Brachytherapy
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A new delivery system to resolve dosimetric issues in intravascular brachytherapy Joseph M. DeCunha1,*, Shirin A. Enger2,3 2
1 Department of Physics, Medical Physics Unit, McGill University, Montreal, Quebec, Canada Medical Physics Unit, Department of Oncology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada 3 Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
ABSTRACT
PURPOSE: Renewed interest is being expressed in intravascular brachytherapy (IVBT). A number of unresolved issues exist in the discipline. Providing a homogeneous and adequate dose to the target remains difficult in IVBT. The guidewire that delivers the device to the target, arterial plaques, and stent struts are all known to reduce the dose delivered to target. The viability and efficacy of a proposed IVBT delivery system designed to resolve the issue of guidewire attenuation is evaluated and compared to that of a popular and commercially available IVBT device. METHODS AND MATERIALS: Monte Carlo simulations are conducted to determine distributions of absorbed dose around an existing and proposed IVBT delivery system. RESULTS: For the Novoste Beta-Cath 3.5F (TeamBestÒ), dose in water varies by 10% as a function of angle in the plane perpendicular to the delivery catheter due to off-centering of seeds in the catheter. Dose is reduced by 52% behind a stainless steel guidewire and 64% behind a guidewire, arterial plaque, and stent strut for the Novoste Beta-Cath 3.5F. Dose is not perturbed by the presence of a guidewire for the proposed device and is reduced by 46% by an arterial plaque and stent strut. CONCLUSIONS: Dose attenuation by guidewire is likely the single greatest source of dose attenuation in IVBT in terms of absolute dose reduction and is greater than previously reported for the Novoste Beta-Cath 3.5F. The Novoste Beta-Cath 3.5F delivers an inhomogeneous dose to target. A delivery system is proposed, which resolves the issue of guidewire attenuation in IVBT and should reduce treatment times. Ó 2018 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Intravascular; Brachytherapy; Physics; Restenosis
Introduction Outstanding issues in intravascular brachytherapy Intravascular brachytherapy (IVBT) is a form of radiotherapy used to cause cell death of proliferating neointimal tissue after stenting and prevent in-stent restenosis (ISR). IVBT has seen reduced use since the advent and adoption of drug-eluting stents (DESs) in the early 2000s. However, a need for IVBT still exists. Patients receiving
Received 12 November 2017; received in revised form 24 January 2018; accepted 27 January 2018. * Corresponding author. Department of Physics, Medical Physics Unit, McGill University, Cedars Cancer Centre, DS1.7141, 1001 boul Decarie, Montreal, Quebec, H4A 3J1, Canada. Tel.: (514) 934-1934 x44158; fax: (514) 934-8229. E-mail address:
[email protected] (J.M. DeCunha).
sirolimus- and paclitaxel-eluting stents required coronary reintervention 13.1% and 15.1% of the time at 5 years, respectively (1). The typical modality of treatment for patients whose DES failed is to insert another DES at the initial site of stent failure. IVBT has been shown to be a safe and effective treatment for patients with recurrent DES failure (2,3). A need for IVBT is still being communicated by cardiologists; a 2016 editorial in the Journal of the American College of Cardiology calls for the use of IVBT for patients with DES failure (4). About 500,000 patients receive angioplasty each year in the United States (5). If just 10% of patients receiving coronary angioplasty each year require coronary reintervention, the number of patients who could benefit from IVBT is 50,000 annually. If IVBT is shown to be an effective adjunct or cotherapy to DES, then the number of patients that would benefit from IVBT may be much greater.
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With renewed interest being expressed in IVBT for treatment of restenosis in patients with DES, the therapy may be undergoing a revival, as evidenced by an increase in sales of IVBT devices since 2010 (6). Despite this, a number of unresolved issues exist regarding IVBT. Dosimetry and treatment planning of IVBT is still limited, and ensuring that patients receive an appropriate dose of radiation in the target arterial walls continues to be a difficulty. Arterial plaques, stent struts, and the guidewire, which deliver the train of b-emitting radiation sources to the treatment site, are all known to absorb the energy from emitted b-particles and reduce the absorbed dose in the target volume. Previous work has demonstrated that dose reductions as high as 60% are possible in IVBT (7,8). The guidewire alone has been shown to reduce dose to the target volume by 35% from a 90Sr90Y-based IVBT afterloader (9). If IVBT is going to see continued and increased use, now seems an opportune time to resolve outstanding dosimetric issues to ensure treatments provide adequate dose to the target volume and to improve patient outcomes. We propose a new IVBT system with hollow cylindrical brachytherapy seeds such that the vascular guidewire can run within the radioactive seeds. We hypothesize that the proposed delivery system will remove localized dose reductions caused by the guidewire. The proposed delivery system may also reduce treatment times because of the placement of the radioisotope closer to the edge of the delivery catheter, increasing the dose rate to the target volume at a given radioisotope activity. Treatment times may also be reduced by the incorporation of more radioactive core material through hollow cylindrical seeds because the volume of a cylinder scales with the radius squared. Each of these factors motivates the investigation of the proposed IVBT delivery system. Aims The aim of this study was to evaluate the efficacy and viability of an optimized delivery system designed to
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resolve the problem of dose reduction due to guidewire interference in IVBT. Dose distributions around the proposed delivery system (or proposed device) are calculated in water and in a model of a human coronary artery using Monte Carlo (MC) methods. Dose distributions around the proposed delivery system are compared to those around a commercially available IVBT delivery system, the Novoste Beta-Cath 3.5F (Beta-Cath). Dose parameters are calculated for both the delivery systems, which may be of use in clinical treatment planning and for further theoretical research.
Methods Design of the proposed IVBT delivery system The only IVBT afterloader/delivery system still commercially available, the Beta-Cath (Fig. 1), was modeled according to information taken from several sources (10e12). The Beta-Cath is a 90Sr90Y-based system, which uses a hydraulic afterloader. Radioactive 90Sr90Y seeds of 0.32 mm diameter and 2.5 mm length are combined to form source trains of 30 mm, 40 mm, or 60 mm length depending on the lesion length. The seeds are composed of a sintered aluminum core (r 5 2.826 g=cm3 , 95% Al, 5% Al2 O3 ) with 0.03 mm of stainless steel (r 5 8.0 g=cm3 ) shielding on each side. A flexible steel jacket of diameter 0.445 mm further shields the seeds. The model of the Beta-Cath simulated in this study used a 40-mm source train (16 seeds arranged along the z-axis in one catheter). The outer catheter diameter of the delivery system is 0.9 mm, and the combined catheter and guidewire displace a volume of 2.9 mm3 =mm. The proposed IVBT device was designed to similar specifications as the Beta-Cath (Fig. 1). The middle and outer catheters of the proposed device were taken to be the same thickness as for the Beta-Cath (~0.1 mm), and
Fig. 1. Cross-sectional diagram of the IVBT devices modeled. (Left) Novoste Beta-Cath 3.5F device with double-lumened delivery catheter. (Right) Proposed device. IVBT 5 intravascular brachytherapy.
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J.M. DeCunha, S.A. Enger / Brachytherapy
the amount of water delivered by the afterloader to propel the radioactive seeds was designed to be similar (0.07 mm3 =mm). Fluid flowing between the middle and outer catheters propels the seeds to the target location while fluid returns to the afterloader between the middle catheter and guidewire. The hollow cylindrical seeds have an inner diameter of 0.78 mm, are 0.1 mm thick, are 2.5 mm in length, and have 0.03 mm of shielding on all sides of their sintered aluminum core (r 5 2.826 g=cm3 ). The volume of the sintered aluminum core is 0.244 mm3 per seed, which allows for 25% greater radioactive isotope material per seed than the Beta-Cath. The outer catheter of the device is 1.1 mm in diameter, and the device displaces a volume of 3.8 mm3 =mm. Simulation Dose calculation software was developed to evaluate the viability of IVBT delivery systems. Dose distributions from both the proposed IVBT delivery system and the Beta-Cath were determined inside a spherical water phantom of 400 mm radius. To evaluate the degree to which absorbed dose is attenuated by inhomogeneities, dose distributions from the two delivery systems were also calculated in a coronary artery model with calcified plaque and stent (Fig. 2). The model depicted an artery of reference vessel diameter 3.0 mm and a 0.5-mm thick plaque (r 5 1.45 g=cm3 ), which subtended the top 180 degrees of the vessel (13). Stainless steel stent struts (r 5 8.0 g=cm3 ) were placed 45 apart and covered 14% of the arterial wall surface area. The developed dose calculation software uses Geant4 MC toolkit version 10.02 (developed by the European Organization for Nuclear Research) patch 2 to simulate interactions of ionizing radiation with matter (14,15). The radioactive decay spectra used for the simulated radionuclides come from the Evaluated Nuclear Structure Data File (16). The PENELOPE physics model was used to model
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electromagnetic interactions including fluorescence and Auger electron emission. The cutoff value for production of secondary particles was set to an energy at which electrons travel a negligible distance in comparison to the voxel size (1 keV). Computations were performed on the GPC supercomputer at the SciNet HPC Consortium (17). Approximately 5 108 b-particles were generated in the decay process and tracked for each delivery system in both phantoms to ensure statistical uncertainties of less than 0.4% near the source and 2% in distant regions. Voxelization Task group report 149 (TG-149) of the American Association of Physicists in Medicine (AAPM) specifies the dose calculation formalisms that should be used in IVBT (12). Dose calculation formalisms are useful such that dose data can be easily imported into treatment planning systems and to ensure that data from different sources can be easily compared. TG-149 refers to dose formalisms previously specified in AAPM TG-43 and TG-60 and recommends their use for seed- and wire-based IVBT systems, respectively. TG-43 dose parameters quantify the dose profile around a single brachytherapy seed. The TG-43 standard consists of three functions that describe the angular dependence of dose, the distance dependence of dose, and the dose rate, which are known as the anisotropy function, radial dose function, and reference absorbed dose rate per unit activity, respectively. The TG-43 parameters were calculated for both delivery systems. Two models of the Beta-Cath seed were simulated for computation of the TG-43 anisotropy function, in which one modeled the seed alone and another included a 2.5-mm-length steel jacket. The recommendations of AAPM TG-149 were followed regarding TG-43 dose parameters, including the use of the line-source geometry function for both systems. The source length of each
Fig. 2. Cross-sectional diagram of the artery model used. (Left) Nonstenoted region of reference vessel diameter 3 mm. (Right) Stenoted region of 20 mm length in which the device is centered.
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seed was taken to be 2.5 mm for computation of the geometry function. To calculate the TG-43 dose parameters, dose was scored in a spherical voxelization. For calculation of the anisotropy function, voxels were 0.2 mm thick radially and subtended 0.5 in theta. For calculation of the radial dose function, voxels were 0.09 mm thick radially and subtended 2 in theta. TG-43 dose parameters of the Beta-Cath are compared to those in the study by Wang and Li (18), which is the data set recommended for consensus dosimetry by AAPM TG-149. TG-60 dose parameters quantify the dose profile around an entire IVBT delivery system, consisting of the catheter, all the seeds of the source train, and occasionally the guidewire. The TG-60 parameters consist of three functions that describe the dose along the length of the delivery system, radially away from the delivery system, and the dose rate, which are known as the nonuniformity function, transverse dose function, and reference absorbed dose rate. The TG-60 parameters were calculated for both delivery systems. A cylindrical voxelization was constructed to measure dose that adhered to the TG-60 standard. The cylindrical voxels were 0.1 mm thick in radius, 0.5 mm along the z-axis, and subtended 2 in theta (Fig. 3 depicts the TG-43 and TG-60 coordinate systems). The cylindrical voxelization was centered about the center of the delivery catheter for each device. For the Beta-Cath, this results in the center of the voxelized region being shifted 0.05 mm down from the center of the brachytherapy seed as the seeds are off-centered in the delivery catheter. Both the delivery systems were centered in the artery model (center of the delivery catheter equidistant to tunica intima at all points, see Fig. 2). In this study, dose information beyond the current formalisms is presented. The TG-60 dose formalism does not consider dose variations in theta. To fully appreciate localized dose reductions, absorbed dose must be considered as a function of theta around the radiation source.
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To compare dose homogeneity around the radioactive seeds, the absorbed dose in the artery model is compared with the absorbed dose in the water phantom. By normalizing the dose in the artery model to the dose in the water phantom at 180 along the same radius, one can quantify changes in dose as a function of theta, which are present in water and in the artery model. This normalization method is different from our previous work in which dose in the artery phantom was normalized to the dose in the water phantom at the same location (7). Results TG-43 dose parameters Values of the anisotropy function of a single seed of the Beta-Cath with and without a steel jacket calculated in this study are compared to consensus dosimetry at a series of radial distances and presented in Fig. 4. At distances greater than 2 mm and for clinically relevant angles of 20 e90 , the calculated values without jacket adhere closely to the consensus dosimetry. At shallow angles, the anisotropy functions differ by up to 10%. The anisotropy function of the Beta-Cath seed with a jacket agrees more closely with the consensus dosimetry than the anisotropy function without a jacket at shallow angles. The calculated anisotropy function for a single seed of the Beta-Cath without jacket is presented in Table 1 for radial distances from 1 mm to 8 mm. Figure 4 also depicts the anisotropy function of the proposed device at a series of radial distances. At shallow angles, the value of the anisotropy function of the proposed device is higher than that of the Beta-Cath. For distances greater than 1 mm and theta between 20 and 90 , the anisotropy function of the proposed device typically varies by less than 3% from the Beta-Cath. The calculated anisotropy function for the proposed device is presented in Table 1 for radial distances from 1 mm to 8 mm.
Fig. 3. Coordinate system relative to a single brachytherapy seed oriented with its length along the z-axis. (Left) TG-43 convention. (Right) TG-60 convention. TG 5 task group report.
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Fig. 4. TG-43 anisotropy function of a single seed at various radii. (Left) Our calculated values for the Novoste Beta-Cath 3.5F and consensus dosimetry. (Right) Our calculated value for the Novoste Beta-Cath 3.5F and the proposed device. TG 5 task group report.
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0.999 0.990 0.985 0.981 0.984 0.976 0.982 0.975 1.002 0.991 0.984 0.980 0.985 0.979 0.979 0.980 0.994 0.974 0.965 0.964 0.967 0.968 0.974 0.985 1.008 0.973 0.963 0.962 0.966 0.968 0.969 0.988 0.992 0.955 0.944 0.945 0.952 0.955 0.973 1.003 1.027 0.950 0.940 0.943 0.952 0.962 0.977 1.000 0.992 0.942 0.933 0.931 0.943 0.952 0.970 1.006 1.042 0.934 0.925 0.929 0.941 0.955 0.973 1.011
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Figure 5 compares the radial dose function values calculated in this study and the consensus dosimetry for a single unjacketed seed of the Beta-Cath device. The values differ up to 3% at 5-mm radial distance. The calculated radial dose function values for a single unjacketed seed of the Beta-Cath and the proposed device are also compared in Fig. 5. The values vary by less than 2.5% at all distances greater than 1.5 mm. At 1 mm, the radial dose function of the proposed device is 8% greater than that of the Beta-Cath. The reference absorbed dose rate per unit activity of the unjacketed Beta-Cath as calculated in this study and derived by Wang and Li is 1.15 and 1.10 Gy=min mCi, respectively. The reference absorbed dose rate per unit activity of the proposed device is 1.14 Gy=min mCi. The values calculated by our software differ by less than 1%.
0.761 0.792 0.820 0.847 0.874 0.918 0.996
0.793 0.815 0.840 0.865 0.892 0.930 0.989 0.744 0.773 0.802 0.832 0.857 0.901 0.977 0.742 0.757 0.789 0.815 0.849 0.888 0.968 0.762 0.742 0.774 0.794 0.836 0.881 1.015
0.764 0.749 0.774 0.808 0.830 0.910 0.978
0.763 0.745 0.772 0.802 0.836 0.893 0.961
0.760 0.750 0.779 0.807 0.841 0.889 0.977
0.758 0.747 0.778 0.806 0.839 0.892 0.972
0.751 0.751 0.780 0.806 0.842 0.886 0.962
0.746 0.756 0.783 0.811 0.839 0.886 0.978
1.017 0.821 0.812 0.824 0.846 0.871 0.917 0.997 1.028 0.783 0.781 0.798 0.823 0.851 0.899 0.987 0.745 0.752 0.776 0.801 0.831 0.881 0.983 0.715 0.727 0.753 0.783 0.814 0.874 0.970 Proposed device
1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 Novoste Beta-Cath 3.5F (without jacket)
0.697 0.686 0.718 0.750 0.779 0.841 0.958
0.701 0.694 0.722 0.750 0.791 0.845 0.956
0.702 0.691 0.725 0.756 0.794 0.831 0.957
0.701 0.698 0.727 0.761 0.794 0.847 0.953
0.699 0.698 0.732 0.767 0.797 0.848 0.959
0.700 0.707 0.735 0.768 0.802 0.853 0.973
0.704 0.716 0.744 0.775 0.811 0.851 0.967
30 1
2
3
5
7
10
12
25 20
TG-60 dose parameters
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0.826 0.836 0.860 0.882 0.907 0.939 1.015
0.997 0.909 0.896 0.899 0.913 0.929 0.962 1.021 1.092 0.889 0.888 0.898 0.915 0.933 0.960 1.005 1.002 0.884 0.870 0.875 0.892 0.912 0.942 1.016 1.132 0.860 0.864 0.880 0.899 0.919 0.954 1.004 1.009 0.854 0.841 0.850 0.868 0.892 0.933 1.014
0.994 0.931 0.916 0.918 0.928 0.942 0.969 1.016 1.064 0.915 0.906 0.915 0.931 0.946 0.968 1.004
80 70 60 55 50 45 40 35
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Dose as a function of theta
r (mm)
q (degrees)
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Figure 6 shows the transverse dose function and nonuniformity function, respectively, of the Beta-Cath and the proposed device. The transverse dose function of the proposed device is 5% higher than that of the Beta-Cath at 1 mm and differs by less than 0.5% at distances from 2 to 4.5 mm. The nonuniformity function of the proposed device and Beta-Cath is in close agreement and differs by less than 0.5% along the length of the source train.
Device
Table 1 Values of the anisotropy function for a single seed of the Novoste Beta-Cath 3.5F (without jacket) and proposed device
1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000
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Figure 7 presents dose as a function of theta (as defined in the TG-60 convention) at a radial distance of 2 mm from the radioactive seeds and at the axial center of the delivery systems (z 5 0) for the Beta-Cath and the proposed device. The absorbed dose around the proposed device is homogeneous in water, and no localized dose reductions are observed from the presence of the guidewire, while the absorbed dose is reduced by 52% behind the guidewire for the Beta-Cath. Dose around the Beta-Cath also varies in theta due to the off-centering of the radioactive seeds in the delivery catheter as shown in Fig. 1. The dose at the ‘‘bottom’’ of the catheter (about 270 ) is reduced by as much as 10% compared to the dose at 180 . In the artery phantom, dose as a function of theta at r 5 2 mm and z 5 0 mm is compared for the Beta-Cath and the proposed device. For both devices, pronounced dose reductions are observed at 45 intervals where stent struts are located. Dose is reduced by 64% behind a guidewire, plaque, and stent strut for the Beta-Cath and by 46% for the proposed device in the same location. Dose distributions around both delivery systems at z 5 0 in the artery model are shown in Fig. 8. Dose is normalized to 20 Gy at 2 mm in water. The proposed device demonstrates smaller average and maximal dose reductions in the artery model at both 2 mm and 4 mm compared to the Beta-Cath (Table 2). In regions unconcluded by a
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Fig. 5. TG-43 radial dose functions. (Left) Novoste Beta-Cath 3.5F.Our values without jacket (diamond) and Wang and Li (circle). (Right) Novoste BetaCath 3.5F without jacket (diamond) and proposed device (triangle). TG 5 task group report.
guidewire, plaque, and stent strut, both devices show less than 1% dose reduction compared to in water.
Discussion The treatment of patients whose DES failed is revealing itself as a nontrivial and pervasive problem in modern interventional cardiology. Rates of restenosis in patients with ISR can be as high as 20% in some at-risk groups (19). This is not a trivial patient population given the half-million patients implanted with stents each year in the United States (5). Current methods to treat ISR for patients with DES are not more effective than repeated DES. The use of drug-eluting balloons has been proposed as a treatment modality for patients with DES ISR; however, meta-analysis has indicated that implantation of additional DES is still a more effective treatment than the use of drug-eluting balloons (20). Similarly, bioabsorbable stents, once hoped to be the next watershed technology that may replace DES, have not yet proven to be a superior technology (21).
As improvements in therapies to treat ISR reach a roadblock and the limitations of DES are becoming evident, now seems an important time to begin the modernization and resolution of outstanding issues in IVBT. In this study, we have proposed improvements to the design of a currently available IVBT system, the Novoste Beta-Cath 3.5F, to resolve the problem associated with dose reductions caused by guidewire interference in IVBT. This allows for the delivery of a more homogenous dose distribution to the target, with improved therapeutic ratio and clinical outcomes as end goals. A complete dosimetric profile of the Beta-Cath and the proposed device is discussed in detail in the following sections, including TG-43 and TG-60 dose parameters along with dose in the plane around each delivery system. In brief, inherent off-centering of the radioactive seeds in the delivery catheter of the Beta-Cath causes dose variations in theta as large as 10% that are not observed around the proposed device. Dose is reduced by 52% by a guidewire alone for the Beta-Cath and by 64% behind a guidewire, arterial plaque, and stent strut at 2 mm. Dose
Fig. 6. Comparison of TG-60 dose parameters of the Novoste Beta-Cath 3.5F device and proposed device. (a) Transverse dose function and (b) nonuniformity function.
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TG-43 and TG-60 dose parameters
Fig. 7. Comparison of the absorbed dose 2 mm away from each device as a function of theta about z 5 0. Dose is normalized to 1 (d 5 1) at 180 for each device. (Top) Both devices in water. (Middle) Novoste Beta-Cath 3.5F. (Bottom) Proposed device.
reduced by the guidewire of the Beta-Cath alone is greater than that previously reported (9). No dose reductions are observed from the guidewires for the proposed device, and the dose is reduced by 46% behind an arterial plaque and stent strut at 2 mm.
Since the publication of AAPM TG-149 in 2007, MC dosimetry in IVBT has been sparse. All of the existing reference dosimetry of Food and Drug Administration approved IVBT devices was published in 2004 and prior and are presented in AAPM TG-149 (12). This work is the first to present TG-43 parameters for the Novoste Beta-Cath calculated using Geant4. There are only two other published sources of TG-43 parameters for the Beta-Cath computed by an MC-based approach (18,22). MC work in IVBT in the last decade consists only of a few works investigating new devices for which no physical prototype exists or estimating dose perturbations by heterogeneities (7,23). We present complete dosimetric profiles of the BetaCath and the proposed delivery system given in both the TG-43 and TG-60 dose formalisms. Comparisons of our TG-43 dose parameters to current consensus dosimetry reveal discrepancies in the anisotropy function. There are possible explanations for this discrepancy, which are apparent to us. The first is that the consensus dosimetry provided in AAPM TG-149 for the Beta-Cath 3.5F model uses parameters calculated for the Beta-Cath 5F model. The models are dosimetrically similar, and dosimetry between the models is not always distinguished. The work of Wang and Li notes that the anisotropy function of the 3.5F model at 1 mm is reduced by up to 10% compared to the 5F consensus dosimetry but adheres closely at all other distances (18). This explains the discrepancy between our calculated anisotropy functions and the consensus dosimetry at 1 mm. At distances greater than 1 mm, the anisotropy function calculated with a steel jacket present agrees more closely with the consensus data at shallow angles of theta, while the anisotropy function without jacket is in closer agreement for theta between 20 and 90 . The failure of either model to agree within 5% to the consensus data at all angles suggests that factors other than the presence of the steel jacket alone caused discrepancies between our anisotropy function and that of Wang and Li. Wang and Li modeled source seeds with a jacket and a ceramic core, and their dose distributions were calculated using the National Research Council of Canada’s, Electron Gamma Shower with different libraries for decay spectra, physics models, and interaction cross-sections; each of these factors may have caused discrepancies between their anisotropy functions and our work. For our calculation of TG-60 dose parameters, a complete description of the Beta-Cath including the stainless steel jacket and multiple layers of catheter was included. Our TG-60 dose parameters have been previously verified by comparison to reference dosimetry (7). Presentation of the TG-43 and the TG-60 parameters mentioned previously allows for the use of such parameters by other investigators to further investigate IVBT devices and are suitable for use in the clinic to conduct treatment planning.
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Fig. 8. Dose as a function of theta and radii about z 5 0 in the artery phantom for each device. Dose is normalized to 20 Gy at 2 mm in the water phantom for each device. (Left) Novoste Beta-Cath 3.5F. (Right) Proposed device.
Dosimetric issues The results presented in this study indicate that the presence of a cardiac guidewire is likely the greatest single source of dose attenuation in IVBT in terms of absolute dose reduction, with a stainless steel guidewire reducing dose by 52% in a localized region for the Beta-Cath. The results presented previously, along with our previous work and the work of others, indicate that the presence of guidewires, arterial plaques, and stents cause nonnegligible dose reductions in IVBT (7,8). Our work reaffirms the existence and severity of dosimetric issues in IVBT and the importance of reporting data that goes beyond both the TG-43 and TG-60 formalisms. The TG-43 formalism does not consider dose in phi, and the TG-60 formalism does not consider dose variation in theta; both of these approximations prevent one from fully quantifying dose perturbations that may affect only a small angular region (e.g., guidewires, stent struts, and plaques). The investigation of the proposed delivery system demonstrates the viability and potential benefits of the use of cylindrical shell radioactive seeds in IVBT. The proposed delivery system resolves the issue of guidewire attenuation without changing current practice. Despite the radioisotope being placed closer to the edge of the delivery catheter, hopes that this would increase the dose rate to the target volume at a given radioisotope activity did not materialize. Regardless, the cylindrical shell seed geometry increases the available source volume, which allows for an increase in radioactive material by 25% compared to the Beta-Cath system. This will also allow treatment times to
be reduced, which may improve patient safety by reducing the amount of time that blood flow is occluded. The future of IVBT The use of g-emitting radioisotopes has been previously suggested as a means of resolving dosimetric issues in IVBT. Although it is known that g-emitting IVBT delivery systems have dose profiles that are insensitive to the presence of heterogeneities (8) and such devices have been commercially produced (Cordis Checkmate, 192Ir), it seems unlikely that they will be reintroduced at this time for two reasons. The use of g-emitting radioisotopes in IVBT fundamentally changes current practice. IVBT is typically given in the catheterization laboratory immediately after emergency angioplasty, and the catheterization team typically remains in the room while the sources dwell at the target lesion. If g-emitting radioisotopes are used, radiation shielding becomes necessary. Depending on the energy of the g-emitting radioisotope, the IVBT procedure may occur in the catheterization laboratory or the patient may have to be transported to shielded bunkers in radiotherapy centers. Furthermore, the standard of treatment in radiotherapy has developed from the time that g-emitting IVBT sources were initially used that it seems unlikely that regulatory agencies or individual institutions will be willing to accept the use of g-emitting radioisotopes without the presence of a rigorous analysis of dose to personnel and dose to the patient’s organs at risk (OARs). OAR analysis is not currently a standard part of IVBT practice. In order for OAR analysis
Table 2 Summary of results from dosimetric analysis in artery phantom 2 mm Device Novoste Beta-Cath Proposed device
Min. dose reduction 0.6% 4.2%
4 mm Avg. dose reduction
Max. dose reduction
18.4% 10.1%
64.0% 35.8%
Min. dose reduction 0.4% 2.1%
Avg. dose reduction
Max. dose reduction
16.6% 6.9%
46.2% 15.4%
Min 5 minimal; Avg 5 average; Max 5 maximal.
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10
J.M. DeCunha, S.A. Enger / Brachytherapy
of IVBT patients to become part of standard practice, CT angiography or other appropriate imaging will have to be performed on IVBT patients. Given the difficulties regarding the use of g-emitting radioisotopes in IVBT, it is encouraging that our results indicate that the issue of guidewire dose attenuation in IVBT can be resolved by the optimization of currently available IVBT delivery systems, without using a new radioisotope or significantly modifying current practice. One hopes that other modifications may be proposed, which can resolve the issue of dose perturbations by stent struts and arterial plaques. If dose attenuation by these factors is resolved and OAR analysis is introduced to IVBT, IVBT may again be thought of as being among other modern forms of radiotherapy. In response to calls from the cardiology community for the reintroduction of IVBT (4), we hope that our proposed delivery system and other developments allow for the introduction of a second generation of IVBT delivery systems that will improve patient outcomes and patient safety and present a viable solution to the problem of DES ISR. Conclusions There exist issues in IVBT, which have yet to be resolved. There is a continued need being organically expressed for IVBT to treat patients with recurrent DES failure. If IVBT is to see continued use, these issues should be examined and potential solutions should be investigated. Dose attenuation by the guidewire is likely the single greatest source of dose reductions in IVBT in terms of absolute dose reduction. We propose a delivery system that resolves the issue of guidewire attenuation in IVBT and should reduce treatment times without significantly changing current practice. If dosimetric issues in IVBT are resolved, treatment outcomes may improve and IVBT could present itself as the standard therapy for patients whose DES failed. Acknowledgments The authors acknowledge support from the Natural Sciences and Engineering Research Council discovery grant number 241018 and CREATE medical physics training network grant number 432290. Computations were performed on the GPC supercomputer at the SciNet HPC Consortium. SciNet is funded by the Canada Foundation for Innovation under the auspices of Compute Canada, the Government of Ontario, Ontario Research Funde Research Excellence, and the University of Toronto (17). References [1] Raber L, Wohlwend L, Wigger M, et al. Five-year clinical and angiographic outcomes of a randomized comparison of sirolimus-eluting and paclitaxel-eluting stents. Circulation 2011;123:2819e2828.
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[2] Negi S, Torguson R, Gai J, et al. Intracoronary brachytherapy for recurrent drug-eluting stent failure. JACC Cardiovasc Interv 2016; 9:1259e1265. [3] Ohri N, Sharma S, Kini A, et al. Intracoronary brachytherapy for instent restenosis of drug-eluting stents. Adv Radiat Oncol 2016;1:4e9. [4] Williams D, Sobieszczyk P. Coronary brachytherapy 2016. JACC Cardiovasc Interv 2016;9:1266e1268. [5] Mozaffarian D, Benjamin E, Go A, et al. Heart disease and stroke statisticse2016 update. Circulation 2015;134:e1ee324. [6] Reed C. Status of intravascular brachytherapy (IVB). Available at: http://chapter.aapm.org/nccaapm/z_meetings/2016-10-21/04_Agendaand-Presentations/0845_Reed.pdf 2016;. Accessed January 21, 2018. [7] Decunha J, Janicki C, Enger SA. A retrospective analysis of catheterbased sources in intravascular brachytherapy. Brachytherapy 2017; 16:586e596. [8] Li XA, O’Neill M, Suntharalingam M. Improving patient-specific dosimetry for intravascular brachytherapy. Brachytherapy 2005;4: 291e297. [9] Demir B, Demir N, Ahmed AS. The effects of non-centred catheter and guidewire on the dose distribution around source in catheterbased intravascular brachytherapy with 90Sr/90Y beta source. Radiat Meas 2006;41:317e322. [10] Roa DE, Song H, Yue N, et al. Measured TG-60 dosimetric parameters of the Novoste Beta-Cath 90Sr/Y source trains for intravascular brachytherapy. Cardiovasc Radiat Med 2002;3:199e204. [11] Beta-cath 3.5F system U.S. customer training program. Available at: www.patlitfundamentals.com/PatentLitClassDocts/D01564D.ppt. Accessed January 21, 2018. [12] Chiu-Tsao ST, Schaart DR, Soares CG, et al. Dose calculation formalisms and consensus dosimetry parameters for intravascular brachytherapy dosimetry: Recommendations of the AAPM Therapy Physics Committee Task Group No. 149. Med Phys 2007;34: 4126e4157. [13] Murungi JI, Thiam S, Tracy RE, et al. Elemental analysis of soft plaque and calcified plaque deposits from human coronary arteries and aorta. J Environ Sci Health A Tox Hazard Subst Environ Eng 2004; 39:1487e1496. [14] Agostinelli S, Allison J, Amako K, et al. Geant4ea simulation toolkit. Nucl Instr Meth Phys Res 2003;506:230e303. [15] Allison J, Amako K, Apostolakis J, et al. Recent developments in Geant4. Nucl Instr Meth Phys Res 2016;835:186e225. [16] Bhat MR. Evaluated nuclear structure data file (ENSDF). In: Qaim SM, editor. Nuclear Data for Science and Technology. Berlin: Springer-Verlag; 1992. p. 817. [17] Loken C, Grunger D, Groer L, et al. SciNet: lessons learned from building a power-efficient top-20 system and data centre. JPCS 2010;256:1e35. [18] Wang R, Li XA. Dosimetric comparison of two 90Sr/90Y sources for intravascular brachytherapy an EGSnrc Monte Carlo calculation. Phys Med Biol 2002;47:4259e4269. [19] Lee M, Banka G. In-stent restenosis. Interv Cardiol Clin 2016;5: 211e220. [20] Lee JM, Rhee TM, Hahn JY, et al. Comparison of outcomes after treatment of in-stent restenosis using newer generation drug-eluting stents versus drug-eluting balloon: patient-level pooled analysis of Korean Multicenter in-Stent Restenosis Registry. Int J Cardiol 2017;230:181e190. [21] Palmerini T, Biondi-Zoccai G, Riva DD, et al. Clinical outcomes with bioabsorbable polymer- versus durable polymer-based drug-eluting and bare-metal stents. J Am Coll Cardiol 2014;63: 299e307. [22] Soares CG, Halpern D, Wang CK. Calibration and characterisation of beta-particle sources for intravascular brachytherapy. Med Phys 1998;25:339e346. [23] Sadeghi M, Taghdiri F, Hosseini SM, et al. TG-60 dosimetry parameters for the b emitter 153Sm brachytherapy source. Med Phys 2010;37:5370e5375.
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