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2 Medical Dosimetry 38 (203) Medical Dosimetry journal homepage: Comparison of whole-field simultaneous integrated boost VMAT and IMRT in the treatment of nasopharyngeal cancer Xiance Jin, Ph.D., Jinling Yi, B.S., Yongqiang Zhou, M.S., Huawei Yan, B.S., Ce Han, B.S., and Congying Xie, Ph.D. Radiotherapy and Chemotherapy Department, The st Affiliated Hospital of Wenzhou Medical College, Wenzhou, China ARTICLE INFO ABSTRACT Article history: Received 2 September 202 Accepted 6 May 203 Keywords: Nasopharyngeal cancer VMAT IMRT Whole field Simultaneous integrated boost To study the feasibility of using volumetric-modulated arc therapy (VMAT) to deliver whole-field simultaneous integrated boost (WF-SIB) to treat patients with nasopharyngeal cancer (NPC). WF-SIB intensity-modulated radiotherapy (IMRT) plans, one-arc WF-SIB VMAT plans, and two-arc WF-SIB VMAT plans were generated with identical objective functions for 8 patients with NPC of various stages. Isodose distributions and dose-volume histograms were evaluated. Dosimetric and biological quality indices of clinical target volume () and organs at risk (OARs) were calculated to study the optimization capability of these 3 modalities in the treatment of patients with NPC. The optimization time, delivery time, required monitor units (MUs), and delivery accuracy were also compared to investigate the feasibility of these 3 modalities. There was no significant difference (p ¼ 0.92) in target coverage (TC) between WF-SIB IMRT ( ) and two-arc WF-SIB VMAT ( ). However, both had higher TC than one-arc VMAT plans ( , p o 0.0). IMRT demonstrated the best protection of the spinal cord, whereas two-arc VMAT showed the minimum D max to OARs. No other significant differences were observed among these 3 modalities on coverage and OAR sparing. The delivery and MU efficiency of one-arc and two-arc WF-SIB VMAT were greatly improved compared with WF-SIB IMRT. The optimization time of one-arc and two-arc WF-SIB VMAT plans were 5 and 0 times greater than that of WF-SIB IMRT, respectively. The delivery accuracy of WF-SIB VMAT was not affected by the increased freedom. For patients with NPC, one-arc WF-SIB VMAT might not be able to achieve sufficient TC, whereas twoarc WF-SIB VMAT was able to achieve reasonable TC. No significant advantage on OAR protection was demonstrated by VMAT compared with IMRT. WF-SIB VMAT has significantly shorter delivery times, but WF-SIB IMRT may still be the first treatment choice for patients with NPC. & 203 American Association of Medical Dosimetrists. Introduction Intensity-modulated radiotherapy (IMRT) has been accepted as a standard treatment modality for nasopharyngeal cancer (NPC) owing to its dose sculpting ability. One critical problem in the treatment of patients with NPC and other head and neck cancer with IMRT is the management of the lower neck region. There is controversy over whether split field (SF) or whole field (WF) should be applied. The major argument against the use of SF is the risk of marginal failure caused by potential matching errors at the junction field. 2 WF IMRT has the advantages of being simpler and avoiding potential matching errors. The main concern when Reprint requests to: Congying Xie, Ph.D., Radiotherapy and Chemotherapy Department, The st Affiliated Hospital of Wenzhou Medical College, No. 2 Fuxue Lane, Wenzhou , China. billy07@wzhospital.cn using WF IMRT is the increased dose to the larynx, causing laryngeal edema, which could cause speech or swallowing difficulties. 3 Simultaneous integrated boost (SIB) technique is a more efficient IMRT delivery method enabling simultaneous escalation of dose to the primary tumor site without compromising the organ at risk (OAR) sparing. It has been reported that it is possible to reduce the larynx dose to clinically acceptable levels by using a WF-SIB IMRT technique without significantly compromising the target coverage (TC) or other normal tissue constraints. 4 Clinical outcome data have also confirmed that WF-SIB IMRT achieves excellent locoregional control with a severe acute pharyngitis rate comparable to that in patients treated with SF-IMRT. 5 The main drawbacks of IMRT are the complexity of the treatment planning process, the time required for treatment planning and delivery, and the burden of quality assurance. IMRT uses a large number of static beams and monitor units (MUs), which increases radiation delivery time and exposes the patients to the /$ see front matter Copyright Ó 203 American Association of Medical Dosimetrists

3 X. Jin et al. / Medical Dosimetry 38 (203) risk of low-dose irradiation owing to increased leakage. Volumetric-modulated arc therapy (VMAT) is an extended form of IMRT with variable dose rate, gantry speed, and dynamic multileaf collimator movement. 6 VMAT plans with faster delivery time, fewer MU, and superior dose distribution than conventional step-and-shoot IMRT have been reported. 7 With this capability of delivering a highly conformal dose distribution within a short time interval, VMAT has been widely accepted by the radiotherapy community. Single-arc VMAT has been reported to achieve superior or equivalent plan quality in prostate cancer and cervical cancer. 7,8 As the complexity of the target is increased, single-arc VMAT was reported to be inferior to IMRT in TC for patients with head and neck cancer, whereas dual-arc VMAT was superior to that in TC and OAR sparing. 9 There have been some contradictory conclusions regarding the application of SIB VMAT to NPC treatment. Cheung et al. compared dual-arc VMAT using RapidArc (Varian Medical Systems, Palo Alto, CA) with sliding window IMRT in 3 NPC cases. They concluded that dual-arc VMAT plans were not as promising as established IMRT plans. 0 Lee et al. compared SmartArc-based (Philips, Fitchburg, WI) dual-arc VMAT with stepand-shoot IMRT for 8 NPC cases and concluded that dual-arc VMAT approached the performance achieved by 8-field IMRT without compromising the delivery efficiency. WF treatment in NPC involves an even larger target volume and more complex shape. We believe this would increase the difficulty for VMAT optimization. To the best of our knowledge, few WF-SIB VMAT studies have been reported for NPC in the literature. The purpose of this study is to investigate the capability of WF-SIB VMAT for patients with NPC by comparing it with the WF-SIB IMRT technique using identical objective functions and optimization parameters. The delivery time, MU efficiency, and delivery accuracy of these modalities were also investigated under identical conditions. Methods and Materials Patients and contours Eight patients with various stages of NPC were enrolled in this prospective study to compare WF-SIB VMAT and WF-SIB IMRT. Target and normal tissue contours have been reported in our previous study and are generalized here. 2 Gross tumor volume () was delineated as the mass shown in the enhanced computed tomography images or magnetic resonance imaging images or both, including the nasopharyngeal tumor, retropharyngeal lymphadenopathy, and enlarged neck nodes. The clinical target volume () was defined as the plus a margin of potential microscopic spread, encompassing the inferior sphenoid sinus, clivus, skull base, nasopharynx, ipsilateral parapharyngeal space, and posterior third of the nasal cavity and maxillary sinuses. High-risk nodal regions, such as the bilateral upper deep jugular nodes; submandibular nodes; jugulodigastric, mid-jugular, low jugular, and supraclavicular nodes; and the posterior cervical nodes, were included. One typical contour is shown in Fig.. The planning target volume was created by adding a 2-mm margin to the account for setup variability. Treatment planning For each patient, one 7-field IMRT plan, one-arc VMAT plan, and two-arc VMAT plan were optimized with identical,, and OAR objective settings using Philips Pinnacle 3 treatment planning system (clinical version 9.2; Philips, Fichburg, WI). Seven equally spaced coplanar fields were used for the IMRT plans. The gantry angles were as follows: 0, 5, 02, 53, 204, 255, and 306. Prescription doses were 2.5 Gy and 2.0 Gy per fraction for the and Fig.. Typical contour of patient with nasopharyngeal cancer for whole-field treatment. (Color version of the figure is available online.)

4 Author's personal copy 420 X. Jin et al. / Medical Dosimetry 38 (203) Table Objective setting and weight for inverse optimization ROI Type Target (cgy) Brainstem Cord R parotid L parotid lens Ring outside of Min dose Uniform dose Min dose Uniform dose Max DVH Max DVH Max DVH DVH ¼ dose-volume histogram. % Volume Weight , respectively. Twenty-eight fractions were delivered with a total dose of 70 Gy and 56 Gy for and, respectively. OARs consisting of the brain stem, spinal cord, lens, and left and right parotids were constrained for optimization. The direct machine parameter optimization (a form of direct aperture optimization) algorithm was applied for IMRT plan optimization. The maximum number of iterations was limited to 50 and the maximum number of segments was 70. For VMAT plan optimization, leaf motion of 0.46 cm/deg and a final arc space degree of 4 were employed. A start angle of 8 and a stop angle of 80 were applied for one-arc plans using clockwise rotation direction. For two-arc plans, another arc would rotate counterclockwise from 80 to 8. Singular value decomposition algorithm was applied for both IMRT and VMAT calculation, but fine-resolution open density matrix was not employed.3 Minimum segment MU was set to 8 MU. Identical objective settings and weights of,, and OARs were applied for all patients and all 3 treatment modalities, as shown in Table. The ring outside of was applied to minimize the hotspot outside of. Final dose distributions were normalized to the same calculation points in. To minimize optimization time, all contours, dose-volume histograms, and evaluation isodose lines were turned off during optimization. Fig. 2. Dose distributions of plans of IMRT, one-arc VMAT, and two-arc VMAT shown in a view of: (a) axial, (b) sagittal, and (c) coronal. (Color version of the figure is available online.)

5 X. Jin et al. / Medical Dosimetry 38 (203) Dosimetric comparison The dose distributions delivered by the tree modalities were compared by evaluating TC and OAR sparing. The maximum dose (D max ), minimum dose (D min ), mean dose (D mean ), the and volumes receiving 93%, 95%, and 0% of the prescribed dose, D max and D mean of OARs, such as brainstem, spinal cord, lens, and parotids, were evaluated and compared. For parotids, the percent of the total volume of each parotid that received 26 Gy (V 26 ), and 32 Gy (V 32 ) was also evaluated and compared. Additional quality indices were calculated for further evaluation and comparison as listed in the following paragraphs. The TC of the is as follows: TC¼ V T,Pi V T ðþ where V T,Pi is the target volume that is covered by the prescription isodose, which is 95% in this study. V T is the volume of the target. A homogeneity index similar to that defined in the ICRU 62 report was adapted for the 4 HI¼ V 95 V 0 V 95 ð2þ Conformity index (CI) 5 and conformation number (CN) 6 were also calculated for. The equations of CI and CN are as follows: CI¼ V T,Pi V Pi CN¼ V T,Pi V T,Pi ð4þ V T V Pi where V Pi is the volume that is covered by the prescription isodose. The maximum value of CI is, corresponding to a perfect coverage of. The CN is the complementary information to compensate for the defects of TC and CI. The first term of the Eq. (4) describes the coverage of the target volume. The second term refers to the volume of healthy tissue receiving a dose equal to or greater than the prescribed dose. CN can take values between 0 and, where an ideal dose distribution would have a CN value of. Radiobiological ranking indices of tumor control probability (TCP) and normal tissue complication probability (NTCP) were calculated using Niemierko model. 7 The equivalent uniform dose (EUD) is defined as the absorbed dose that causes, if homogeneously deliveredtoatumor,thesameexpectednumberofclonogenstosurviveastheactual nonhomogeneous absorbed dose distribution does. Clonogen survival is a stochastic magnitude governed by Poisson statistics, and EUD is obtained as an expectation value. ð3þ EUD¼ =a N N Da i ð5þ where N is the number of voxels in the structure of interest, D i isthedoseinthei-th voxel, and a is the tumor normal tissue-specific parameter that describes the dosevolume effect. Based on the EUD, the TCP can be calculated by TCP¼ ð6þ þ½tcd 50 =EUDŠ 4γ 50 where TCD 50 is the tumor dose required to produce 50% TCP and γ 50 is the slope of dose response at 50% TCP. All these tumor-specific parameters were cited from the study by Okunieff et al. 8 In the case of normal tissue, the NTCP is determined as NTCP¼ ð7þ þ½td 50 =EUDŠ 4γ 50 where TD 50 is the dose at which the probability of complication becomes 50% in 5 years and γ 50 is the slope of sigmoidal dose-response curve of normal tissue at 50% complication probability. These tissue-specific parameters were based on Niemierko model. 7 The TCP of and NTCPs of brainstem, spinal cord, and both parotids were calculated for plan evaluation. Nondosimetric comparison The deliverability of the IMRT, one-arc VMAT, and two-arc VMAT plans were compared by an ArcCheck phantom and the SNCP Patient analysis software (Version 6, Sun Nuclear Corporation, Melbourne, FL) with a gamma criterion of 3%/ 3 mm. For profile analysis, a threshold dose of 0% of the maximum dose was used. All plans were delivered on an Elekta Synergy linac (Elekta Ltd., Crawley, UK) with a MOSAIQ record and verify system (version.60q3, IMPAC Medical Systems, Inc., Sunnyvale, CA). Besides, the optimization time, MU efficiency, and delivery time were compared. Statistical analysis Comparison of dosimetric and nondosimetric indices among plans with different treatment modalities were analyzed with one-way analysis of variance method. Fig. 3. DVH comparisons among IMRT, one-arc VMAT, and two-arc VMAT. DVH ¼ dose-volume histogram. (Color version of the figure is available online.) All statistical analysis was conducted with SPSS 7.0 software. Differences were considered statistically significant if p o 0.05 and the linear trend F 4. Results Twenty-four plans were generated for 8 patients with NPC. The average and volumes of these patients were (range, 5.40 to 34.0)cm 3 and (range, to 699.0)cm 3, respectively. The axial, sagittal, and coronal dose distributions of patient for IMRT, one-arc, and two-arc VMAT are shown in Fig. 2. Compared with IMRT plan, the 95% isodose line of one-arc VMAT plan was much closer to the and insufficient coverage was observed in some areas. Two-arc VMAT plan showed similar coverage compared with IMRT plan. Figure 3 reports a typical comparative dose-volume histogram of these 3 modalities. The coverage was similar for these 3 modalities. IMRT showed a clear advantage on the coverage as indicated by the higher shoulder of the curve, and two-arc VMAT showed advantage in the high-dose region of brainstem protection. IMRT spared more on spinal cord as indicated by the lower curve of the cord. One-arc VMAT was the worst in parotids protection. No significant difference was observed on lens sparing. Table 2 lists the detailed statistical analysis on the quality indices of and. There was no significant difference in the percent TC between WF-SIB IMRT ( ) and two-arc WF-SIB VMAT ( ) (p ¼ 0.9), but both were higher than that of one-arc WF-SIB VMAT ( ) (p o 0.0). IMRT had a higher value in CI Table 2 ANOVA analysis on target coverage IMRT One-arc VMAT Two-arc VMAT F Sig (p) D min (Gy) D mean (Gy) D max (Gy) EUD (Gy) TCP D min (Gy) D mean (Gy) D max (Gy) EUD (Gy) HI TC (%) o0.0 CI o0.0 CN o0.0 ANOVA ¼ analysis of variance; HI ¼ homogeneity index.

6 422 X. Jin et al. / Medical Dosimetry 38 (203) Table 3 ANOVA analysis on OAR protection OAR IMRT One-arc VMAT Two-arc VMAT F Sig (p) Brainstem D max (Gy) D mean (Gy) EUD (Gy) NTCP (0 4 ) Cord D max (Gy) D mean (Gy) o0.0 EUD (Gy) NTCP (0 4 ) Left parotid D max (Gy) o0.0 D mean (Gy) EUD (Gy) V 26 (%) V 32 (%) Right parotid D max (Gy) o0.0 D mean (Gy) EUD (Gy) V 26 (%) V 32 (%) Lens D max (Gy) D mean (Gy) ANOVA ¼ analysis of variance. ( ) and CN ( ) than one-arc and two-arc VMAT (p o 0.0 for both indices). For plan quality indices, such as D min,d max, D mean, and EUD, IMRT and two-arc VMAT plans had similar values, whereas one-arc VMAT plan showed inferiority in these quality indices. However, no statistical significance was found among them. The TCP was not significantly different among these 3 modalities. Detailed analysis for the OAR quality indices is presented in Table 3. There was no statistical difference on the brainstem protection among 3 modalities. The D max of cord of IMRT was Gy, which was lower (p ¼ 0.04) than that of one-arc VMAT ( Gy) but higher (p ¼ 0.02) than that of two-arc VMAT ( Gy). IMRT had the lowest value (p o 0.0) in the EUD of cord ( Gy), which resulted in the lowest (p ¼ 0.03) NTCP ( ) 0 4 compared with those of one-arc VMAT (.59.80) 0 4 and two-arc VMAT ( ) 0 4. The D max values of the left and right parotids of IMRT were the highest (p o 0.0) compared with those of VMAT plans. No significant differences were observed between IMRT and VMATs on other indices, such as the mean dose, V 26, and V 32 of parotids. The optimization time of IMRT, one-arc VMAT, and two-arc VMAT were , , and minutes, respectively. VMAT plans took longer (p o 0.0) optimization time than IMRT plans. The total MU of IMRT ( ) was much more than (p o 0.0) those of one-arc ( ) and two-arc VMAT ( ). IMRT took the longest (p o 0.0) delivery time of minutes compared with and minutes of one-arc and two-arc VMAT, respectively. The percentage gamma pass ratios of IMRT, one-arc VMAT, and two-arc VMAT were , , and , respectively. The delivery accuracy of VMAT plans was better (p o 0.02) than that of IMRT plans. Discussion To the best of our knowledge, this is the first study to investigate the feasibility of WF-SIB VMAT in the treatment of patients with NPC. By comparing 7-field step-and-shoot WF-SIB IMRT, one-arc WF-SIB VMAT, and two-arc WF-SIB VMAT with identical objective functions, we found that WF-SIB VMAT might not be as good as WF- SIB IMRT in the treatment of NPC. Single-arc VMAT has been reported to achieve superior or equivalent plan quality in prostate cancer compared with IMRT. 7 As the complexity of target increased, single-arc SIB VMAT was reported to be inferior to IMRT in TC for patients head and neck cancer, whereas dual-arc SIB VMAT was superior in TC and OAR sparing compared with IMRT. 9 In this study, we also observed the association of improved VMAT plan quality with an increasing VMAT arcs from one-arc WF-SIB VMAT to two-arc WF-SIB VMAT in the treatment of patients with NPC. This may be owing to the increased freedom of two-arc WF-SIB VMAT compared with onearc WF-SIB VMAT for substantial intensity modulation. The TC of WF-SIB IMRT was better than that of one-arc VMAT and close to that of two-arc WF-SIB VMAT. Although numerous studies have demonstrated a marked improvement on OAR sparing with VMAT, 9,9 our study found OAR sparing was not favored for WF-SIB VMAT. This was consistent with the Cheung et al. s 0 study that used SIB VMAT in the treatment of NPC. One-arc WF-SIB VMAT plans were inferior in the protection on brainstem and spinal cord, and they achieved similar protection on parotids compared with WF-SIB IMRT plans. Two-arc WF-SIB VMAT plans delivered a lower maximum dose to spinal cord but achieved similar protection on other OAR qualities compared with IMRT plans. In the current study, the MU and delivery efficiency of WF-SIB VMAT were greatly improved compared with WF-SIB IMRT. One-arc and two-arc WF-SIB VMAT delivery times were approximately 6 and 3 times faster than that of WF-SIB IMRT, respectively. Delivery speed is a major advantage of VMAT as it reduces the risk of intrafraction movements. In addition, the shorter time needed for delivery is more patient friendly and would enable the treatment of more patients per machine. The MUs of one-arc and two-arc WF-SIB VMAT were only approximately 42% and 55.5% of those of WF-SIB IMRT. This is another advantage of VMAT as it reduces the risk of exposure to low-dose irradiation owing to leakage caused by the large MUs used in IMRT. These advantages have also been reported in previous studies. 9,

7 X. Jin et al. / Medical Dosimetry 38 (203) The optimization time of WF-SIB VMAT was much longer than that of WF-SIB IMRT. The optimization time required for one-arc and two-arc WF-SIB VMAT was nearly 5 and 0 times more than that of WF-SIB IMRT, respectively. This is one of the major disadvantages of VMAT. The longer optimization time would be a heavy burden for medical physicists. However, the computation efficiency would be increased with the continued optimization of VMAT planning techniques and the increased computer processor speed in the future. The increased freedom of leaf positions of WF-SIB VMAT did not compromise its delivery accuracy in this study. Both one-arc and two-arc WF-SIB VMAT showed a higher gamma pass ratio than WF-SIB IMRT. Adding more arc to two-arc WF-SIB VMAT did not affect the delivery accuracy. Similar finding that the dose accuracy of the VMAT delivery was clinically acceptable as the IMRT delivery was reported. 20 To minimize the intrinsic comparative bias as discussed in previous studies, 8,2 all the targets were contoured by senior radiation oncologist, and all the plans were generated by an experienced physicist. Identical objective functions utilized from accepted IMRT plan were applied to all the patients and to all the treatment modalities. Except for the optimization objective functions, additional quality indices were introduced to facilitate the evaluation and comparison for 3 treatment modalities. Optimization parameters were applied as similarly as possible to these 3 modalities. No effort was made to push the optimization achievable for individual patient or plan. This might cause the failure of some plans to reach the normal accepted criteria in TC or in OAR sparing. It was possible for individual patient to achieve a better TC or OAR sparing or both by adjusting the objective function and optimization parameters with each of these 3 modalities, but this was not within the scope of the current investigation. Conclusions For patients with very large and irregular shape target, such as NPC, one-arc WF-SIB VMAT may not be able to achieve sufficient TC. Two-arc WF-SIB VMAT is able to achieve reasonable TC, but it is still inferior to WF-SIB IMRT. No significant advantage on OAR protections are found by WF-SIB VMAT compared with WF-SIB IMRT. WF-SIB IMRT may still be the first treatment choice for patients with NPC except for the long delivery time. Acknowledgment The paper was supported by Wenzhou Science and Technology Bureau Funding (Y202037) and the Scientific Research Foundation for the Returned Overseas Chinese Scholars ( /037). References. Lee, N.; Kramer, A.; Xia, P. 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