Radiobiological Impact of Acuros XB Dose Calculation Algorithm on Low-Risk Prostate Cancer Treatment Plans Created by RapidArc Technique.

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1 Radiobiological Impact of Acuros XB Dose Calculation Algorithm on Low-Risk Prostate Cancer Treatment Plans Created by RapidArc Technique. 1,2 Suresh Rana, M.S., 2 Kevin Rogers, M.S. 1 Department of Medical Physics, ProCure Proton Therapy Center, 5901 West Memorial Road, Oklahoma City, OK 73142, USA. 2 Department of Radiation Oncology, Arizona Center for Cancer Care, N 83rd Avenue, #127, Peoria, Arizona 85381, USA. ABSTRACT Objective: The purpose of this study was to assess the radiobiological impact of Acuros XB dose calculation algorithm (AXB) on prostate cancer treatment plans created by RapidArc technique. Materials and Methods: A computed tomography (CT) dataset of ten patients with low-risk prostate cancer was selected for this retrospective study. The delineation of prostate, seminal vesicles and organs at risk (OARs) was done on the axial CT images. The treatment plans were created for 6 MV photon beam using RapidArc technique in the Varian Eclipse treatment planning system. The initial dose calculations on treatment plans were performed with Anisotropic Analytical Key words: Acuros XB, Anisotropic Analytical Algorithm, Prostate Cancer, TCP, NTCP, RapidArc.. Algorithm (AAA). Next, AXB plans were created by performing dose re-calculation using AXB for same number of monitor units and identical beam set up as in the corresponding AAA plans. Radiobiological modeling response evaluation was done by calculating Niemierko s Equivalent Uniform Dose (EUD)-based Normal Tissue Complication Probability (NTCP) and Tumor Control Probability (TCP) values. Additionally, the PTV coverage in AXB and AAA plans was evaluated. Results: The averaged TCP values of AAA plan (98.39%) and AXB plans (98.26%) were comparable with difference of 0.14% (P = ). The averaged NTCP values for bladder (P = 0.265) and femur heads (P = 0.281) were well below 0.1 % with no statistical significant differences. However, the averaged NTCP values for the rectum of 0.56 % (AAA) vs % (AXB) suggested the statistical significance (P = ). The PTV coverage in AXB plans was lower by an average 0.89% compared to AAA plans with no statistical significance (P = 0.254). Conclusion: Both the AAA and AXB predicted comparable NTCP and TCP values for low-risk prostate cancer plans created by RapidArc technique. The reduced PTV coverage due to dose re-calculation from AAA to AXB was observed. Corresponding author: Suresh Rana, M.S., Department of Medical Physics, ProCure Proton Therapy Center, 5901 West Memorial Road, Oklahoma City, OK 73142, USA. suresh.rana@gmail.com, Telephone:

2 Suresh Rana INTRODUCTION RapidArc (Varian Medical Systems, Palo Alto, CA) is a volumetric arc therapy (VMAT) technique that delivers modulated radiation beams with simultaneous adjustment of multi-leaf collimator (MLC) field aperture, dose rate and gantry rotation speed. 1, 2 The radiation dose distributions from RapidArc planning are conformal to the tumor while minimizing to the surrounding critical structures. 1, 2 One of the major components that plays a crucial role in the resultant dose distribution and extent of tumor dose heterogeneity is the dose calculation algorithm. 3 Thus, in order to achieve the best therapeutic advantage from RapidArc planning for prostate cancer, media heterogeneities in the photon beam path must be incorporated in the dose calculation algorithm. Moreover, the incident of modulated radiation beams from different directions results in dose heterogeneity within the tumor and small volumes of normal tissues receive doses higher than the prescribed dose. 3 Several authors have investigated the treatment planning for prostate cancer 4, 5, 6, 7, 8, 9 and reported the inconsistent dosimetric results mainly due to the variations found among these studies in terms of target shape, planning target volume (PTV) margins, planning techniques and objectives, beam angles, plan optimization methods and choice of dose calculation algorithm. 4 9 To the best of our knowledge, no previous study has been done on prostate cancer treatment plans investigating the radiobiological impact of commercially available new dose calculation algorithm called Acuros XB algorithm (AXB). Thus, it is important to further investigate how the choice of AXB in RapidArc planning will affect the radiobiological parameters for prostate cancer before using the AXB for real patient treatment cases. The objective of this study was to asses the radiobiological impact of AXB using real computed tomography (CT) data sets of low-risk prostate cancer patients. No comparison between AXB calculations and measurements or Monte Carlo simulations was exploited in this study. However, for the purpose of comparison, the results from prostate cancer treatment plans calculated by Anisotropic Analytical Algorithm (AAA) were used as the standard since AAA is widely tested and validated for radiation dose calculation. Both algorithms (AXB and AAA) are implemented within the Eclipse treatment planning system (TPS) (Varian Medical Systems, Palo Alto, CA). METHODS AND MATERIALS CT Simulation Ten patients with localized prostate cancer underwent through the AnchorMarker-fiducial markers (Biocompatibles, Inc., Oxford, CT) placement performed by the radiation oncologist at our cancer center. Prior to CT simulation, the patients were immobilized in a supine position on a flat tabletop of General Electric LightSpeed CT Scanner using head sponge and vac-lok cushions (CIVCO Medical Solutions, Kalona, Iowa). The CT scans were acquired with pixels at 0.25 cm slice spacing from the top of the iliac crests superiorly to the perineum inferiorly. All the CT images were verified by the radiation oncologist before transferring them via computer network to the Eclipse TPS for subsequent contouring and planning purposes Contouring The clinical target volume (CTV) comprised of prostate and seminal vesicles were contoured by the radiation oncologist on the axial CT slices. The organs at risk (OARs) such as rectum, bladder and femur heads were delineated based on the CT images. The planning target volume (PTV) was generated from the CTV by an isotropic expansion of 5 mm in all directions to compensate for the variability of treatment setup and internal organ motion. A shell-shaped avoidance structure called Ring was created at a distance of 5 mm from the PTV for the plan optimization process in order to achieve the conformal dose plans. Treatment Planning and Optimization Dose Prescription and Dose Constraints The total dose prescribed to the PTV was 79.2 Gy with a daily dose of 1.8 Gy to be treated in 44 fractions, and this treatment regimen was applied for all ten patients in this study. The dose constraints to the OARs summarized in TABLE 1 are based on the recommendation of Radiation Therapy Oncology Group (RTOG)

3 Radiobiological Impact of Acuros XB Dose Calculation Algorithm on... TABLE 1: Dose specification for OARs Normal Organ Limit* D15% D25% D35% D50% Rectum < 75 Gy < 70 Gy < 65 Gy < 60 Gy Bladder < 80 Gy < 75 Gy < 70 Gy <65 Gy Femoral Heads Mean Dose < 45 Gy *Normal organ limit refers to the volume of that organ that should not exceed the dose limit. Abbreviations: OAR = Organ at risk, Dx% = Dose received by X% of total OAR volume, where X % = 15, 25, 35 and 50. Treatment Plan Setup The beam parameters for prostate cancer treatment plans were set up in the Eclipse TPS (version ) using Varian Clinac ix with 120-leaf millennium MLC and 6X mode of 600 MU/min dose rate. All treatment plans were generated using a single coplanar arc and the Beam s-eye-view graphics in Eclipse TPS was used to define the field sizes. The isocenter of each treatment plan was placed at the center of prostate (Figure 1). Treatment Plan Optimization All treatment plans were generated using the volumetric dose optimization method that followed the same systematic strategy in regarding objectives and priorities, which are summarized in TABLE 2. Dose Calculation In this study, the plans computed by AAA and AXB (both include same version ) are referred as AAA and AXB plans respectively. First, initial dose calculation of the optimized plans was performed by AAA. The AAA plans were then normalized such that 100% of the prescribed dose covers the 95% of the PTV (V100 = 95%), and monitor units (MUs) from the normalized AAA plans were recorded. Second, the AXB plans were calculated using the identical beam setup and same number of MUs as in the normalized AAA plans. The dose calculation grid was set to 2.5 mm for all cases. Figure 1: A transversal view of RapidArc plan setup for prostate cancer using single arc technique. 263

4 Suresh Rana Table 2: Parameters used to calculate Niemierko s EUD-based TCP and NTCP Tissue Volume Type 100% dpf #f a γ 50 TD 50 (Gy) TCD 50 (Gy) Dpf(Gy) α/β(gy) Prostate Tumor Rectum Normal Bladder Normal Femur Normal Abbreviations: 100% dpf = 100% dose per fraction; # f =number of fractions; α/β = alpha-beta ratio; and dpf= parameters source data s dose per fraction; EUD = Equivalent Uniform Dose, TCP = Tumor Control Probability, NTCP = Normal Tissue Complication Probability, Femur = Femur Heads Since this study was focused on real clinical usage of AAA and AXB, only brief introduction of dose calculation algorithms are presented. The AXB, first published by Vassiliev et al., 10 solves numerically Linear Boltzmann Transport Equation (LBTE) which describes the macroscopic behavior of radiation particles as they travel through and interact with matter. The AXB is considered to be similar to classic Monte Carlo methods for accurate modeling of dose deposition in heterogeneous media. 10, 11, 12 Since AXB explicitly solves for radiation transport in materials, the by default dose reporting mode in AXB is dose-to-medium (Dm) and we selected Dm for all the AXB calculations in this study. The AAA, first developed by Ulmer et al., 13, 14 and Tillikainen et al. 15, 16 is an analytical photon dose calculation algorithm based on a pencil-beam convolution/superposition technique. The beam model for AAA include separately-modeled contributions from three different photon sources and the tissue heterogeneity is handled by radiologic scaling of primary photons and photon scatter kernel scaling in lateral directions according to local electron density For more detailed descriptions on the AAA and AXB, readers are advised to refer to publications by Tillikainen et al. 15, 16 and Vassilev et al. 10 Radiobiological Modeling For radiobiological model response evaluation, cumulative dose-volume histograms (DVHs) of calculated treatment plans (AAA and AXB) were exported from the Eclipse TPS using dose bins of 40 cgy. The MATLAB and Simulink Student Version -R2012a (The MathWorks, Inc., Natick, Massachusetts) was used for radiobiological modeling analysis. We utilized the MatLab program 17 to calculate the Niemierko s Equivalent Uniform Dose (EUD)-based Normal Tissue Complication Probability (NTCP) and Tumor Control Probability (TCP) values. The Niemierko s phenomenological model was based on the original definition of the EUD that was derived on the basis of a mechanistic formulation using a linear-quadratic (LQ) cell survival model. 17, 18 According to Niemierko s phenomenological model, EUD 17, 19 is defined as a ( ( )) 1 a v i EQD i EUD = i = 1 (1) This model can be used for both tumors and normal tissues. In equation (1), a is a unit less model parameter that is specific to the normal structure or tumor of interest, and vi is unit less and represents the i th partial volume receiving dose D i in Gy. Since the relative volume of the whole structure of interest corresponds to 1, the sum of all partial volumes vi will equal 1 17 Furthermore, in equation (1), EQD 19 is the biologically equivalent physical dose of 2 Gy and defined as: EQD = D α D + β n f α + 2 β (2) 264

5 Radiobiological Impact of Acuros XB Dose Calculation Algorithm on... where, n f and d f = D/n f are the number of fractions and dose per fraction size of the treatment course, respectively. The α/b is the tissue-specific LQ parameter of the organ being exposed 19 Tumor Control Probability Niemierko s EUD-based TCP 17, 19 is defined as TCP = 1 1 γ 50 TCD + 50 EUD (3) where, TCD 50 is the tumor dose to control 50% of the tumors when the tumor is homogeneously irradiated and the g 50 is a unit less model parameter that is specific to the tumor of interest and describes the slope of the dose response curve. 17 Malignant tumor targets generally have large negative values of a. 19, 20 In this study, we chose a = -10 which was reported by Oinam et al. 19 Other EUD-based TCP parameters (Table 3) used in this study are based on the data published by Okunieff et al. 21 For prostate tumor, the alpha/beta value of 1.2 Gy 22 was selected for this study. TABLE 3: Dose-volume constraints and priorities used for optimization of RapidArc prostate plan Structure Objective Volume (%) Dose (cgy) Priority PTV Upper Lower Upper Rectum Upper Upper Upper Upper Bladder Upper Upper Upper Femoral Heads Upper Upper Ring Upper Abbreviations: PTV = Planning Target Volume 265

6 Suresh Rana Normal Tissue Complication Probability Niemierko s EUD-based NTCP 17, 19 is defined as NTCP = 1 1 γ 50 TD + 50 EUD (4) where, TD 50 is the tolerance dose for a 50% complication rate at a specific time interval (e.g., 5 years in the Emami et al. normal tissue tolerance data 23 ) when the whole organ of interest is homogeneously irradiated. The γ 50 is a unit less model parameter that is specific to the normal structure of interest and describes the slope of the dose response curve17, 19, 21 Since parameter a and the Lyman model parameter n are related by a =1/n, 19, 20 the values for a and TD50 were obtained from the Emmai-Burman parameters for NTCP calculations. 24 The same model parameter γ 50 = 4 was used for all OARs. 19 For bladder, Stewart et al. 25 published a high value for the alpha/beta ratio, in the region of 5 to 10 Gy, and we chose to investigate for alpha/beta = 8 Gy. The alpha/beta values for femur heads (0.85) and rectum (3.9) were taking from the studies of Withers et al. 26 and Deore et al. 27 respectively. Statistical Analysis The statistical analysis was done using two-sided student s t-test in a Microsoft Excel spreadsheet, and P value of less than 0.05 (i.e., P < 0.05) was considered to be statistically significant. RESULTS AND DISCUSSION In this radiobiological model response study, we compared two dose calculation algorithms (AAA and AXB) that were used to calculate the dose for low-risk prostate cancer treatment plans created by RapidArc technique. Figure 2 shows the Niemierko s EUD-based TCP value averaged over the ten analyzed patients for AXB and AAA plans. For the localized prostate cancer at Stages T0 and T1, the average TCP values of AAA plans (98.39 ± 0.06 %) and AXB plans (98.26 ± 0.05%) were comparable with average difference of 0.14%. Although the comparison between the TCP values of AAA and AXB plans showed the statistical significance (P = ), the difference (0.14%) between them is unlikely to be clinically significant. Figure 2: The EUD-based average TCP from DVHs of AAA and AXB plans. Abbreviations: EUD = Equivalent Uniform Dose, TCP = Tumor Control Probability, DVH = Dose-Volume Histogram, AAA = Anisotropic Analytical Algorithm, AXB = Acuros XB Algorithm (Values are averaged over the 10 analyzed prostate cancer patients) 266

7 Radiobiological Impact of Acuros XB Dose Calculation Algorithm on... Figure 3: The PTV coverage by 100 % of the prescribed dose of 79.2 Gy in AAA and AXB plans. Abbreviations: PTV = Planning Target Volume, V100 (%) = Percentage of PTV covered by 100% of the prescribed dose, AAA = Anisotropic Analytical Algorithm, AXB = Acuros XB Algorithm. For the purpose of discussion, the percentage of PTV covered by 100% of the prescribed dose (V100) due to dose re-calculation from AAA to AXB was studied. Figure 3 shows the V100 for the ten individual prostate cancer patients in AAA and AXB plans. The averaged V100 of AXB plans (average: 94.15%; range: %) was slightly lower than the V100 of AAA plans (95%). However, the V100 values of AAA and AXB were differed by an average of 0.89%, which is a smaller value compared to its standard deviation (±1.47%), and the difference did not show the statistical significance (P = 0.254). Table 4 summarizes the Niemierko s EUD-based NTCP values averaged over the ten analyzed patients in the AAA and AXB plans. The averaged bladder NTCP values were very small for both the AAA ( %) and AXB ( %), and the difference was not statistically Figure 3: The PTV coverage by 100 % of the prescribed dose of 79.2 Gy in AAA and AXB plans. Abbreviations: PTV = Planning Target Volume, V100 (%) = Percentage of PTV covered by 100% of the prescribed dose, AAA = Anisotropic Analytical Algorithm, AXB = Acuros XB Algorithm. Table 4: EUD-based average NTCP values from DVHs of AAA and AXB plans Organ NCTP AAA AXB (Avg. ± SD) % (Avg. ± SD) % Rectum NTCP 0.56 ± ± Bladder NTCP ± ± Femur NTCP ± ± Abbreviations: EUD = Equivalent Uniform Dose, NTCP = Normal Tissue Complication Probability, DVH = Dose-Volume Histogram, AAA = Anisotropic Analytical Algorithm, AXB = Acuros XB Algorithm; Avg. = Average, SD = Standard Deviation, Femur = Femur Heads * = statistically significant p-value calculated with two-sided Student s t-test (Values are averaged over the 10 analyzed patients) P 267

8 Suresh Rana significant (P = 0.265). Again, for femur heads, the averaged NTCP values of AAA ( %) and AXB ( %) were very low and the difference between their values was not statistically significant (P = 0.281) either. However, the averaged NTCP values for the rectum of 0.56 % (AAA) vs % (AXB) suggested the statistical significance (P = ). In this study, both the AXB and AAA demonstrated comparable TCP and NTCP values; however, the difference between the results of AXB and AAA may become clinically significant for high-risk prostate cancer that generally involves radiation doses to the lymph nodes as well as to the larger volume of tissues with different densities such as pelvic bone, bladder, femur heads and rectum. Thus, the more accurate dose calculation algorithm plays an important role in avoiding the MU miscalculation which will result into dose overestimation or underestimation during the actual patient treatment. It is essential to further investigate the limitations of AXB before using it for real patient treatment cases because the dose underestimation may increase the local disease recurrence, whereas the dose overestimation will likely increase the normal tissue toxicities. The presence of metallic hip prosthesis and its effect on the TCP and NTCP due to dose recalculation from AAA to AXB will be an interesting topic for future studies. Although we could not find the literature to make the direct comparisons against our radiobiological modeling study data for prostate cancer treatment plans created with RapidArc technique, it is relevant to mention two previous radiobiological modeling studies done on prostate cancer. 28, 29 In the study by Vlachaki et al., 28 the averaged TCP values were 99.52% and 97.92% using 3D conformation radiation therapy (3DCRT) and intensity modulation radiation therapy (IMRT) respectively. In the study by Luxton et al., 29 the averaged NTCP values for rectum were 1.7% for IMRT vs. 3.2% for 3DCRT, and these values were later confirmed by Vlachaki et al. 28 By using RapidArc technique in our study, rectum NTCP values were found to be less than 1% for both the AAA and AXB. Both the previous studies 28, 29 reported NTCP values of bladder and femur heads below 0.1%. Similar findings were observed in our study for NTCP values of bladder and femur heads being well below 0.1%. CONCLUSION Both the AAA and AXB predicted comparable NTCP and TCP values for low-risk prostate cancer plans created by RapidArc technique. In comparison to AAA, the AXB produced slightly lower PTV coverage by average 0.89% due to dose recalculation from AAA to AXB. Conflict of Interest: None References 1. Ling CC, Zhang P, Archambault Y, Bocanek J, Tang G, Losasso T. Commissioning and quality assurance of RapidArc radiotherapy delivery system. 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