The dose to the macula showed no correlation with total visual acuity loss and worse visual acuity at the last individual follow-up. Scatter plots of the maximum retina dose and basal diameters with respect to the investigated endpoints are displayed in Fig. 1. The highlighted data points in this figure demonstrate how interrelated the parameters (i.e. diameter and retinal dose) are in many cases. A three-dimensional representation of the co-dependence between potential predictors retina dose, diameter and visual outcome is given as an animated graph in the Supplementary data. Threshold values for maximum tolerated retinal doses before visual loss is significantly decreased were identified by evaluating Kaplan–Meier estimates and the Cox proportional hazards model. Significant loss of visual acuity was defined as a loss of more than 0.3 Snellen for the purpose of this study. The probabilities for visual acuity loss displayed in a Kaplan–Meier curve in Fig. 2 showed a significant difference between patients receiving less than 500 Gy to the retina and patients receiving equal or more than 500 Gy to the retina (p = 0.002). Similarly, a dose of more than 5 Gy to the macula showed a significant difference in visual outcome (p = 0.025). On the other hand, a basal diameter of more than 10.8 mm, which is the median diameter of patients in this study, only showed a trend for worse visual outcome (p = 0.145). Other factors, e.g. plaque type and dose rate, did not show any significant difference in outcome (p = 0.733 and p = 0.821, respectively). Combining these factors in a Cox multivariate analysis only the retinal dose as a risk factor showed significance (p = 0.013) while the macula dose revealed only a very weak trend to significance
(p = 0.237) and the other parameters were not significant at all. The results are summarized in Table 2. Similarly, a Cox multivariate analysis showed that the only significant predicting factor for the visual acuity to fall below 0.5 Snellen at the last individual follow up was a high retina dose (>500 Gy, p = 0.022). The remaining parameters did not show any significance (see Table 2). Anterior tumor locations To assess possible correlations in eyes with anteriorly located tumors, a further analysis of the data of 20 patients with a minimum distance between tumor base and macula of more than 4 mm was conducted. For such tumor locations, visual outcome showed a significant correlation to maximum retina dose (r = 0.469, p = 0.043). In contrast to the statistical calculation for the entire patient cohort, the diameter did not correlate significantly with visual acuity loss in this subgroup (p = 0.173). As expected, the maximum macula dose did not correlate with visual acuity loss (r = 0.125, p = 0.610). Retina dose and plaque type Changing from CCA to CCB did not increase the risk for loss of visual acuity in a Cox regression model (p = 0.992). The maximum dose to the retina was not significantly higher for patients treated with CCB type plaques (p = 0.37). Factors responsible for increased retina doses are tumor height and plaque type. As expected, the apex height of a tumor was higher for larger basal diameters (r = 0.576, p < 0.001). This in turn increases the applied doses to the retina (r = 0.74, p < 0.001). The larger tumor diameter required the use of the larger CCB type
Fig. 1. Correlation of visual outcome with factors near maximum retina dose and diameter. The difference of baseline visual acuity and visual acuity at last follow-up was plotted with respect to maximum retina dose (A) and largest basal diameter (B). The filled points represent two different cases. The comparison demonstrates the different predictive value of the two parameters for the visual outcome. For the first case (diamond) the diameter had weak potential in predicting the visual outcome, while a retina dose of > 1300 Gy strongly suggested a high loss in visual acuity. Vice versa the second case (square) showed the opposite behavior. The visual acuity at last follow-up was plotted with respect to maximum retina dose and diameter in (C) and (D), respectively. Again, two cases (diamonds and squares) highlight the co-dependence of the risk factors.
Please cite this article in press as: Heilemann G et al. Retina dose as a predictor for visual acuity loss in nomas. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2017.11.010
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Fig. 2. Kaplan–Meier Curve showing the proportion of patients with an of visual loss equal or larger than 0.3.
Table 2 Results of multivariate Cox analysis summarizing all factors and significance levels. The clinical outcome in the left part was a recorded loss of >0.3 Snellen before radiotherapy and at the last follow-up. For the right part, the event was considered to be a drop of VA below 0.5 Snellen. Factor
Retina dose D2 (500 Gy) Macula dose D2 (5 Gy) Diameter (10.8 mm) Dose rate (65 mGy/min) Plaque type (CCA/CCB)
Loss of >0.3 total Snellen
Drop of VA below 0.5 Snellen
Significance level p
Odds ratio Exp(b)
Significance level p
Odds ratio Exp(b)
0.013 0.237 0.791 0.524 0.686
0.14 2.18 1.10 1.49 1.33
0.022 0.233 0.245 0.567 0.287
0.18 0.48 1.50 1.34 1.93
plaque. Consequently, CCB type plaques were used for tumors with larger apex heights compared to CCA (p = 0.018). Mean apex heights for CCB were 5.3 mm (±1.5 SD) and 3.7 mm (±1.6 SD) for CCA, respectively. On the other hand, it was shown that for larger tumor apex heights the retina dose is increased when switching from a CCB type to a CCA type plaque in a previous study [20]. The larger dose distribution produced by the CCB type plaque allows delivering a higher dose to the tumor apex in a shorter time compared to the CCA plaque. This means that retina doses are increased from 10% for 5 mm apex heights up to 25% for 8 mm apex heights in CCA.
Physical dose versus BED Statistical analysis was performed with dose-volume metrics in terms of BED and compared to the same analysis using physical doses. The evaluation of Pearson correlation coefficients showed weaker significance levels for correlations with the BED (see Table 1). Kaplan–Meier statistics using BED as input to categorize the samples provided the same significances as for physical dose. The dose rate to either retina or macula – a major factor in calculating BED – did not show any correlation with visual acuity loss (r = 0.05, p = 0.75 and r = 0.07, p = 0.66, respectively).
Discussion In the present study, dosimetric tolerance levels (e.g. retina and macula dose) as well as other risk factors for visual acuity loss were evaluated using a novel treatment planning system for 106Ru eye plaque brachytherapy of uveal melanomas. Most past studies have shown that the main predictors for worse visual outcome aside from age and initial visual acuity are tumor location and size [11,13]. However, to the authors’ knowledge, there is no publication to this date demonstrating the direct correlation of visual acuity loss to the retinal dose in these patients. Parameters like tumor height or basal diameters as well as the location are indirect indicators of the overall applied dose to OARs. Larger apex heights require longer application times and larger basal diameters require a larger plaque size, both of which result in higher doses to tumor and surrounding tissue. This study aimed to translate these geometric tumor characteristics into direct, i.e. dosimetric, indicators. Damato et al. proposed that loss of visual acuity is less a problem of scleral dose but rather a delicate relationship of a broad variety of factors, such as age, pre-treatment visual acuity, basal diameter and tumor location [11]. However, a study on 106Ru and multiple studies on 125I eye plaques associate visual acuity loss with tumor height, which in turn directly influences the retinal dose [15,25,26].
Retinal detachment outcome The occurrence of retinal detachment as a side effect of 106Ru brachytherapy showed a high correlation with the near maximum and mean dose to the retina (table 3). When separating the patients into a group receiving high (>500 Gy) and lower retina maximum doses (<500 Gy), a Pearson’s chi-squared test showed a significantly reduced occurrence of retinal detachments for patients receiving lower retinal doses (p = 0.008).
Table 3 Independent samples T-Test for retinal detachments and retinal doses as risk factors. Factors
Significance p-value
Max dose retina BED Max dose retina physical Mean dose retina BED Mean dose retina physical
<0.001 <0.001 <0.001 <0.001
Please cite this article in press as: Heilemann G et al. Retina dose as a predictor for visual acuity loss in nomas. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2017.11.010
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Taking advantage of the detailed dose calculation for the outer layers of the eye in the novel treatment planning system, the current study was able to provide data on the retina dose as a risk factor for visual acuity loss and confirm findings on geometric factors of past studies [15,25,26]. However, it was demonstrated, that for many cases the geometric information did not correlate with the recorded visual acuity loss, whereas the retina dose did. A substantial number of patients in this study presented tumors in anterior position and almost no dose was delivered to the macula. However, these patients showed a similar trend of loss of visual acuity, which can clearly not be caused by the macula dose alone. The present study showed that by adding the information from calculated actual absorbed doses in the retina, a better estimation of VA loss can be performed, especially in anterior tumors where the geometric parameters or macula dose tend to be less predictive. While the exact mechanisms causing an impairment of visual acuity are not fully understood, the assumption here is that there are multiple reasons. It might be possible that radiation damage to the retina can lead to different manifestations which can cause visual acuity loss. Furthermore, the importance of a best suitable plaque was shown in order to be able to reduce the amount of retina exposed. In some cases, it might even be preferable to choose the larger CCB type plaque if that reduces the overall dose to the retina. One reason is the lower dose to the adjacent surface, caused by the larger CCB plaque compared to the small CCA type, when delivering the same dose level to relatively large apex heights. The underlying study demonstrated the importance of retinal dose in visual outcome. Another factor influencing the dose to the retina is the radionuclide used for plaque brachytherapy. Compared to 125I plaque the retinal dose in 106Ru is significantly larger [27]. Future studies need to investigate how the choice of radionuclide impacts visual outcome. All analyses were performed with respect to the physical and biologically effective doses. In most cases the physical dose was equally good or better as a predictor for visual acuity loss. One factor the BED accounts for is the dose rate. Regarding the clinical outcome this study found no correlation to dose rate. However, a similar study for secondary malignancies was not yet performed and requires more data. The present study suggested however, that no such correlation exists for VA loss as a clinical endpoint. To summarize, the present study showed that the retina dose is a good indicator for visual acuity loss. Especially in anterior tumors the additional information can help predicting visual outcome where other factors such as tumor location and macula dose fail.
Conflict of interest statement The persons listed as authors of this submitted publication certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.
Acknowledgments The study was financially supported by the Austrian Science Fund (FWF) Project No. P25936.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.radonc.2017.11. 010. References [1] Bergman L, Nilsson B, Lundell G, Lundell M, Seregard S. Ruthenium brachytherapy for uveal melanoma, 1979–2003: survival and functional outcomes in the Swedish population. Ophthalmology 2005;112:834–40. https://doi.org/10.1016/j.ophtha.2004.11.038. [2] Damato B, Patel I, Campbell IR, Mayles HM, Errington RD. Local tumor control after 106Ru brachytherapy of choroidal melanoma. Int J Radiat Oncol Biol Phys 2005;63:385–91. https://doi.org/10.1016/j.ijrobp.2005.02.017. [3] Zehetmayer M. Stereotactic photon beam irradiation of uveal melanoma. Dev Ophthalmol 2012;49:58–65. https://doi.org/10.1159/000328259. [4] Georg D, Dieckmann K, Bogner J, Zehetmayer M, Pötter R. Impact of a micromultileaf collimator on stereotactic radiotherapy of uveal melanoma. Int J Radiat Oncol Biol Phys 2003;55:881–91. https://doi.org/10.1016/S0360-3016 (02)04119-6. [5] Dendale R, Lumbroso-Le Rouic L, Noel G, Feuvret L, Levy C, Delacroix S, et al. Proton beam radiotherapy for uveal melanoma: results of Curie Institut-Orsay proton therapy center (ICPO). Int J Radiat Oncol Biol Phys 2006;65:780–7. https://doi.org/10.1016/j.ijrobp.2006.01.020. [6] Castro J, Char D, Petti P, Daftari I, Quivey J, Singh R, et al. 15 years experience with helium ion radiotherapy for uveal melanoma. Int J Radiat Oncol Biol Phys 1997;39:989–96. https://doi.org/10.1016/S0360-3016(97)00494-X. [7] Jampol LM, Moy CS, Murray TG, Reynolds SM, Albert DM, Schachat AP, et al. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: IV. Local treatment failure and enucleation in the first 5 years after brachytherapy. COMS report no. 19. Ophthalmology 2002;109:2197–206. https://doi.org/10.1016/S0161-6420(02)01277-0. [8] Dunavoelgyi R, Dieckmann K, Gleiss A, Sacu S, Kircher K, Georgopoulos M, et al. Local tumor control, visual acuity, and survival after hypofractionated stereotactic photon radiotherapy of choroidal melanoma in 212 patients treated between 1997 and 2007. Int J Radiat Oncol 2011;81:199–205. https:// doi.org/10.1016/j.ijrobp.2010.04.035. [9] 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. Int J Radiat Oncol Biol Phys 2005;63:373–84. https://doi.org/10.1016/j.ijrobp.2005.01.057. [10] Dieckmann K, Georg D, Zehetmayer M, Bogner J, Georgopoulos M, Pötter R. LINAC based stereotactic radiotherapy of uveal melanoma: 4 years clinical experience. Radiother Oncol 2003;67:199–206. https://doi.org/10.1016/ S0167-8140(02)00345-6. [11] Damato B, Patel I, Campbell IR, Mayles HM, Errington RD. Visual acuity after Ruthenium(106) brachytherapy of choroidal melanomas. Int J Radiat Oncol Biol Phys 2005;63:392–400. https://doi.org/10.1016/j.ijrobp.2005.02.059. [12] Shields CL, Shields JA, Cater J, Gündüz K, Miyamoto C, Micaily B, et al. Plaque radiotherapy for uveal melanoma: long-term visual outcome in 1106 consecutive patients. Arch Ophthalmol 2000;118:1219–28. https://doi.org/ 10.1097/00132578-200104000-00007. [13] Aziz HA, Singh N, Bena J, Wilkinson A, Singh AD. Vision loss following episcleral brachytherapy for uveal melanoma: development of a vision prognostication tool. JAMA Ophthalmol 2016;44106:615–20. https://doi.org/ 10.1001/jamaophthalmol.2016.0104. [14] Anastassiou G, Bornfeld N, Schueler a O, Schilling H, Weber S, Fluehs D,, et al. Ruthenium-106 plaque brachytherapy for symptomatic vasoproliferative tumours of the retina. Br J Ophthalmol 2006;90:447–50. https://doi.org/ 10.1136/bjo.2005.081422. [15] Verschueren KMS, Creutzberg CL, Schalij-Delfos NE, Ketelaars M, Klijsen FLL, Haeseker BI, et al. Long-term outcomes of eye-conserving treatment with Ruthenium(106) brachytherapy for choroidal melanoma. Radiother Oncol 2010;95:332–8. https://doi.org/10.1016/j.radonc.2010.03.023. [16] Peer J, Damato B, Zehetmayer M, Desjardins L, Lumbroso-Le Rouic L, LevyGabriel C. Current concepts in uveal melanoma. In: Jager M, Desjardins L, Kivelä T, Damato B, editors. Dev Ophthalmol. Basel: Karger; 2012. p. 1–65. [17] Pötter R, Van Limbergen E, Melanoma Uveal. In: GEC ESTRO handb brachytherapy. ESTRO; 2002. p. 591–610. [18] Dieckmann K, Bogner J, Georg D, Zehetmayer M, Kren G, Pötter R. A linac-based stereotactic irradiation technique of uveal melanoma. Radiother Oncol 2001;61:49–56. https://doi.org/10.1016/S0167-8140(01)00413-3. [19] 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;217:315–9. https://doi.org/10.1159/ 000071345. [20] Heilemann G, Fetty L, Dulovits M, Blaickner M, Nesvacil N, Georg D, et al. Treatment plan optimization and robustness of 106Ru eye plaque brachytherapy using a novel software tool. Radiother Oncol 2017;123 (1):119–24. https://doi.org/10.1016/j.radonc.2017.01.010. [21] Heilemann G, Nesvacil N, Blaickner M, Kostiukhina N, Georg D. Multidimensional dosimetry of 106Ru eye plaques using EBT3 films and its
Please cite this article in press as: Heilemann G et al. Retina dose as a predictor for visual acuity loss in nomas. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2017.11.010
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impact on treatment planning. Med Phys 2015;42:5798–808. https://doi.org/ 10.1118/1.4929564. [22] Dale RG, Jones B. The clinical radiobiology of brachytherapy. Br J Radiol 1998;71:465–83. https://doi.org/10.1259/bjr.71.845.9691890. [23] Gagne NL, Leonard KL, Huber KE, Mignano JE, Duker JS, Laver NV, et al. BEDVH—A method for evaluating biologically effective dose volume histograms: Application to eye plaque brachytherapy implants. Med Phys 2012;39:976. https://doi.org/10.1118/1.3679010. [24] Gagne NL, Leonard KL, Rivard MJ. Radiobiology for eye plaque brachytherapy and evaluation of implant duration and radionuclide choice using an objective function. Med Phys 2012;39:3332. https://doi.org/10.1118/1.4718683.
[25] Perez BA, Mettu P, Vajzovic L, Rivera D, Alkaissi A, Steffey BA, et al. Uveal melanoma treated with iodine-125 episcleral plaque: an analysis of dose on disease control and visual outcomes. Int J Radiat Oncol Biol Phys 2014;89:127–36. https://doi.org/10.1016/j.ijrobp.2014.01.026. [26] Wisely CE, Hadziahmetovic M, Reem RE, Hade EM, Nag S, Davidorf FH, et al. Long-term visual acuity outcomes in patients with uveal melanoma treated with 125I episcleral OSU-Nag plaque brachytherapy. Brachytherapy 2016;15:12–22. [27] Wilkinson DA, Kolar M, Fleming PA, Singh AD. Dosimetric comparison of 106Ru and 125I plaques for treatment of shallow choroidal melanoma lesions. Br J Radiol 2008;81:784–9. https://doi.org/10.1259/bjr/76813976.
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Retina dose as a predictor for visual acuity loss in brachytherapy of uveal melanomas
106
Ru eye plaque
Gerd Heilemann a,⇑, Lukas Fetty a, Matthias Blaickner b, Nicole Nesvacil a,c, Martin Zehetmayer d, Dietmar Georg a,c, Roman Dunavoelgyi d a Division Medical Radiation Physics, Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna/AKH Vienna; b Austrian Institute of Technology GmbH, Health & Environment Department Biomedical Systems, Vienna; c Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna; and d Department of Ophthalmology and Optometry, Medical University of Vienna/AKH Vienna, Austria
a r t i c l e
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Article history: Received 21 December 2016 Received in revised form 22 September 2017 Accepted 20 November 2017 Available online xxxx Keywords: Uveal melanoma Brachytherapy Eye plaque Ruthenium Visual acuity
a b s t r a c t 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 (>0.3 Snellen) 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. Ó 2017 The Authors. Published by Elsevier Ireland Ltd. Radiotherapy and Oncology xxx (2018) xxx–xxx This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).
The preservation of visual acuity is a major objective in conservative treatments of uveal melanoma, such as brachytherapy using either 106Ru or 125I plaques and external beam stereotactic radiotherapy with photons or charged particle therapy [1–10]. Among these techniques brachytherapy using 106Ru or 125I plaques achieves excellent local control while providing a treatment option that allows to preserve useful vision, good cosmetic and quality of life results [2,7,11]. However, the loss of visual acuity is a common side effect of these techniques and can be associated with different factors [11–14]. In 106Ru brachytherapy, mainly geometric characteristics of the tumor were identified to be associated with worse visual outcome in earlier studies [1,11,15]. Only recent publications were able to correlate the loss of visual acuity to dosimetric parameters such as the dose to the fovea [13]. Increased tumor height and basal diameters were both associated with a decreased visual acu⇑ Corresponding author at: Division Medical Radiation Physics, Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna/ AKH Vienna, Austria. E-mail address: [email protected] (G. Heilemann).
ity [13,15]. But while both parameters directly affect the overall dose to the retina, the retina dose itself was not found to be a risk factor for bad visual outcome in past studies [11]. The present study is focusing on the effect of retina dose on visual acuity and secondary toxicities after 106Ru plaque brachytherapy using a newly developed treatment planning system. Materials and methods Patient cohort and data collection In this retrospective study patients with choroidal and/or ciliary body melanoma were included who had been treated with 106Ru eye plaque brachytherapy at the Department of Ophthalmology and the Department of Radiotherapy, Medical University, Vienna, between 1995 and 2015. Patients were selected for 106Ru eye plaques according to common recommendations [16,17]. Patients were treated with 106Ru plaques unless tumor height was above 7 mm or in case of centrally located tumors (distance to macula and/or optic disk < 3 mm) – in these cases, patients were treated
https://doi.org/10.1016/j.radonc.2017.11.010 0167-8140/Ó 2017 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Heilemann G et al. Retina dose as a predictor for visual acuity loss in nomas. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2017.11.010
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using hypofractionated stereotactic photon radiotherapy [10,18]. The presence of metastatic disease was an exclusion criterion for this study. Of all these patients 45 patients could be used for dose recalculation. The remainder had to be excluded due to a lack of follow-up data. Standard A- and B-scan echography was performed to assess tumor dimensions. The tumor location was determined using A- and B-scan echography, ophthalmoscopy, funduscopy (using wide angle contact glasses if necessary) and diaphanoscopy. 106
R0 ð1 ekT Þ 2R0 k 1þ k ðl kÞða=bÞð1 ekT Þ 1 1 1 e2kT 1 eðlþkÞT 2k ðl þ kÞ
BED ¼
ð1Þ
Values for the tissue repair constant of sublethal damage l and a=b values were defined according to studies by Gagne et al. [23,24]. The implant duration T and initial dose rate R0 were derived from the recorded treatment parameters. Outcome measures and statistical methods
Ru plaque treatment protocol 106
All patients in this retrospective study were treated with Ru plaques manufactured by BEBIG (Eckert & Ziegler BEBIG GmbH, Berlin, Germany). Depending on tumor size and location one of two available plaque types (CCB, CCA) with diameters of 19.8 and 15.3 mm was chosen. Typically, tumors up to around 11 mm were treated with the CCA type plaque. Larger tumors were treated with the CCB type plaque. The treatment was aimed to deliver a minimum of 100 Gy to the tumor apex [19]. The required treatment time was calculated using the specification data provided by the manufacturer. The surgical implantation for all patients was done by the same physician. Treatment planning and dose calculation For this study, post-implantation treatment planning, dose calculation and the calculation of dose-volume metrics were performed using a novel treatment planning system that was described in a previous publication [20]. The underlying Monte Carlo generated dose lookup tables were benchmarked against experimental measurements [21]. Tumor size and location were used to recalculate dose distributions based on a standard 3D model of an eye. Typically, the plaque was centered on the tumor center. In some cases, in which a centered position would expose adjacent critical structures to higher doses, an eccentric plaque placement was chosen if the tumor diameter allowed for such a shift. Dose volume histograms were generated for the organs at risk (e.g. retina, lens, optic nerve, and macula). Doses were reported as near maximum (D2%) and mean doses (Dmean). The retina was assumed to be a finite layer with constant thickness of 400 mm, whereas the macula was rendered as a disk of 3 mm diameter and a height of 400 mm. The structures were interpolated from the 3D eye model onto the calculation grid with a voxel size of 200 200 200 mm3. Additionally to the physical dose, biologically equivalent doses (BED) to the OARs were calculated. The treatment planning software allowed to transform physical dose distributions into BED using an equation for temporary brachytherapy implants introduced by Dale and Jones [22]:
Visual acuity was documented using Snellen charts. The difference between the baseline visual acuity and visual acuity at the date of the last individual follow-up was considered as visual acuity lost or gained after 106Ru brachytherapy. Statistical analysis was first done for the entire patient cohort and in a second step for a subgroup of patients with more anteriorly located tumors with a minimum distance of 4 mm or more between tumor base and macula. Statistical calculations were performed using SPSS software (IBM SPSS Statistics version 21). Descriptive statistics were used to characterize the patient cohort (i.e. median and interquartile ranges (IQR) and mean plus standard deviation (SD) when data was normally distributed). To show differences between normally distributed data sets Student’s t-tests were performed as well as Pearson’s chi-squared tests for categorized samples. Risk factors were compared to loss of visual acuity by using Pearson correlation coefficients at the time of last follow-up. Predictors for visual acuity loss were evaluated using the Cox proportional hazards models and Kaplan–Meier estimations for loss of visual acuity at each follow-up. Statistical significance was defined to as p 0.05. Results Patient population and treatment characteristics The median follow-up time was 29.5 months (IQR 15.0–39.8) for all patients. The median apex dose was 131 Gy (IQR 113.0– 150.4). Median tumor height and tumor basal diameters were 4.6 mm (IQR 3.5–6.0), 10.8 mm (IQR 8.3–12.6) and 9.3 mm (IQR 7.9–11.4), respectively. The average distances to the optic nerve and macula were 5.0 mm (IQR 3.5–8.5) and 6.0 mm (IQR 4.0–9.5). Visual acuity outcome Visual acuity at baseline was 0.82 (±0.23) Snellen and declined to 0.59 (±0.28) at the last individual follow-up (p < 0.001). The results of the Pearson Correlation analysis and respective significance levels are listed in Table 1. A high net loss of visual acuity
Table 1 Summary of parameters associated with loss of visual acuity and worse post treatment visual acuity outcome obtained from Pearson correlation. Both physical (D2% and Dmean) and biological dose (BED2% and BEDmean) were evaluated. Factors
Loss of visual acuity in Snellen equivalent
Worse post treatment visual acuity in Snellen equivalent
Pearson correlation
p
Pearson correlation
p
Max retina dose D2%
D2% BED2%
0.472 0.381
0.001 0.010
0.538 0.414
<0.001 0.005
Mean retina dose
Dmean BEDmean
0.492 0.359
0.001 0.015
0.552 0.374
<0.001 0.011
Basal diameter
Largest Smallest
0.503 0.475
<0.001 <0.001
0.622 0.577
<0.001 <0.001
Max macula dose D2%
D2% BED2%
0.238 0.265
0.115 0.079
0.188 0.195
0.216 0.199
Please cite this article in press as: Heilemann G et al. Retina dose as a predictor for visual acuity loss in nomas. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2017.11.010
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between baseline VA and VA at last follow-up showed a significant correlation to tumor basal diameter and mean and maximum retina dose (physical and biological). Factors correlating with a worse post-treatment VA, meaning net VA at the last follow-up, were basal diameter, mean and maximum retina dose. The dose to the macula showed no correlation with total visual acuity loss and worse visual acuity at the last individual follow-up. Scatter plots of the maximum retina dose and basal diameters with respect to the investigated endpoints are displayed in Fig. 1. The highlighted data points in this figure demonstrate how interrelated the parameters (i.e. diameter and retinal dose) are in many cases. A three-dimensional representation of the co-dependence between potential predictors retina dose, diameter and visual outcome is given as an animated graph in the Supplementary data. Threshold values for maximum tolerated retinal doses before visual loss is significantly decreased were identified by evaluating Kaplan–Meier estimates and the Cox proportional hazards model. Significant loss of visual acuity was defined as a loss of more than 0.3 Snellen for the purpose of this study. The probabilities for visual acuity loss displayed in a Kaplan–Meier curve in Fig. 2 showed a significant difference between patients receiving less than 500 Gy to the retina and patients receiving equal or more than 500 Gy to the retina (p = 0.002). Similarly, a dose of more than 5 Gy to the macula showed a significant difference in visual outcome (p = 0.025). On the other hand, a basal diameter of more than 10.8 mm, which is the median diameter of patients in this study, only showed a trend for worse visual outcome (p = 0.145). Other factors, e.g. plaque type and dose rate, did not show any significant difference in outcome (p = 0.733 and p = 0.821, respectively). Combining these factors in a Cox multivariate analysis only the retinal dose as a risk factor showed significance (p = 0.013) while the macula dose revealed only a very weak trend to significance
(p = 0.237) and the other parameters were not significant at all. The results are summarized in Table 2. Similarly, a Cox multivariate analysis showed that the only significant predicting factor for the visual acuity to fall below 0.5 Snellen at the last individual follow up was a high retina dose (>500 Gy, p = 0.022). The remaining parameters did not show any significance (see Table 2). Anterior tumor locations To assess possible correlations in eyes with anteriorly located tumors, a further analysis of the data of 20 patients with a minimum distance between tumor base and macula of more than 4 mm was conducted. For such tumor locations, visual outcome showed a significant correlation to maximum retina dose (r = 0.469, p = 0.043). In contrast to the statistical calculation for the entire patient cohort, the diameter did not correlate significantly with visual acuity loss in this subgroup (p = 0.173). As expected, the maximum macula dose did not correlate with visual acuity loss (r = 0.125, p = 0.610). Retina dose and plaque type Changing from CCA to CCB did not increase the risk for loss of visual acuity in a Cox regression model (p = 0.992). The maximum dose to the retina was not significantly higher for patients treated with CCB type plaques (p = 0.37). Factors responsible for increased retina doses are tumor height and plaque type. As expected, the apex height of a tumor was higher for larger basal diameters (r = 0.576, p < 0.001). This in turn increases the applied doses to the retina (r = 0.74, p < 0.001). The larger tumor diameter required the use of the larger CCB type
Fig. 1. Correlation of visual outcome with factors near maximum retina dose and diameter. The difference of baseline visual acuity and visual acuity at last follow-up was plotted with respect to maximum retina dose (A) and largest basal diameter (B). The filled points represent two different cases. The comparison demonstrates the different predictive value of the two parameters for the visual outcome. For the first case (diamond) the diameter had weak potential in predicting the visual outcome, while a retina dose of > 1300 Gy strongly suggested a high loss in visual acuity. Vice versa the second case (square) showed the opposite behavior. The visual acuity at last follow-up was plotted with respect to maximum retina dose and diameter in (C) and (D), respectively. Again, two cases (diamonds and squares) highlight the co-dependence of the risk factors.
Please cite this article in press as: Heilemann G et al. Retina dose as a predictor for visual acuity loss in nomas. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2017.11.010
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Fig. 2. Kaplan–Meier Curve showing the proportion of patients with an of visual loss equal or larger than 0.3.
Table 2 Results of multivariate Cox analysis summarizing all factors and significance levels. The clinical outcome in the left part was a recorded loss of >0.3 Snellen before radiotherapy and at the last follow-up. For the right part, the event was considered to be a drop of VA below 0.5 Snellen. Factor
Retina dose D2 (500 Gy) Macula dose D2 (5 Gy) Diameter (10.8 mm) Dose rate (65 mGy/min) Plaque type (CCA/CCB)
Loss of >0.3 total Snellen
Drop of VA below 0.5 Snellen
Significance level p
Odds ratio Exp(b)
Significance level p
Odds ratio Exp(b)
0.013 0.237 0.791 0.524 0.686
0.14 2.18 1.10 1.49 1.33
0.022 0.233 0.245 0.567 0.287
0.18 0.48 1.50 1.34 1.93
plaque. Consequently, CCB type plaques were used for tumors with larger apex heights compared to CCA (p = 0.018). Mean apex heights for CCB were 5.3 mm (±1.5 SD) and 3.7 mm (±1.6 SD) for CCA, respectively. On the other hand, it was shown that for larger tumor apex heights the retina dose is increased when switching from a CCB type to a CCA type plaque in a previous study [20]. The larger dose distribution produced by the CCB type plaque allows delivering a higher dose to the tumor apex in a shorter time compared to the CCA plaque. This means that retina doses are increased from 10% for 5 mm apex heights up to 25% for 8 mm apex heights in CCA.
Physical dose versus BED Statistical analysis was performed with dose-volume metrics in terms of BED and compared to the same analysis using physical doses. The evaluation of Pearson correlation coefficients showed weaker significance levels for correlations with the BED (see Table 1). Kaplan–Meier statistics using BED as input to categorize the samples provided the same significances as for physical dose. The dose rate to either retina or macula – a major factor in calculating BED – did not show any correlation with visual acuity loss (r = 0.05, p = 0.75 and r = 0.07, p = 0.66, respectively).
Discussion In the present study, dosimetric tolerance levels (e.g. retina and macula dose) as well as other risk factors for visual acuity loss were evaluated using a novel treatment planning system for 106Ru eye plaque brachytherapy of uveal melanomas. Most past studies have shown that the main predictors for worse visual outcome aside from age and initial visual acuity are tumor location and size [11,13]. However, to the authors’ knowledge, there is no publication to this date demonstrating the direct correlation of visual acuity loss to the retinal dose in these patients. Parameters like tumor height or basal diameters as well as the location are indirect indicators of the overall applied dose to OARs. Larger apex heights require longer application times and larger basal diameters require a larger plaque size, both of which result in higher doses to tumor and surrounding tissue. This study aimed to translate these geometric tumor characteristics into direct, i.e. dosimetric, indicators. Damato et al. proposed that loss of visual acuity is less a problem of scleral dose but rather a delicate relationship of a broad variety of factors, such as age, pre-treatment visual acuity, basal diameter and tumor location [11]. However, a study on 106Ru and multiple studies on 125I eye plaques associate visual acuity loss with tumor height, which in turn directly influences the retinal dose [15,25,26].
Retinal detachment outcome The occurrence of retinal detachment as a side effect of 106Ru brachytherapy showed a high correlation with the near maximum and mean dose to the retina (table 3). When separating the patients into a group receiving high (>500 Gy) and lower retina maximum doses (<500 Gy), a Pearson’s chi-squared test showed a significantly reduced occurrence of retinal detachments for patients receiving lower retinal doses (p = 0.008).
Table 3 Independent samples T-Test for retinal detachments and retinal doses as risk factors. Factors
Significance p-value
Max dose retina BED Max dose retina physical Mean dose retina BED Mean dose retina physical
<0.001 <0.001 <0.001 <0.001
Please cite this article in press as: Heilemann G et al. Retina dose as a predictor for visual acuity loss in nomas. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2017.11.010
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Taking advantage of the detailed dose calculation for the outer layers of the eye in the novel treatment planning system, the current study was able to provide data on the retina dose as a risk factor for visual acuity loss and confirm findings on geometric factors of past studies [15,25,26]. However, it was demonstrated, that for many cases the geometric information did not correlate with the recorded visual acuity loss, whereas the retina dose did. A substantial number of patients in this study presented tumors in anterior position and almost no dose was delivered to the macula. However, these patients showed a similar trend of loss of visual acuity, which can clearly not be caused by the macula dose alone. The present study showed that by adding the information from calculated actual absorbed doses in the retina, a better estimation of VA loss can be performed, especially in anterior tumors where the geometric parameters or macula dose tend to be less predictive. While the exact mechanisms causing an impairment of visual acuity are not fully understood, the assumption here is that there are multiple reasons. It might be possible that radiation damage to the retina can lead to different manifestations which can cause visual acuity loss. Furthermore, the importance of a best suitable plaque was shown in order to be able to reduce the amount of retina exposed. In some cases, it might even be preferable to choose the larger CCB type plaque if that reduces the overall dose to the retina. One reason is the lower dose to the adjacent surface, caused by the larger CCB plaque compared to the small CCA type, when delivering the same dose level to relatively large apex heights. The underlying study demonstrated the importance of retinal dose in visual outcome. Another factor influencing the dose to the retina is the radionuclide used for plaque brachytherapy. Compared to 125I plaque the retinal dose in 106Ru is significantly larger [27]. Future studies need to investigate how the choice of radionuclide impacts visual outcome. All analyses were performed with respect to the physical and biologically effective doses. In most cases the physical dose was equally good or better as a predictor for visual acuity loss. One factor the BED accounts for is the dose rate. Regarding the clinical outcome this study found no correlation to dose rate. However, a similar study for secondary malignancies was not yet performed and requires more data. The present study suggested however, that no such correlation exists for VA loss as a clinical endpoint. To summarize, the present study showed that the retina dose is a good indicator for visual acuity loss. Especially in anterior tumors the additional information can help predicting visual outcome where other factors such as tumor location and macula dose fail.
Conflict of interest statement The persons listed as authors of this submitted publication certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.
Acknowledgments The study was financially supported by the Austrian Science Fund (FWF) Project No. P25936.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.radonc.2017.11. 010. References [1] Bergman L, Nilsson B, Lundell G, Lundell M, Seregard S. Ruthenium brachytherapy for uveal melanoma, 1979–2003: survival and functional outcomes in the Swedish population. Ophthalmology 2005;112:834–40. https://doi.org/10.1016/j.ophtha.2004.11.038. [2] Damato B, Patel I, Campbell IR, Mayles HM, Errington RD. Local tumor control after 106Ru brachytherapy of choroidal melanoma. Int J Radiat Oncol Biol Phys 2005;63:385–91. https://doi.org/10.1016/j.ijrobp.2005.02.017. [3] Zehetmayer M. Stereotactic photon beam irradiation of uveal melanoma. Dev Ophthalmol 2012;49:58–65. https://doi.org/10.1159/000328259. [4] Georg D, Dieckmann K, Bogner J, Zehetmayer M, Pötter R. Impact of a micromultileaf collimator on stereotactic radiotherapy of uveal melanoma. Int J Radiat Oncol Biol Phys 2003;55:881–91. https://doi.org/10.1016/S0360-3016 (02)04119-6. [5] Dendale R, Lumbroso-Le Rouic L, Noel G, Feuvret L, Levy C, Delacroix S, et al. Proton beam radiotherapy for uveal melanoma: results of Curie Institut-Orsay proton therapy center (ICPO). Int J Radiat Oncol Biol Phys 2006;65:780–7. https://doi.org/10.1016/j.ijrobp.2006.01.020. [6] Castro J, Char D, Petti P, Daftari I, Quivey J, Singh R, et al. 15 years experience with helium ion radiotherapy for uveal melanoma. Int J Radiat Oncol Biol Phys 1997;39:989–96. https://doi.org/10.1016/S0360-3016(97)00494-X. [7] Jampol LM, Moy CS, Murray TG, Reynolds SM, Albert DM, Schachat AP, et al. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: IV. Local treatment failure and enucleation in the first 5 years after brachytherapy. COMS report no. 19. Ophthalmology 2002;109:2197–206. https://doi.org/10.1016/S0161-6420(02)01277-0. [8] Dunavoelgyi R, Dieckmann K, Gleiss A, Sacu S, Kircher K, Georgopoulos M, et al. Local tumor control, visual acuity, and survival after hypofractionated stereotactic photon radiotherapy of choroidal melanoma in 212 patients treated between 1997 and 2007. Int J Radiat Oncol 2011;81:199–205. https:// doi.org/10.1016/j.ijrobp.2010.04.035. [9] 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. Int J Radiat Oncol Biol Phys 2005;63:373–84. https://doi.org/10.1016/j.ijrobp.2005.01.057. [10] Dieckmann K, Georg D, Zehetmayer M, Bogner J, Georgopoulos M, Pötter R. LINAC based stereotactic radiotherapy of uveal melanoma: 4 years clinical experience. Radiother Oncol 2003;67:199–206. https://doi.org/10.1016/ S0167-8140(02)00345-6. [11] Damato B, Patel I, Campbell IR, Mayles HM, Errington RD. Visual acuity after Ruthenium(106) brachytherapy of choroidal melanomas. Int J Radiat Oncol Biol Phys 2005;63:392–400. https://doi.org/10.1016/j.ijrobp.2005.02.059. [12] Shields CL, Shields JA, Cater J, Gündüz K, Miyamoto C, Micaily B, et al. Plaque radiotherapy for uveal melanoma: long-term visual outcome in 1106 consecutive patients. Arch Ophthalmol 2000;118:1219–28. https://doi.org/ 10.1097/00132578-200104000-00007. [13] Aziz HA, Singh N, Bena J, Wilkinson A, Singh AD. Vision loss following episcleral brachytherapy for uveal melanoma: development of a vision prognostication tool. JAMA Ophthalmol 2016;44106:615–20. https://doi.org/ 10.1001/jamaophthalmol.2016.0104. [14] Anastassiou G, Bornfeld N, Schueler a O, Schilling H, Weber S, Fluehs D,, et al. Ruthenium-106 plaque brachytherapy for symptomatic vasoproliferative tumours of the retina. Br J Ophthalmol 2006;90:447–50. https://doi.org/ 10.1136/bjo.2005.081422. [15] Verschueren KMS, Creutzberg CL, Schalij-Delfos NE, Ketelaars M, Klijsen FLL, Haeseker BI, et al. Long-term outcomes of eye-conserving treatment with Ruthenium(106) brachytherapy for choroidal melanoma. Radiother Oncol 2010;95:332–8. https://doi.org/10.1016/j.radonc.2010.03.023. [16] Peer J, Damato B, Zehetmayer M, Desjardins L, Lumbroso-Le Rouic L, LevyGabriel C. Current concepts in uveal melanoma. In: Jager M, Desjardins L, Kivelä T, Damato B, editors. Dev Ophthalmol. Basel: Karger; 2012. p. 1–65. [17] Pötter R, Van Limbergen E, Melanoma Uveal. In: GEC ESTRO handb brachytherapy. ESTRO; 2002. p. 591–610. [18] Dieckmann K, Bogner J, Georg D, Zehetmayer M, Kren G, Pötter R. A linac-based stereotactic irradiation technique of uveal melanoma. Radiother Oncol 2001;61:49–56. https://doi.org/10.1016/S0167-8140(01)00413-3. [19] 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;217:315–9. https://doi.org/10.1159/ 000071345. [20] Heilemann G, Fetty L, Dulovits M, Blaickner M, Nesvacil N, Georg D, et al. Treatment plan optimization and robustness of 106Ru eye plaque brachytherapy using a novel software tool. Radiother Oncol 2017;123 (1):119–24. https://doi.org/10.1016/j.radonc.2017.01.010. [21] Heilemann G, Nesvacil N, Blaickner M, Kostiukhina N, Georg D. Multidimensional dosimetry of 106Ru eye plaques using EBT3 films and its
Please cite this article in press as: Heilemann G et al. Retina dose as a predictor for visual acuity loss in nomas. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2017.11.010
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impact on treatment planning. Med Phys 2015;42:5798–808. https://doi.org/ 10.1118/1.4929564. [22] Dale RG, Jones B. The clinical radiobiology of brachytherapy. Br J Radiol 1998;71:465–83. https://doi.org/10.1259/bjr.71.845.9691890. [23] Gagne NL, Leonard KL, Huber KE, Mignano JE, Duker JS, Laver NV, et al. BEDVH—A method for evaluating biologically effective dose volume histograms: Application to eye plaque brachytherapy implants. Med Phys 2012;39:976. https://doi.org/10.1118/1.3679010. [24] Gagne NL, Leonard KL, Rivard MJ. Radiobiology for eye plaque brachytherapy and evaluation of implant duration and radionuclide choice using an objective function. Med Phys 2012;39:3332. https://doi.org/10.1118/1.4718683.
[25] Perez BA, Mettu P, Vajzovic L, Rivera D, Alkaissi A, Steffey BA, et al. Uveal melanoma treated with iodine-125 episcleral plaque: an analysis of dose on disease control and visual outcomes. Int J Radiat Oncol Biol Phys 2014;89:127–36. https://doi.org/10.1016/j.ijrobp.2014.01.026. [26] Wisely CE, Hadziahmetovic M, Reem RE, Hade EM, Nag S, Davidorf FH, et al. Long-term visual acuity outcomes in patients with uveal melanoma treated with 125I episcleral OSU-Nag plaque brachytherapy. Brachytherapy 2016;15:12–22. [27] Wilkinson DA, Kolar M, Fleming PA, Singh AD. Dosimetric comparison of 106Ru and 125I plaques for treatment of shallow choroidal melanoma lesions. Br J Radiol 2008;81:784–9. https://doi.org/10.1259/bjr/76813976.
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