International Journal of Cancer Therapy and Oncology www.ijcto.org Copyright © Pokharel et al. ISSN 2330-4049 Shyam Pokharel Department of Medical Physics, Premier Oncology, Fort Myers, Florida, USA Received August 02, 2013; Revised August 29, 2013; Accepted August 31, 2013; Published Online August 31, 2013 Original Research Abstract Purpose: This study investigated the dosimetric impact of mixing low and high energy treatment plans for high prostate cancer treated with volumetric modulated arc therapy (VMAT) technique in the form of RapidArc. Methods: A cohort of 12 prostate cases involving proximal seminal vesicles and lymph nodes was selected for this retrospective study. For each prostate case, the single-energy plans (SEPs) and mixed-energy plans (MEPs) were generated. First, the SEPs were created using 6 mega-voltage (MV) energy for both the primary and boost plans. Second, the MEPs were created using 16 MV energy for the primary plan and 6 MV energy for the boost plan. The primary and boost MEPs used identical beam parameters and same dose optimization values as in the primary and boost SEPs for the corresponding case. The dosimetric parameters from the composite plans (SE Ps and MEPs) were evaluated. Results: The dose to the target volume was slightly higher (on average <1%) in the SEPs than in the MEPs. The conformity index (CI) and homogeneity index (HI) values between the SEPs and MEPs were comparable. The dose to rectum and bladder was always higher in the SEPs (average difference up to 3.7% for the rectum and up to 8.4% for the bladder) than in the MEPs. The mean dose to femoral heads was higher by about 0.8% (on average) in the MEPs than in the SEPs. The number of monitor units and integral dose were higher in the SEPs compared to the MEPs by average differences of 9.1% and 5.5%, respectively. Conclusion: The preliminary results from this study suggest that use of mixed-energy VMAT plan for high-risk prostate cancer could reduce the integral dose and minimize the dose to rectum and bladder, but for the higher femoral head dose. Keywords: Prostate Cancer; Mixed Energy Plan; VMAT; RapidArc Introduction In external beam radiation therapy, treatment techniques such as 3-dimensional conformal therapy (3DCRT), intensity modulated radiation therapy (IMRT), and volumetric modu- lated arc therapy (VMAT) are generally used to treat prostate cancer with an objective of delivering conformal dose dis- tributions to the target while minimizing the doses to the normal tissues. Since prostate cancer involves the deep-seated target, the high-energy photon beams are gener- ally used for 3DCRT due to their greater penetrating power.1 However, the photon beams with energy 10 mega-voltage (MV) or higher also create the secondary neutrons due to interaction between the photons and treatment head of the machine.1 Despite high-energy photon having an advantage in penetrating power and skin sparing, use of lower energy (6–10 MV) photon beams have been found to be an effective energy choices for the majority of IMRT prostate cases.1,2 Furthermore, several studies demonstrated no clear dosimetric advantages using high-energy photon beams for IMRT prostate cases when compared to the low-energy photon beams.2-8 Recently, Park et al.8 investigated the effect of changing beam energy according to the penetration depths on the quality of IMRT plans for prostate cancer and made the comparisons between mixed-energy plans (MEPs) and sin- gle-energy plans (SEPs) of either low or high energy. In that study8, Park et al. showed that mixing energy in an IMRT plan for deep-seated tumors could improve the overall plan quality. However, the dosimetric impact of MEPs for pros- Corresponding author: Shyam Pokharel, PhD; Premier Oncology, 4571 Colonial Blvd, Unit 100, Fort Myers, FL 33966, USA; Email: pokharel@livemail.uthscsa.edu Cite this article as: Pokharel S. Dosimetric impact of mixed-energy volumetric modulated arc therapy plans for high-risk prostate cancer. Int J Cancer Ther Oncol 2013;1(1):01011. DOI: 10.14319/ijcto.0101.1 Dosimetric impact of mixed-energy volumetric modulated arc therapy plans for high-risk prostate cancer http://dx.doi.org/10.14319/ijcto.0101.1 Pokharel: Dosimetric impact of mixed energy in VMAT plans International Journal of Cancer Therapy and Oncology www.ijcto.org Copyright © Pokharel et al. ISSN 2330-4049 2 tate cancer using VMAT technique remains to be addressed. Thus, we investigated the effect of mixing the low energy (6 MV) and high energy (16 MV) treatment plans for prostate cancer treated with VMAT technique in the form of RapidArc (Varian Medical Systems, Palo Alto, CA, USA). The dosimetric comparisons between SEPs and MEPs were done for 12 prostate cases. Methods and Materials A cohort of 12 prostate cases involving proximal seminal vesicles and lymph nodes was selected for this retrospective study. All 12 cases were treated with RapidArc technique at Premier Oncology, Fort Myers. Florida, USA. The computed tomography (CT) simulation of patients was performed in a supine position on the Phillips Brilliance CT Scanner (Philips Healthcare, Andover, MA, USA), and the CT images were acquired with a 3 mm spacing. The contouring of prostate, proximal seminal vesicles, lymph nodes, and organs at risk (OARs) (rectum, bladder, and femoral heads) was done on the axial slices of the CT in the Eclipse treatment planning system (TPS), version 11.1 (Varian Medical Systems, Palo Alto, CA, USA). The primary clinical target volume (CTVp) was defined as the prostate, seminal vesicles, and lymph nodes, whereas the boost clinical target volume (CTVb) was defined as the prostate only. The primary and boost planning target volume (PTVp and PTVb, respectively) was generated with a margin of 7 mm around the CTVp and CTVb, respec- tively, in all directions except in the posterior direction, where a margin of 0.5 cm was used. The RapidArc treatment plans of all 12 cases were generated in the Eclipse TPS using 6 and 16 MV X-ray beams Varian Clinac iX (Varian Medical Systems, Palo Alto, CA, USA). Each treatment plan consisted of primary and boost plan, and the total prescription dose was 81 Gy with a daily dose of 1.8 Gy over 45 fractions. Furthermore, the prescription dose to the primary plan was 45 Gy to the PTVp, and the prescription dose to the boost plan was 36 Gy to the PTVb. For each prostate case, the SEPs and MEPs were generated. FIG. 1: A transversal view of VMAT (RapidArc) plan set up for boost PTV (case #7) using one arc in Eclipse treatment planning system. Abbreviations: VMAT = volumetric modulated arc therapy, PTV = planning target volume. First, the SEPs were created using a 6 MV photon beam for both the primary plan and separate boost plan. The treat- ment plan was set up using one, two or three arcs depending on the size of the target volume. [Figure 1] The length of gantry rotations, collimator angle, and field sizes of the co- planar arcs for the primary as well as boost plans were cho- sen based on the location of the PTV and OARs using the beam-eye-view (BEV) graphics. [Figure 2] FIG. 2: Beam's-eye-view of case #7 showing (a) primary planning target volume (PTV), and (b) boost PTV in the Eclipse treatment planning system. The isocenter of the plan was placed at the center of the target volume (i.e., PTVp or PTVb). The primary and boost plans were optimized using Progressive Resolution Optimiz- er (PRO) (version 11.1). The dose-volume constraints and their weightings were adjusted during the optimization pro- cess of SEPs such that at least 95% of the target volume was covered by the prescription dose while keeping the dose to the OARs as minimum as possible. The plan optimization process was carried out with an objective of meeting the planning criteria listed in Table 1. TABLE 1: Dose specifications for rectum, bladder, and femoral heads in the composite plan 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 Mean Dose < 45 Gy *Normal organ limit refers to the volume of that organ that should not exceed the dose limit. Abbreviation: Dx% = Dose received by x% of total OAR volume, where x % = 15, 25, 35 and 50; OAR = Organ at risk. Second, the MEPs were created using a 16 MV photon beam for the primary plan and a 6 MV photon beam for the boost plan. Specifically, the primary MEP used the identical beam parameters and same optimization dose-constraints and their weightings as in the final primary SEP plan for the corre- sponding case. Similarly, the boost MEP and boost SEP had the same beam parameters and plan optimization values for the corresponding case. No modifications of dose-volume constraints and weightings were made during the optimiza- tion processes of MEPs. The optimized SEPs and MEPs plans were calculated with the anisotropic analytical algorithm (AAA), version 11.1, using dose calculation grid size of 2.5 mm. All calculated Volume 1 • Number 1 • 2013 International Journal of Cancer Therapy and Oncology www.ijcto.org Copyright © Pokharel et al. ISSN 2330-4049 3 plans were then normalized such that at least 95% of the PTV volume was covered by the prescription dose. The pri- mary and boost plans were combined to generate a compo- site (COMP) plan. This allowed us to perform the dosimetric comparison between the SEPs and MEPs using the dose-volume histograms (DVHs) of the COMP plans that were generated in the Eclipse TPS. The DVH parameters evaluated for the target volume (PTVb) were: mean dose, maximum dose, conformity index (CI) defined as the ratio of volume of the isodose cloud receiving 100% of the prescrip- tion dose (V100%) to volume of the PTVb, and homogeneity index (HI) defined as the ratio of dose at 5% of the PTVb (D5%) to dose at 95% of the PTVb (D95%). For rectum and bladder, the volumes that received 70 Gy, 40 Gy, and 20 Gy, (V70Gy, V40Gy, and V20Gy, respectively) as well as mean dose were compared. The mean dose to the femoral heads was evaluated. In addition, the number of monitor units (MUs) and normal tissue integral dose were compared too. For the purpose of comparison, the average percentage dif- ference (Davg.) between the SEPs and MEPs at the corre- sponding dosimetric parameter of the same case was calcu- lated using Equation 1. where x is a corresponding dosimetric parameter in the COMP SEPs and MEPs for the nth case. In Equation 1, the Davg. is expressed in percentage and averaged over all twelve cases in this study. At a given dosimetric parameter, a posi- tive Davg. means higher dosimetric value in the SEPs com- pared with the MEPs, and a negative Davg. means higher dosimetric value in the MEPs compared with the SEPs. The statistical analysis was done using paired two-sided student’s t-test in a Microsoft Excel spreadsheet, and a p- value of less than 0.05 was considered to be statistically significant. Results Table 2 and Figures 3, 4, 5, and 6 summarize the dosimetric results in the COMP plans, and the values are averaged over the twelve analyzed cases. The dosimetric results obtained in this study were clinically acceptable. The maximum and mean doses to the target volume were slightly higher in the SEPs than in the MEPs by an average difference of less than 1%, and the results showed the statis- tical significance with p-values of 0.001 and 0.044 for the maximum and mean dose, respectively. The CI and HI values between SEPs and MEPs were comparable with average dif- ferences of 1% for the CI (p = 0.009) and 0.4% for the HI (p = <0.000) showing statistical significance. The dose to the rectum was always higher in the SEPs and FIG. 3: The Davg. (%) between SEPs and MEPs for the PTV doses, CI, and HI. The values are averaged over the twelve analyzed cases. Note: The error bars represent the standard deviations. The Davg. (%) is defined in equation 1 (Materials and Methods). Abbreviations: Davg. = average difference, SEPs = single energy plans, MEPs = mixed energy plans, PTV = planning target volume, CI = conformity index, HI = homogeneity index. FIG. 4: The Davg. (%) between SEPs and MEPs for the V70Gy, V40Gy, V20Gy, and mean does to the rectum. The values are averaged over the twelve analyzed cases. Note: The error bars represent the stand- ard deviations. The Davg. (%) is defined in Equation 1 (Materials and Methods). Abbreviations: Davg. = average difference, SEPs = single energy plans, MEPs = mixed energy plans, VnGy = percentage volume irradiated by n Gy or more of a certain structure lower in the MEPs with an average difference ranging from 0.6% (at V40Gy) to 3.7% (at V20Gy). The statistical significance was obtained for the mean dose (p = 0.009) and V20Gy (p = 0.003), whereas the statistical significance was not seen for the V70Gy (p = 0.427) and V40Gy (p = 0.277). Similar to the dosimetric results for the rectum, the dose to the bladder was higher in the SEPs and lower in the MEPs. However, the range of average difference values between the SEPs and MEPs were larger for bladder compared to the one for rec- tum. Specifically, the average difference values in bladder ranged from 0.1% (at V20Gy) to 8.4% (at V40Gy). Furthermore, the statistical significance was obtained for the mean dose (p <0.000), V70Gy (p = 0.007), and V40Gy (p = 0.002), whereas the results for V20Gy (p = 0.384) were not statistically significant.       12 n n avg. n=1 n SEP MEP1 D (x) = ×100 Eq.1 12 EP – S         Pokharel: Dosimetric impact of mixed energy in VMAT plans International Journal of Cancer Therapy and Oncology www.ijcto.org Copyright © Pokharel et al. ISSN 2330-4049 4 FIG. 5: The Davg. (%) between SEPs and MEPs for the V70Gy, V40Gy, V20Gy, and mean does to the bladder. The values are averaged over the twelve analyzed cases. Note: The error bars represent the stand- ard deviations. The Davg. (%) is defined in equation 1 (Materials and Methods). Abbreviations: Davg. = average difference, SEPs = single energy plans, MEPs = mixed energy plans, VnGy = percentage volume irradiated by n Gy or more of a certain structure In contrast to the results seen for the rectum and bladder in this study, the mean dose to the femoral heads was higher in the MEPs by an average difference of 0.8% with no statistical significance (p = 0.684). In comparison to the MEPs, the number of MUs and integral dose were higher in the SEPs by average differences of 9.1% (p < 0.000) and 5.5% (p < 0.000), respectively, showing the statistical significances. FIG. 6: The Davg. (%) between SEPs and MEPs for the femoral head mean dose, normal tissue integral dose, and MUs. The values are averaged over the twelve analyzed cases. Note: The error bars rep- resent the standard deviations. The Davg. (%) is defined in equation 1 (Materials and Methods). Abbreviations: Davg. = average difference, SEPs = single energy plans, MEPs = mixed energy plans, MUs = Monitor Units. Discussion In this study, we investigated the dosimetric impact of mix- ing low energy (6 MV) and high energy (16 MV) treatment plans for prostate cancer treated with RapidArc technique. The results from this study showed no clear dosimetric dif- ferences between the SEPs and MEPs for the target volume. However, the results suggested that the use of mixed energy treatment plans for prostate cancer could potentially reduce the dose to the OARs, especially for bladder and rectum. TABLE 2: Comparison of dosimetric parameters for the single and mixed energy composite (primary + boost) plans. SEP MEP p-value (Avg. ± SD) (Avg. ± SD) PTVb (127.2 ± 35.2 cc) Mean Dose (Gy) 83.2 ± 0.4 82.9 ± 0.3 0.044 Max. Dose (Gy) 86.3 ± 0.6 85.6 ± 0.6 0.001 CI 1.09 ± 0.05 1.08 ± 0.05 0.009 HI 1.03 ± 0.00 1.03 ± 0.00 <0.000 Rectum (77.6 ± 47.1 cc) Mean Dose (Gy) 34.6 ± 3.9 34.3 ± 3.9 0.009 V70Gy (%) 6.5 ± 2.8 6.5 ± 2.8 0.427 V40Gy (%) 26.1 ± 7.0 25.9 ± 6.9 0.277 V20Gy (%) 89.3 ± 3.9 86.1 ± 13.2 0.003 Bladder (325.9 ± 218.2 cc) Mean Dose (Gy) 43.2 ± 5.2 42.2 ± 5.0 <0.000 V70Gy (%) 9.3 ± 4.3 9.0 ± 4.1 0.007 V40Gy (%) 45.4 ± 17.2 41.4 ± 15.3 0.002 V20Gy (%) 99.8 ± 0.5 99.7 ± 0.8 0.384 Femoral Heads (135.7 ± 16.5 cc) Mean Dose (Gy) 28.0 ± 3.8 28.2 ± 3.4 0.684 Monitor Units (MUs) 590 ± 35 538 ± 34 <0.000 Integral Dose (105 Gy-cc) 3.2 ± 0.5 3.0 ± 0.5 <0.000 Abbreviations: SEP = Single Energy Plan, MEP = Mixed Energy Plan, Avg. = Average, SD = Standard Deviation, PTV b = Boost Planning Target Volume, Max. Dose = Maximum Dose, VnGy = Percentage volume irradiated by n Gy or more of a certain structure, CI = Conformity Index, HI = Homogeneity Index. (The values are averaged over the 12 analyzed cases. The p-values were obtained from paired two-sided student’s t-test. The p-values less than 0.05 were considered to be statistically significant). Volume 1 • Number 1 • 2013 International Journal of Cancer Therapy and Oncology www.ijcto.org Copyright © Pokharel et al. ISSN 2330-4049 5 The use of lower energy photon beams generally minimizes the head leakage, internal scatter, and secondary neutrons.2-7 However, the low-energy photon beams also requires greater number of MUs to deposit high doses in the area peripheral to the target, resulting increase in the integral dose and radi- ation exposure to the OARs.4 The results in our study also showed that the number of MUs in the lower energy (6 MV) plans (i.e., SEPs) were about 9% higher (on average) in com- parison to the MEPs that contained higher energy (16 MV) photon beam. Furthermore, the integral dose to the normal tissues was lower in the MEPs by about 5.5% (on average), and this would also reduce the radiation-induced secondary cancer. 9, 10 The dosimetric differences in the treatment plans from the use of low and high energy photon beams depend on the beam modeling employed within the dose calculation algo- rithm.11 In this study, we used AAA to calculate the dose in all treatment plans. Several studies12-17 have documented the limitation of AAA in estimating the dose more accurately when heterogeneous media are involved along the photon beam path. Recently, a number of studies have shown that Acuros XB, new dose calculation algorithm employed within Eclipse TPS, is more accurate than AAA for photon dose calculation, especially in the heterogeneous media.14-17 The dosimetric and radiobiological impact of Acuros XB on the prostate cancer treatment plans due to change in photon beam energy will be an interesting topic for future studies. 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