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Robustness of patient positioning for interfractional error in carbon ion radiotherapy for stage I lung cancer: Bone matching versus tumor matching
Radiotherapy and Oncology xxx (2017) xxx–xxx
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Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Original article
Robustness of patient positioning for interfractional error in carbon ion radiotherapy for stage I lung cancer: Bone matching versus tumor matching Makoto Sakai, Yoshiki Kubota ⇑, Jun-ichi Saitoh, Daisuke Irie, Katsuyuki Shirai, Ryosuke Okada, Masami Torikoshi, Tatsuya Ohno, Takashi Nakano Gunma University Heavy Ion Medical Center, Maebashi, Japan
a r t i c l e
i n f o
Article history: Received 24 February 2017 Received in revised form 30 September 2017 Accepted 1 October 2017 Available online xxxx Keywords: Carbon ion radiotherapy Patient positioning Tumor matching Bone matching Lung cancer
a b s t r a c t Background and purpose: Patient positioning was compared by tumor matching (TM) and conventional bony structure matching (BM) in carbon ion radiotherapy for stage I non-small cell lung cancer to evaluate the robustness of TM and BM in determining interfractional error. Material and methods: Sixty irradiation fields were analyzed. Computed tomography (CT) images acquired before treatment initiation for confirmation (Conf-CT) were obtained under the same settings as the treatment planning CT images and used to evaluate both positioning methods. The dose distributions were recalculated for Conf-CT using both BM and TM, and the dose–volume histogram parameters [V95% of clinical target volume, V5Gy(RBE) of normal lung, and acceptance ratio (ratio of cases with V95% > 95%)] were evaluated. The required margin, which in 90% of cases achieved the acceptable condition, was also examined. Results: Using BM and TM, the median V95% was 98.93% and 100% (p < 0.001) and the mean V5Gy(RBE) was 135.9 and 125.8 (p = 0.694), respectively. The estimated required margins were 7.9 and 3.3 mm and increased by 53.9% and 2.5% of V5Gy(RBE), respectively, compared with planning. Conclusions: TM ensured a better dose distribution than did BM. To enable TM, volumetric imaging is crucial and should replace 2D radiographs for carbon therapy of stage I lung cancer. Ó 2017 Elsevier B.V. All rights reserved. Radiotherapy and Oncology xxx (2017) xxx–xxx
In carbon ion radiotherapy (CIRT), carbon ions penetrate tissue to a depth that depends on their energy level, depositing almost all of their energy near the end of the range and creating a Bragg peak [1]. The relative biological efficiency (RBE) increases near the Bragg peak, and accommodating the Bragg peak to the tumor position can result in high accumulation of the clinical dose [2]. Because the dose distribution is easily affected by target positioning, precise patient positioning is required [3,4]. In particular, the water-equivalent path length (WEL) upstream of the target must be static to match the Bragg peak position to the target [5,6]. The WEL is calculated from the physical thickness and density of the target; thus, bony structure matching (BM), which most substantially impacts the WEL, is the most commonly employed matching technique in particle therapy [3]. Orthogonal X-ray images are acquired for positioning in our facility, as in other facilities [7,8]. ⇑ Corresponding author at: Gunma University Heavy Ion Medical Center, 3-39-22, Showa-machi, Maebashi, Gunma 371-8511, Japan. E-mail address: [email protected] (Y. Kubota).
Our studies have revealed that the dose distribution changes by position variation and/or internal deformation during CIRT in patients with stage I non-small cell lung cancer (NSCLC) [9]. When the tumor moves a large distance with respect to bony structures, it deviates from the irradiation field and critically decreases dose coverage [9,10]. We are planning to introduce in-room computed tomography (CT) and match the tumor to the dose with high accuracy. The WEL of the beam pass is important for CIRT, as described above; thus, tumor matching (TM) may not necessarily improve dose coverage. The advantages of TM have been demonstrated for organs with a homogeneous density, such as the liver [11]. However, whether these results from the liver can be applied to the lung has not been clarified because the tissue density around the lung is inhomogeneous and the range can easily change. Thus, the utility of TM for CIRT in patients with lung cancer was examined by comparing the dose–volume histogram (DVH) parameters. We also evaluated the required margin in which acceptable conditions were achieved in 90% of all cases.
https://doi.org/10.1016/j.radonc.2017.10.003 0167-8140/Ó 2017 Elsevier B.V. All rights reserved.
Please cite this article in press as: Sakai M et al. Robustness of patient positioning for interfractional error in carbon ion radiotherapy for stage I lung cancer: Bone matching versus tumor matching. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.10.003
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Bone matching vs. tumor matching for lung CIRT
Materials and methods Patient selection Thirty patients with NSCLC were studied. They were randomly selected from patients treated with CIRT with passive irradiation methods in our facility from 2012 to 2016. The patient and treatment characteristics are summarized in Table 1. The tumor location was longitudinally divided into three equal parts according to its geometric position instead of the affected lung lobe. This study was approved by the Institutional Review Board at Gunma University Hospital (approval number: 15-111). Image acquisition A gated CT scan was performed for treatment planning (PlanCT) using a multi-slice CT system (Aquilion LB; Toshiba Medical Systems, Japan) at approximately the end of the expiration phase with monitoring by a respiration laser sensor (AZ-733V; Anzai Medical, Japan). Basically, the adopted gating level of respiratory motion was 30%Lv of the wave amplitude around peak exhalation. The patients were immobilized with a customized patient pillow (Moldcare; Alcare, Japan) and a body shell (Shellfitter; Sanyo Polymer Industrial, Japan). At 1–2 days before treatment (1–2 weeks after the previous CT acquisition), a gated CT scan was performed to confirm the reproducibility of the tumor position and dose distribution (Conf-CT) using the same technique as that used for the Plan-CT. Treatment planning A radiation oncologist delineated the gross tumor volume (GTV) on the Plan-CT. The clinical target volume (CTV) was contoured by adding 5-mm margins to the GTV in all directions. The planning target volume (PTV) was generated by anisotropically adding the total margin, which was calculated with a previously established procedure [12]. In brief, the tumor motion in each direction during the gating window is measured on four-dimensional CT, which was acquired together with the Plan-CT. The internal margin was patient-specific and calculated by adding one-third of the motion in each direction. The total margin was calculated from the square root of the sum of the squares of the internal margin and 3 mm of setup margin. To ensure the prescription dose from the change of the WEL in each direction, two-thirds of the total margins in the forward and backward directions against the beam were set as the proximal margin and distal margin. Additionally, the maximum value of the total margins perpendicular to the beam axis was adopted for the smearing [8]. As a result, the mean (±standard deviation) size of the margins was 4.1 (±1.4) for the superior–inferior (SI) direction and 3.3 (±0.7) in the transverse section. A treatment planning system that employs a pencil beam algorithm was used (XiO-N; Elekta, Sweden and Mitsubishi Electric, Japan). The RBE was included in the absorbed dose, and the clinical dose incorporating this was defined as Gy(RBE).
Table 1 Patient characteristics (n = 30). Number or Value Age in years Sex Treatment position Tumor location Tumor side CTV in cm3
Male/female Supine/prone Upper/middle/lower Left/right
Data are presented as median (range) or n. CTV, clinical target volume.
72.5 (47–89) 19/11 19/11 10/9/11 13/17 22.57 (5.52–110.50)
In the NSCLC protocol of our facility, a total dose of 60 Gy(RBE) in four fractions is prescribed to the CTV, and 95% of the prescribed dose must cover the PTV [12]. To reduce the skin dose and ensure administration of the prescribed dose, four directions are used (two vertical and two horizontal fields). In the present study, two directions (one vertical and one horizontal field) were randomly chosen in each case. Tumor position reproducibility To assess the reproducibility of the tumor position, tumor displacement was calculated as the displacement of the center of the tumor mass on each CT image after registration with BM using Plan-CT and Conf-CT images. Superior, left, the anterior was the positive side in the SI, left–right (LR) and antero–posterior (AP) axis, respectively. Comparison of DVH parameters The dose distributions of the vertical and horizontal fields under BM and TM were recalculated using the Conf-CT images. The TM position was calculated from the difference in the center of the mass in the GTV on the Plan-CT and that on the Conf-CT with BM. The percentages of the CTV receiving 80%, 90%, or 95% of the prescription dose (V80%, V90%, or V95%, respectively) and the percentage of minimum doses covering 95% of the CTV (D95%) were calculated. The obtained values were compared using the Wilcoxon test, with 0.05 considered statistically significant. The absolute volume of normal lung receiving 5 Gy(RBE) (V5Gy (RBE)) was calculated to assess toxicity. Comparisons were performed using a double-sided t-test with a 0.05 significance level. Calculations of V95% and acceptance ratio in some characteristics The clinical factors improving V95% and the acceptance ratio with BM or TM were assessed. The acceptance ratio was defined as the ratio of cases with a V95% of CTV of >95%. In this study, we accounted for four factors (treatment position, tumor axial location, tumor location side, and effective lateral displacement (ELD)). The ELD in the horizontal and vertical directions was defined as follows:
qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi ðDSI Þ2 þ ðDAP Þ2 ðMSI Þ2 þ ðM AP Þ2 qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi ELDV ¼ ðDSI Þ2 þ ðDLR Þ2 ðMSI Þ2 þ ðM LR Þ2
ELDH ¼
ð1Þ
where DSI , DAP , and DLR represent tumor displacement in the SI, AP, and LR directions, respectively, and M SI , MAP , and MLR represent the margins in the SI, AP, and LR directions, respectively. V95% was compared with both BM and TM on the Conf-CT images using a Wilcoxon test with a 0.05 significance level. Required PTV margin calculation To estimate the required margin for BM and TM if the dose distributions would satisfy the acceptance condition with an isotropic margin, the values of V95% of CTV on Conf-CT images were recalculated using treatment plans with 1-, 3-, 4-, 5-, 6-, 7-, and 8-mm isotropic margins on the CTV for 14 cases from 7 patients whose coverage was critically worse (the average V95% of two fields was <95%). In parallel, the lung V5Gy(RBE) was calculated for each case. Sigmoid functions were fitted to the plot of coverage against the isotropic margin size, and the required margin that enables 90% of the examined patients to achieve an acceptable condition was calculated for TM or BM. D95% of CTV were compared using the Wilcoxon test, and V5Gy(RBE) of lung were compared with double-sided t-test, with 0.05 considered statistically significant, respectively.
Please cite this article in press as: Sakai M et al. Robustness of patient positioning for interfractional error in carbon ion radiotherapy for stage I lung cancer: Bone matching versus tumor matching. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.10.003
M. Sakai et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx
Results The average ± SD (range) of tumor displacement in all directions was as follows: SI, 2.0 ± 3.4 mm (median, 2.0 mm; range, 10.0 to 6.0 mm); LR, 1.0 ± 2.4 mm (median, 0.5 mm; range, 3.7 to 7.9 mm); and AP, 0.4 ± 2.6 mm (median, 0.1 mm; range, 6.1 to 6.1 mm). The absolute distance was 4.7 ± 0.76 mm (median, 4.3 mm; range, 0.7–9.8 mm). The average was not zero, and it included some systematic error. However, it was difficult to estimate the systematic error while maintaining separation from random error because the systematic error was smaller than the random error and this analysis was performed on a single fraction. The SI displacement was slightly larger than the others. Fig. 1 shows an example of the dose distribution under BM and TM. In Fig. 2, V95% is plotted for TM vs. BM. The median V95% using BM and TM was 98.93% (range, 70.05–100%) and 100% (range,
3
80.42–100%), respectively. The median V95% using TM was significantly higher than that using BM (<0.001). Details of the other DVH parameters are shown in Table 2. For almost all parameters, TM was statistically superior to BM. Although the lung V5Gy(RBE) under TM was smaller than that under BM, there was no significant difference. The effects of clinical factors on V95% and the acceptance ratio are shown in Table 3. The acceptance ratios with BM in the ‘‘lower (i.e., tumor axial location)” and ‘‘ELD > 0 (i.e., the lateral displacement is larger than the margin)” groups were significantly worse and greatly improved with TM. After isotropic margins of 1–8 mm were incrementally added to the CTV (without a conventional anisotropic margin) to estimate the required margins for BM and TM, the V95%, acceptable ratio, and V5Gy(RBE) were calculated for the 7 patients with critically worse coverage (Fig. 3). The values increased as the margin became
Fig. 1. Dose distribution with one horizontal field on Plan-CT and Conf-CT. (a), (c), and (e) axial plane on the Plan-CT, with BM, and TM on Conf-CT, respectively. (b), (d), and (f) coronal plane on the Plan-CT, with BM, and TM on Conf-CT, respectively. The cyan and red lines show the CTV and GTV, respectively. The dose distribution is displayed on a graduated scale from 10% to 95%. In this case, the fields were acceptable both with BM and TM (V95% of CTV was 96.2%, 96.6%, 100%, and 100% for vertical field with BM, horizontal field with BM, vertical field with TM, and horizontal field with TM, respectively).
Please cite this article in press as: Sakai M et al. Robustness of patient positioning for interfractional error in carbon ion radiotherapy for stage I lung cancer: Bone matching versus tumor matching. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.10.003
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Bone matching vs. tumor matching for lung CIRT
Table 2 Dose–volume histogram parameters of BM and TM. BM Horizontal
CTV
Lung Vertical
CTV
All
CTV
Lung
Lung
TM
p-Value
V80% (%) V90% (%) V95% (%) D95% (Gy(RBE)) V5Gy(RBE) (cm3)
100 99.9 98.8 14.9 129.2
(83.4–100) (76.8–100) (70.1–100) (13.2–15.2) (62.2–272.0)
100 100 100 14.9 114.2
(97.7–100) (93.5–100) (87.7–100) (13.4–15.1) (55.7–284.6)
0.109 0.007 0.002 0.049 0.478
V80% (%) V90% (%) V95% (%) D95% (Gy(RBE)) V5Gy(RBE) (cm3)
100 99.9 99.3 14.9 140.9
(85.8–100) (77.6–100) (71.6–100) (14–15.2) (70.1–261.2)
100 100 100 14.9 133.3
(91.4–100) (85.8–100) (80.4–100) (14.3–15.2) (70.9–267.4)
0.022 0.002 <0.001 0.27 0.21
V80% (%) V90% (%) V95% (%) D95% (Gy(RBE)) V5Gy(RBE) (cm3)
100 99.9 99.1 14.9 140.4
(83.4–100) (76.8–100) (70.1–100) (13.2–15.2) (62.2–272.0)
100 100 100 15.0 128.2
(91.4–100) (85.8–100) (80.4–100) (14.3–15.2) (55.7–284.6)
0.008 <0.001 <0.001 0.029 0.694
Data are presented as median (range). BM, bony structure matching; TM, tumor matching; CTV, clinical target volume; V80%, V90%, and V95%, percentage of CTV receiving 80%, 90%, or 95% of the dose, respectively; D95%, minimum doses covering 95% of the CTV; V5Gy(RBE), absolute volume of normal lung receiving 5 Gy(RBE) [where Gy(RBE) is the clinical dose incorporating the relative biological efficiency included in the absorbed dose].
Table 3 Clinical factor assessment affecting on V95% and acceptance ratio. Characteristics (number of fields)
V95%
Acceptance ratio
BM (%) Treatment position Tumor axial location
Tumor location side Effective lateral displacement Total fields
Spine Prone Upper Middle Lower Left Right <0 >0
TM (%)
p-Value
BM (%)
TM(%)
(32) (28) (20) (18) (22) (26) (34) (41) (19)
98.0 99.3 98.0 99.3 99.3 98.8 99.4 99.4 83.3
(70.1–100) (70.7–100) (71.6–100) (92.3–100) (70.1–100) (70.1–100) (70.7–100) (91.2–100) (70.1–100)
100 100 99.6 100 100 99.9 100 100 100
(80.4–100) (95.6–100) (80.4–100) (95.6–100) (93.6–100) (80.4–100) (95.6–100) (94.9–100) (80.4–100)
<0.001 0.001 0.010 0.011 0.001 0.001 0.001 0.004 0.001
75 71 75 89 59 69 76 90 37
81 100 80 100 91 77 97 98 74
(60)
98.9
(70.1–100)
100
(80.4–100)
<0.001
73
90
larger. So that V95% of 90% of the patients exceeded the acceptable condition, the required isotropic margins were 7.9 and 3.3 mm for BM and TM, respectively. The estimated isotropic margins expanded the V5Gy(RBE) by 53.9% with BM and 2.5% with TM compared with the conventional margin. Discussion We evaluated the CTV coverage (V95%) using Plan-CT and ConfCT images to analyze the effectiveness of TM for CIRT. We use two fixed beam snouts in our facility. Thus, the patients are immobilized in the spine or prone position depending on the tumor site, and they are rotated only ±15 degrees around the SI axis to be irradiated from four directions. This means that the distance angle between each of the two directions in the vertical or horizontal field is small (only 30 degrees). Therefore, we randomly selected two fields (one horizontal and one vertical field) among the four fields in this study to avoid overestimation for the statistical analysis. The V95% in 54 cases and the means of other DVH parameters obtained using TM was superior or equal to that obtained using BM (Fig. 2, Table 2). BM generated 16 unacceptable fields in 10 patients, while TM generated only 6 unacceptable fields in 4 patients (p = 0.018 with chi-square test). The V95% delivered by each field was not equal but strong correlated with the area of the V95% after summation of four fields (Supplementary Fig. 1(a)).
V95 with TM (%)
Data in V95% are presented as median (range). BM, bony structure matching; TM, tumor matching; V95%, percentage of CTV receiving 95% of the dose. V95% was compared between BM and TM using the Mann–Whitney U-test.
:V :H V95 with BM (%) Fig. 2. Comparison of V95% obtained using TM vs. BM for vertical and horizontal fields.
The CIRT dose is accumulated by matching the lateral and depth positions of the Bragg peak to the target. Thus, both misalignment of the beam axis and changes in the beam range down-regulate the dose distribution. BM realizes an approximately consistent WEL to the surface of the target, but the beam axis becomes mismatched with the target position. In contrast, TM works in reverse.
Please cite this article in press as: Sakai M et al. Robustness of patient positioning for interfractional error in carbon ion radiotherapy for stage I lung cancer: Bone matching versus tumor matching. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.10.003
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M. Sakai et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx
(a) *
*
*
*
V95 (%)
*
:BM :TM Margin (mm)
(c)
V5 (cm3)
*
Acceptance Ratio (%)
*
(b)
:BM :TM Margin (mm)
:BM :TM Margin (mm)
Fig. 3. Relationship between isotropic margin and (a) V95%, (b) acceptance ratio, and (c) V5Gy(RBE). *Statistically significant difference.
When a tumor moves a great distance beyond the margin, it is assumed that V95% using BM would be considerably degraded. Therefore, as the first step, we estimated the tumor displacement and V95%. The displacement and V95% values for both directional fields were similar to those generated in previous studies of lung cancer [9,10,13]. Meanwhile, Abe et al. [11] reported that in patients with liver cancer, the V95% using BM and TM were higher than in the present study, although the tumor displacements were greater. The cause of this discrepancy is assumed to be the fact that the density of the tissue around the lung is less homogeneous than that of the tissue around the liver, and this relative inhomogeneity affected both the range of the carbon beam and the coverage. The beam range is affected by the WEL with respect to both physical distance and density. In the case of lung cancer irradiation, the lung tissue thickness varies according to the beam trajectory if the tumor moves along the beam axis. Because lung tissue has low density (about one-third of that of common tissue) and the carbon beam does not deposit its energy, the position of the Bragg peak shifts with the tumor position [14]. This means that the beam range has a smaller effect on the coverage. Thus, displacement in the plane perpendicular to the beam axis is important when estimating the impact on the coverage. In particular, lateral displacement values larger than the margin lead to coverage degradation. Thus, we calculated the ELD, which is the lateral displacement considering the lateral margin, and evaluated its effect on the coverage. We then determined the effects of patient characteristics on the CTV coverage (Table 3). The V95% and acceptance ratio obtained using TM for all cases were superior to those obtained using BM. Particularly in the ‘‘lower” and ‘‘ELD > 0” groups, the acceptance ratios with BM were worse and were greatly improved with TM. When a tumor is located in the lower lung, it readily moves in the SI direction as a consequence of diaphragm positioning, separately from respiratory movement [15]. SI displacement affects the coverage in both the horizontal and vertical fields. In this study, the absolute SI displacement in the ‘‘lower” group was 4.1 ± 3.4 mm; it was also significantly larger than that of the others (2.2 ± 2.0 mm). Considering the ELD, TM improved the dose distribution because the V95% with BM was significantly worse when the ELD was >0. The ELD represents the difference between the tumor displacement and the margin (Eq. (1)), and it has a stronger correlation with the target coverage (V95%) than with other factors (Supplementary Fig. 2, Table 1). If the ELD is >0 (i.e., the lateral displacement of the tumor is larger than the margin), irradiation with BM is not recommended. We also considered the degradation caused by the change in the WEL if
TM is applied. However, improving the coverage in TM, even if the tumor displacement is large, means that the effects of changes in the WEL are relatively small at the destination. The effects of the ribs on the WEL might be small because the density is relatively low. Additionally, the smearing with the total margin would have prevented the degradation caused by the change in the WEL. Toxicity to normal tissue must be considered when performing radiation therapy. Some studies have demonstrated that the lung V20Gy is correlated with the severity of lung toxicity [16,17]. Although the region of the V5Gy(RBE) delivered by each field is not equal to the V20Gy(RBE) related to pneumonitis, the area of the V5Gy(RBE) of each field is correlated with the area of the V20Gy(RBE) after summation of four fields (Supplementary Fig. 1(b)). When analyzing V5Gy(RBE) as a risk indicator, the mean V5Gy(RBE) using TM was less than that using BM, although the difference was not significant. Thus, the risk of adverse events is unlikely to be increased by TM. We examined a method with which to enhance V95% to 95% by adding an isotropic margin to the 14 cases among 7 patients with poor coverage whose average V95% with BM or TM was <95% (Fig. 3); a 7.9-mm isotropic margin was required for 90% of the patients with poor coverage in which BM was used. In contrast, only a 3.3-mm isotropic margin was satisfactory in TM. Under these conditions, the average (±SD) V5Gy(RBE) using BM and TM was 164.6 ± 35.8 and 109.6 ± 27.1 cm3, respectively, and the difference was significant (p = 0.004). Additionally, a 7.9-mm margin using BM increased the V5Gy(RBE) by 53.9% relative to conventional methods. Although the margin is anisotropic in practical treatment as described above, an isotropic margin was used in this study to enable simple comparison of the robustness of BM and TM in dealing with tumor displacement because the interfractional error of the tumor position was random as shown by the tumor displacements and the report by Irie et al. [9]. When using TM, the V5Gy (RBE) with a 3.3-mm isotropic margin was almost identical to that with a conventional margin. Conversely, a 7.9-mm isotropic margin with BM was wider than the practical method. The type of trend (the required margin with BM is larger than that with TM) must be the same if an anisotropic margin is added instead of the isotropic margin used in ‘‘Required PTV margin calculation”. Many patients who undergo radiation therapy are inoperable because of their reduced lung function [18,19]. Multiplication of the lung dose is not desirable because it diminishes the ability of dose accumulation inherent in CIRT. In this study, V95% was compared between BM and TM using gated CT, and the acceptance was determined in an experimental
Please cite this article in press as: Sakai M et al. Robustness of patient positioning for interfractional error in carbon ion radiotherapy for stage I lung cancer: Bone matching versus tumor matching. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.10.003
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Bone matching vs. tumor matching for lung CIRT
manner. In reality, because respiratory motion may degrade the distribution of both BM and TM, a future study that includes the motion effect with gating is necessary. TM is a robust method that can ensure a dose distribution superior to that of BM when performing CIRT of NSCLC. Our facility plans to install an in-room CT scanner. If the divergence between the bony structure and tumor position is large, more emphasis should be placed on the tumor position. Hence, to enable TM, volumetric imaging is crucial and should replace 2D radiographs for carbon therapy of stage I lung cancer. This study was conducted using two series of CT images with adjustment of the patient position between each series. Thus, the tumor displacement in each position is important. For precise registration with tumor position, the position must be pinpointed during or before treatment. Fiducial markers are sometimes used; however, these markers are sometimes dropped or migrated with deformation and/or distortion of the lung. Therefore, we encourage the use of in-room CT or cone-beam CT to confirm the tumor position. Conflict of interest statement All authors declare that they have no conflicts of interest regarding the work described in this paper. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.radonc.2017.10. 003. References [1] Brown A, Suit H. The centenary of the discovery of the bragg peak. Radiother Oncol 2004;73:265–8. [2] Kraft G. Tumor therapy with heavy charged particles. Prog Part Nucl Phys 2000;45:S473–544. [3] Kubota Y, Tashiro M, Shinohara A, et al. Development of an automatic evaluation method for patient positioning error. J Appl Clin Med Phys 2015;16:5400.
[4] Steitz J, Naumann P, Ulrich S, et al. Worst case optimization for interfractional motion mitigation in carbon ion therapy of pancreatic cancer. Radiat Oncol 2016;11:134. [5] Mori S, Kumagai M, Karube M, et al. Dosimetric impact of 4dct artifact in carbon-ion scanning beam treatment: worst case analysis in lung and liver treatments. Phys Med 2016;32:787–94. [6] Mori S, Wolfgang J, Lu H-M, et al. Quantitative assessment of range fluctuations in charged particle lung irradiation. Int J Radiat Oncol Biol Phys 2008;70:253–61. [7] Ohno T, Kanai T, Yamada S, et al. Carbon ion radiotherapy at the gunma university heavy ion medical center: new facility set-up. Cancers 2011;3:4046–60. [8] Tashiro M, Ishii T, J-i Koya, et al. Technical approach to individualized respiratory-gated carbon-ion therapy for mobile organs. Radiol Phys Technol 2013;6:356–66. [9] Irie D, Saitoh JI, Shirai K, et al. Verification of dose distribution in carbon ion radiation therapy for stage i lung cancer. Int J Radiat Oncol Biol Phys 2016;96:1117–23. [10] Soukup M, Sohn M, Yan D, et al. Study of robustness of impt and imrt for prostate cancer against organ movement. Int J Radiat Oncol Biol Phys 2009;75:941–9. [11] Abe S, Kubota Y, Shibuya K, et al. Fiducial marker matching versus vertebral body matching: dosimetric impact of patient positioning in carbon ion radiotherapy for primary hepatic cancer. Phys Med 2017;33:114–20. [12] Miyamoto T, Baba M, Sugane T, et al. Carbon ion radiotherapy for stage i nonsmall cell lung cancer using a regimen of four fractions during 1 week. J Thorac Oncol 2007;2:916–26. [13] Chang J, Mageras GS, Yorke E, et al. Observation of interfractional variations in lung tumor position using respiratory gated and ungated megavoltage conebeam ct. Int J Radiat Oncol Biol Phys 2007;67:1548–58. [14] Mori S, Lu HM, Wolfgang JA, et al. Effects of interfractional anatomical changes on water-equivalent pathlength in charged-particle radiotherapy of lung cancer. J Radiat Res 2009;50:513–9. [15] Sonke JJ, van Lebesque J, Herk M. Variability of four-dimensional computed tomography patient models. Int J Radiat Oncol Biol Phys 2008;70:590–8. [16] Kim TH, Cho KH, Pyo HR, et al. Dose-volumetric parameters for predicting severe radiation pneumonitis after three-dimensional conformal radiation therapy for lung cancer. Radiology 2005;235:208–15. [17] Kong F-M, Hayman JA, Griffith KA, et al. Final toxicity results of a radiationdose escalation study in patients with non–small-cell lung cancer (nsclc): predictors for radiation pneumonitis and fibrosis. Int J Radiat Oncol Biol Phys 2006;65:1075–86. [18] Mery CM, Pappas AN, Bueno R, et al. Similar long-term survival of elderly patients with non-small cell lung cancer treated with lobectomy or wedge resection within the surveillance, epidemiology, and end results database. Chest 2005;128:237–45. [19] Raz DJ, Zell JA, Ou SHI, et al. Natural history of stage i non-small cell lung cancer: implications for early detection. Chest 2007;132:193–9.
Please cite this article in press as: Sakai M et al. Robustness of patient positioning for interfractional error in carbon ion radiotherapy for stage I lung cancer: Bone matching versus tumor matching. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.10.003
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Original article
Robustness of patient positioning for interfractional error in carbon ion radiotherapy for stage I lung cancer: Bone matching versus tumor matching Makoto Sakai, Yoshiki Kubota ⇑, Jun-ichi Saitoh, Daisuke Irie, Katsuyuki Shirai, Ryosuke Okada, Masami Torikoshi, Tatsuya Ohno, Takashi Nakano Gunma University Heavy Ion Medical Center, Maebashi, Japan
a r t i c l e
i n f o
Article history: Received 24 February 2017 Received in revised form 30 September 2017 Accepted 1 October 2017 Available online xxxx Keywords: Carbon ion radiotherapy Patient positioning Tumor matching Bone matching Lung cancer
a b s t r a c t Background and purpose: Patient positioning was compared by tumor matching (TM) and conventional bony structure matching (BM) in carbon ion radiotherapy for stage I non-small cell lung cancer to evaluate the robustness of TM and BM in determining interfractional error. Material and methods: Sixty irradiation fields were analyzed. Computed tomography (CT) images acquired before treatment initiation for confirmation (Conf-CT) were obtained under the same settings as the treatment planning CT images and used to evaluate both positioning methods. The dose distributions were recalculated for Conf-CT using both BM and TM, and the dose–volume histogram parameters [V95% of clinical target volume, V5Gy(RBE) of normal lung, and acceptance ratio (ratio of cases with V95% > 95%)] were evaluated. The required margin, which in 90% of cases achieved the acceptable condition, was also examined. Results: Using BM and TM, the median V95% was 98.93% and 100% (p < 0.001) and the mean V5Gy(RBE) was 135.9 and 125.8 (p = 0.694), respectively. The estimated required margins were 7.9 and 3.3 mm and increased by 53.9% and 2.5% of V5Gy(RBE), respectively, compared with planning. Conclusions: TM ensured a better dose distribution than did BM. To enable TM, volumetric imaging is crucial and should replace 2D radiographs for carbon therapy of stage I lung cancer. Ó 2017 Elsevier B.V. All rights reserved. Radiotherapy and Oncology xxx (2017) xxx–xxx
In carbon ion radiotherapy (CIRT), carbon ions penetrate tissue to a depth that depends on their energy level, depositing almost all of their energy near the end of the range and creating a Bragg peak [1]. The relative biological efficiency (RBE) increases near the Bragg peak, and accommodating the Bragg peak to the tumor position can result in high accumulation of the clinical dose [2]. Because the dose distribution is easily affected by target positioning, precise patient positioning is required [3,4]. In particular, the water-equivalent path length (WEL) upstream of the target must be static to match the Bragg peak position to the target [5,6]. The WEL is calculated from the physical thickness and density of the target; thus, bony structure matching (BM), which most substantially impacts the WEL, is the most commonly employed matching technique in particle therapy [3]. Orthogonal X-ray images are acquired for positioning in our facility, as in other facilities [7,8]. ⇑ Corresponding author at: Gunma University Heavy Ion Medical Center, 3-39-22, Showa-machi, Maebashi, Gunma 371-8511, Japan. E-mail address: [email protected] (Y. Kubota).
Our studies have revealed that the dose distribution changes by position variation and/or internal deformation during CIRT in patients with stage I non-small cell lung cancer (NSCLC) [9]. When the tumor moves a large distance with respect to bony structures, it deviates from the irradiation field and critically decreases dose coverage [9,10]. We are planning to introduce in-room computed tomography (CT) and match the tumor to the dose with high accuracy. The WEL of the beam pass is important for CIRT, as described above; thus, tumor matching (TM) may not necessarily improve dose coverage. The advantages of TM have been demonstrated for organs with a homogeneous density, such as the liver [11]. However, whether these results from the liver can be applied to the lung has not been clarified because the tissue density around the lung is inhomogeneous and the range can easily change. Thus, the utility of TM for CIRT in patients with lung cancer was examined by comparing the dose–volume histogram (DVH) parameters. We also evaluated the required margin in which acceptable conditions were achieved in 90% of all cases.
https://doi.org/10.1016/j.radonc.2017.10.003 0167-8140/Ó 2017 Elsevier B.V. All rights reserved.
Please cite this article in press as: Sakai M et al. Robustness of patient positioning for interfractional error in carbon ion radiotherapy for stage I lung cancer: Bone matching versus tumor matching. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.10.003
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Bone matching vs. tumor matching for lung CIRT
Materials and methods Patient selection Thirty patients with NSCLC were studied. They were randomly selected from patients treated with CIRT with passive irradiation methods in our facility from 2012 to 2016. The patient and treatment characteristics are summarized in Table 1. The tumor location was longitudinally divided into three equal parts according to its geometric position instead of the affected lung lobe. This study was approved by the Institutional Review Board at Gunma University Hospital (approval number: 15-111). Image acquisition A gated CT scan was performed for treatment planning (PlanCT) using a multi-slice CT system (Aquilion LB; Toshiba Medical Systems, Japan) at approximately the end of the expiration phase with monitoring by a respiration laser sensor (AZ-733V; Anzai Medical, Japan). Basically, the adopted gating level of respiratory motion was 30%Lv of the wave amplitude around peak exhalation. The patients were immobilized with a customized patient pillow (Moldcare; Alcare, Japan) and a body shell (Shellfitter; Sanyo Polymer Industrial, Japan). At 1–2 days before treatment (1–2 weeks after the previous CT acquisition), a gated CT scan was performed to confirm the reproducibility of the tumor position and dose distribution (Conf-CT) using the same technique as that used for the Plan-CT. Treatment planning A radiation oncologist delineated the gross tumor volume (GTV) on the Plan-CT. The clinical target volume (CTV) was contoured by adding 5-mm margins to the GTV in all directions. The planning target volume (PTV) was generated by anisotropically adding the total margin, which was calculated with a previously established procedure [12]. In brief, the tumor motion in each direction during the gating window is measured on four-dimensional CT, which was acquired together with the Plan-CT. The internal margin was patient-specific and calculated by adding one-third of the motion in each direction. The total margin was calculated from the square root of the sum of the squares of the internal margin and 3 mm of setup margin. To ensure the prescription dose from the change of the WEL in each direction, two-thirds of the total margins in the forward and backward directions against the beam were set as the proximal margin and distal margin. Additionally, the maximum value of the total margins perpendicular to the beam axis was adopted for the smearing [8]. As a result, the mean (±standard deviation) size of the margins was 4.1 (±1.4) for the superior–inferior (SI) direction and 3.3 (±0.7) in the transverse section. A treatment planning system that employs a pencil beam algorithm was used (XiO-N; Elekta, Sweden and Mitsubishi Electric, Japan). The RBE was included in the absorbed dose, and the clinical dose incorporating this was defined as Gy(RBE).
Table 1 Patient characteristics (n = 30). Number or Value Age in years Sex Treatment position Tumor location Tumor side CTV in cm3
Male/female Supine/prone Upper/middle/lower Left/right
Data are presented as median (range) or n. CTV, clinical target volume.
72.5 (47–89) 19/11 19/11 10/9/11 13/17 22.57 (5.52–110.50)
In the NSCLC protocol of our facility, a total dose of 60 Gy(RBE) in four fractions is prescribed to the CTV, and 95% of the prescribed dose must cover the PTV [12]. To reduce the skin dose and ensure administration of the prescribed dose, four directions are used (two vertical and two horizontal fields). In the present study, two directions (one vertical and one horizontal field) were randomly chosen in each case. Tumor position reproducibility To assess the reproducibility of the tumor position, tumor displacement was calculated as the displacement of the center of the tumor mass on each CT image after registration with BM using Plan-CT and Conf-CT images. Superior, left, the anterior was the positive side in the SI, left–right (LR) and antero–posterior (AP) axis, respectively. Comparison of DVH parameters The dose distributions of the vertical and horizontal fields under BM and TM were recalculated using the Conf-CT images. The TM position was calculated from the difference in the center of the mass in the GTV on the Plan-CT and that on the Conf-CT with BM. The percentages of the CTV receiving 80%, 90%, or 95% of the prescription dose (V80%, V90%, or V95%, respectively) and the percentage of minimum doses covering 95% of the CTV (D95%) were calculated. The obtained values were compared using the Wilcoxon test, with 0.05 considered statistically significant. The absolute volume of normal lung receiving 5 Gy(RBE) (V5Gy (RBE)) was calculated to assess toxicity. Comparisons were performed using a double-sided t-test with a 0.05 significance level. Calculations of V95% and acceptance ratio in some characteristics The clinical factors improving V95% and the acceptance ratio with BM or TM were assessed. The acceptance ratio was defined as the ratio of cases with a V95% of CTV of >95%. In this study, we accounted for four factors (treatment position, tumor axial location, tumor location side, and effective lateral displacement (ELD)). The ELD in the horizontal and vertical directions was defined as follows:
qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi ðDSI Þ2 þ ðDAP Þ2 ðMSI Þ2 þ ðM AP Þ2 qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi ELDV ¼ ðDSI Þ2 þ ðDLR Þ2 ðMSI Þ2 þ ðM LR Þ2
ELDH ¼
ð1Þ
where DSI , DAP , and DLR represent tumor displacement in the SI, AP, and LR directions, respectively, and M SI , MAP , and MLR represent the margins in the SI, AP, and LR directions, respectively. V95% was compared with both BM and TM on the Conf-CT images using a Wilcoxon test with a 0.05 significance level. Required PTV margin calculation To estimate the required margin for BM and TM if the dose distributions would satisfy the acceptance condition with an isotropic margin, the values of V95% of CTV on Conf-CT images were recalculated using treatment plans with 1-, 3-, 4-, 5-, 6-, 7-, and 8-mm isotropic margins on the CTV for 14 cases from 7 patients whose coverage was critically worse (the average V95% of two fields was <95%). In parallel, the lung V5Gy(RBE) was calculated for each case. Sigmoid functions were fitted to the plot of coverage against the isotropic margin size, and the required margin that enables 90% of the examined patients to achieve an acceptable condition was calculated for TM or BM. D95% of CTV were compared using the Wilcoxon test, and V5Gy(RBE) of lung were compared with double-sided t-test, with 0.05 considered statistically significant, respectively.
Please cite this article in press as: Sakai M et al. Robustness of patient positioning for interfractional error in carbon ion radiotherapy for stage I lung cancer: Bone matching versus tumor matching. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.10.003
M. Sakai et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx
Results The average ± SD (range) of tumor displacement in all directions was as follows: SI, 2.0 ± 3.4 mm (median, 2.0 mm; range, 10.0 to 6.0 mm); LR, 1.0 ± 2.4 mm (median, 0.5 mm; range, 3.7 to 7.9 mm); and AP, 0.4 ± 2.6 mm (median, 0.1 mm; range, 6.1 to 6.1 mm). The absolute distance was 4.7 ± 0.76 mm (median, 4.3 mm; range, 0.7–9.8 mm). The average was not zero, and it included some systematic error. However, it was difficult to estimate the systematic error while maintaining separation from random error because the systematic error was smaller than the random error and this analysis was performed on a single fraction. The SI displacement was slightly larger than the others. Fig. 1 shows an example of the dose distribution under BM and TM. In Fig. 2, V95% is plotted for TM vs. BM. The median V95% using BM and TM was 98.93% (range, 70.05–100%) and 100% (range,
3
80.42–100%), respectively. The median V95% using TM was significantly higher than that using BM (<0.001). Details of the other DVH parameters are shown in Table 2. For almost all parameters, TM was statistically superior to BM. Although the lung V5Gy(RBE) under TM was smaller than that under BM, there was no significant difference. The effects of clinical factors on V95% and the acceptance ratio are shown in Table 3. The acceptance ratios with BM in the ‘‘lower (i.e., tumor axial location)” and ‘‘ELD > 0 (i.e., the lateral displacement is larger than the margin)” groups were significantly worse and greatly improved with TM. After isotropic margins of 1–8 mm were incrementally added to the CTV (without a conventional anisotropic margin) to estimate the required margins for BM and TM, the V95%, acceptable ratio, and V5Gy(RBE) were calculated for the 7 patients with critically worse coverage (Fig. 3). The values increased as the margin became
Fig. 1. Dose distribution with one horizontal field on Plan-CT and Conf-CT. (a), (c), and (e) axial plane on the Plan-CT, with BM, and TM on Conf-CT, respectively. (b), (d), and (f) coronal plane on the Plan-CT, with BM, and TM on Conf-CT, respectively. The cyan and red lines show the CTV and GTV, respectively. The dose distribution is displayed on a graduated scale from 10% to 95%. In this case, the fields were acceptable both with BM and TM (V95% of CTV was 96.2%, 96.6%, 100%, and 100% for vertical field with BM, horizontal field with BM, vertical field with TM, and horizontal field with TM, respectively).
Please cite this article in press as: Sakai M et al. Robustness of patient positioning for interfractional error in carbon ion radiotherapy for stage I lung cancer: Bone matching versus tumor matching. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.10.003
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Bone matching vs. tumor matching for lung CIRT
Table 2 Dose–volume histogram parameters of BM and TM. BM Horizontal
CTV
Lung Vertical
CTV
All
CTV
Lung
Lung
TM
p-Value
V80% (%) V90% (%) V95% (%) D95% (Gy(RBE)) V5Gy(RBE) (cm3)
100 99.9 98.8 14.9 129.2
(83.4–100) (76.8–100) (70.1–100) (13.2–15.2) (62.2–272.0)
100 100 100 14.9 114.2
(97.7–100) (93.5–100) (87.7–100) (13.4–15.1) (55.7–284.6)
0.109 0.007 0.002 0.049 0.478
V80% (%) V90% (%) V95% (%) D95% (Gy(RBE)) V5Gy(RBE) (cm3)
100 99.9 99.3 14.9 140.9
(85.8–100) (77.6–100) (71.6–100) (14–15.2) (70.1–261.2)
100 100 100 14.9 133.3
(91.4–100) (85.8–100) (80.4–100) (14.3–15.2) (70.9–267.4)
0.022 0.002 <0.001 0.27 0.21
V80% (%) V90% (%) V95% (%) D95% (Gy(RBE)) V5Gy(RBE) (cm3)
100 99.9 99.1 14.9 140.4
(83.4–100) (76.8–100) (70.1–100) (13.2–15.2) (62.2–272.0)
100 100 100 15.0 128.2
(91.4–100) (85.8–100) (80.4–100) (14.3–15.2) (55.7–284.6)
0.008 <0.001 <0.001 0.029 0.694
Data are presented as median (range). BM, bony structure matching; TM, tumor matching; CTV, clinical target volume; V80%, V90%, and V95%, percentage of CTV receiving 80%, 90%, or 95% of the dose, respectively; D95%, minimum doses covering 95% of the CTV; V5Gy(RBE), absolute volume of normal lung receiving 5 Gy(RBE) [where Gy(RBE) is the clinical dose incorporating the relative biological efficiency included in the absorbed dose].
Table 3 Clinical factor assessment affecting on V95% and acceptance ratio. Characteristics (number of fields)
V95%
Acceptance ratio
BM (%) Treatment position Tumor axial location
Tumor location side Effective lateral displacement Total fields
Spine Prone Upper Middle Lower Left Right <0 >0
TM (%)
p-Value
BM (%)
TM(%)
(32) (28) (20) (18) (22) (26) (34) (41) (19)
98.0 99.3 98.0 99.3 99.3 98.8 99.4 99.4 83.3
(70.1–100) (70.7–100) (71.6–100) (92.3–100) (70.1–100) (70.1–100) (70.7–100) (91.2–100) (70.1–100)
100 100 99.6 100 100 99.9 100 100 100
(80.4–100) (95.6–100) (80.4–100) (95.6–100) (93.6–100) (80.4–100) (95.6–100) (94.9–100) (80.4–100)
<0.001 0.001 0.010 0.011 0.001 0.001 0.001 0.004 0.001
75 71 75 89 59 69 76 90 37
81 100 80 100 91 77 97 98 74
(60)
98.9
(70.1–100)
100
(80.4–100)
<0.001
73
90
larger. So that V95% of 90% of the patients exceeded the acceptable condition, the required isotropic margins were 7.9 and 3.3 mm for BM and TM, respectively. The estimated isotropic margins expanded the V5Gy(RBE) by 53.9% with BM and 2.5% with TM compared with the conventional margin. Discussion We evaluated the CTV coverage (V95%) using Plan-CT and ConfCT images to analyze the effectiveness of TM for CIRT. We use two fixed beam snouts in our facility. Thus, the patients are immobilized in the spine or prone position depending on the tumor site, and they are rotated only ±15 degrees around the SI axis to be irradiated from four directions. This means that the distance angle between each of the two directions in the vertical or horizontal field is small (only 30 degrees). Therefore, we randomly selected two fields (one horizontal and one vertical field) among the four fields in this study to avoid overestimation for the statistical analysis. The V95% in 54 cases and the means of other DVH parameters obtained using TM was superior or equal to that obtained using BM (Fig. 2, Table 2). BM generated 16 unacceptable fields in 10 patients, while TM generated only 6 unacceptable fields in 4 patients (p = 0.018 with chi-square test). The V95% delivered by each field was not equal but strong correlated with the area of the V95% after summation of four fields (Supplementary Fig. 1(a)).
V95 with TM (%)
Data in V95% are presented as median (range). BM, bony structure matching; TM, tumor matching; V95%, percentage of CTV receiving 95% of the dose. V95% was compared between BM and TM using the Mann–Whitney U-test.
:V :H V95 with BM (%) Fig. 2. Comparison of V95% obtained using TM vs. BM for vertical and horizontal fields.
The CIRT dose is accumulated by matching the lateral and depth positions of the Bragg peak to the target. Thus, both misalignment of the beam axis and changes in the beam range down-regulate the dose distribution. BM realizes an approximately consistent WEL to the surface of the target, but the beam axis becomes mismatched with the target position. In contrast, TM works in reverse.
Please cite this article in press as: Sakai M et al. Robustness of patient positioning for interfractional error in carbon ion radiotherapy for stage I lung cancer: Bone matching versus tumor matching. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.10.003
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M. Sakai et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx
(a) *
*
*
*
V95 (%)
*
:BM :TM Margin (mm)
(c)
V5 (cm3)
*
Acceptance Ratio (%)
*
(b)
:BM :TM Margin (mm)
:BM :TM Margin (mm)
Fig. 3. Relationship between isotropic margin and (a) V95%, (b) acceptance ratio, and (c) V5Gy(RBE). *Statistically significant difference.
When a tumor moves a great distance beyond the margin, it is assumed that V95% using BM would be considerably degraded. Therefore, as the first step, we estimated the tumor displacement and V95%. The displacement and V95% values for both directional fields were similar to those generated in previous studies of lung cancer [9,10,13]. Meanwhile, Abe et al. [11] reported that in patients with liver cancer, the V95% using BM and TM were higher than in the present study, although the tumor displacements were greater. The cause of this discrepancy is assumed to be the fact that the density of the tissue around the lung is less homogeneous than that of the tissue around the liver, and this relative inhomogeneity affected both the range of the carbon beam and the coverage. The beam range is affected by the WEL with respect to both physical distance and density. In the case of lung cancer irradiation, the lung tissue thickness varies according to the beam trajectory if the tumor moves along the beam axis. Because lung tissue has low density (about one-third of that of common tissue) and the carbon beam does not deposit its energy, the position of the Bragg peak shifts with the tumor position [14]. This means that the beam range has a smaller effect on the coverage. Thus, displacement in the plane perpendicular to the beam axis is important when estimating the impact on the coverage. In particular, lateral displacement values larger than the margin lead to coverage degradation. Thus, we calculated the ELD, which is the lateral displacement considering the lateral margin, and evaluated its effect on the coverage. We then determined the effects of patient characteristics on the CTV coverage (Table 3). The V95% and acceptance ratio obtained using TM for all cases were superior to those obtained using BM. Particularly in the ‘‘lower” and ‘‘ELD > 0” groups, the acceptance ratios with BM were worse and were greatly improved with TM. When a tumor is located in the lower lung, it readily moves in the SI direction as a consequence of diaphragm positioning, separately from respiratory movement [15]. SI displacement affects the coverage in both the horizontal and vertical fields. In this study, the absolute SI displacement in the ‘‘lower” group was 4.1 ± 3.4 mm; it was also significantly larger than that of the others (2.2 ± 2.0 mm). Considering the ELD, TM improved the dose distribution because the V95% with BM was significantly worse when the ELD was >0. The ELD represents the difference between the tumor displacement and the margin (Eq. (1)), and it has a stronger correlation with the target coverage (V95%) than with other factors (Supplementary Fig. 2, Table 1). If the ELD is >0 (i.e., the lateral displacement of the tumor is larger than the margin), irradiation with BM is not recommended. We also considered the degradation caused by the change in the WEL if
TM is applied. However, improving the coverage in TM, even if the tumor displacement is large, means that the effects of changes in the WEL are relatively small at the destination. The effects of the ribs on the WEL might be small because the density is relatively low. Additionally, the smearing with the total margin would have prevented the degradation caused by the change in the WEL. Toxicity to normal tissue must be considered when performing radiation therapy. Some studies have demonstrated that the lung V20Gy is correlated with the severity of lung toxicity [16,17]. Although the region of the V5Gy(RBE) delivered by each field is not equal to the V20Gy(RBE) related to pneumonitis, the area of the V5Gy(RBE) of each field is correlated with the area of the V20Gy(RBE) after summation of four fields (Supplementary Fig. 1(b)). When analyzing V5Gy(RBE) as a risk indicator, the mean V5Gy(RBE) using TM was less than that using BM, although the difference was not significant. Thus, the risk of adverse events is unlikely to be increased by TM. We examined a method with which to enhance V95% to 95% by adding an isotropic margin to the 14 cases among 7 patients with poor coverage whose average V95% with BM or TM was <95% (Fig. 3); a 7.9-mm isotropic margin was required for 90% of the patients with poor coverage in which BM was used. In contrast, only a 3.3-mm isotropic margin was satisfactory in TM. Under these conditions, the average (±SD) V5Gy(RBE) using BM and TM was 164.6 ± 35.8 and 109.6 ± 27.1 cm3, respectively, and the difference was significant (p = 0.004). Additionally, a 7.9-mm margin using BM increased the V5Gy(RBE) by 53.9% relative to conventional methods. Although the margin is anisotropic in practical treatment as described above, an isotropic margin was used in this study to enable simple comparison of the robustness of BM and TM in dealing with tumor displacement because the interfractional error of the tumor position was random as shown by the tumor displacements and the report by Irie et al. [9]. When using TM, the V5Gy (RBE) with a 3.3-mm isotropic margin was almost identical to that with a conventional margin. Conversely, a 7.9-mm isotropic margin with BM was wider than the practical method. The type of trend (the required margin with BM is larger than that with TM) must be the same if an anisotropic margin is added instead of the isotropic margin used in ‘‘Required PTV margin calculation”. Many patients who undergo radiation therapy are inoperable because of their reduced lung function [18,19]. Multiplication of the lung dose is not desirable because it diminishes the ability of dose accumulation inherent in CIRT. In this study, V95% was compared between BM and TM using gated CT, and the acceptance was determined in an experimental
Please cite this article in press as: Sakai M et al. Robustness of patient positioning for interfractional error in carbon ion radiotherapy for stage I lung cancer: Bone matching versus tumor matching. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.10.003
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Bone matching vs. tumor matching for lung CIRT
manner. In reality, because respiratory motion may degrade the distribution of both BM and TM, a future study that includes the motion effect with gating is necessary. TM is a robust method that can ensure a dose distribution superior to that of BM when performing CIRT of NSCLC. Our facility plans to install an in-room CT scanner. If the divergence between the bony structure and tumor position is large, more emphasis should be placed on the tumor position. Hence, to enable TM, volumetric imaging is crucial and should replace 2D radiographs for carbon therapy of stage I lung cancer. This study was conducted using two series of CT images with adjustment of the patient position between each series. Thus, the tumor displacement in each position is important. For precise registration with tumor position, the position must be pinpointed during or before treatment. Fiducial markers are sometimes used; however, these markers are sometimes dropped or migrated with deformation and/or distortion of the lung. Therefore, we encourage the use of in-room CT or cone-beam CT to confirm the tumor position. Conflict of interest statement All authors declare that they have no conflicts of interest regarding the work described in this paper. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.radonc.2017.10. 003. References [1] Brown A, Suit H. The centenary of the discovery of the bragg peak. Radiother Oncol 2004;73:265–8. [2] Kraft G. Tumor therapy with heavy charged particles. Prog Part Nucl Phys 2000;45:S473–544. [3] Kubota Y, Tashiro M, Shinohara A, et al. Development of an automatic evaluation method for patient positioning error. J Appl Clin Med Phys 2015;16:5400.
[4] Steitz J, Naumann P, Ulrich S, et al. Worst case optimization for interfractional motion mitigation in carbon ion therapy of pancreatic cancer. Radiat Oncol 2016;11:134. [5] Mori S, Kumagai M, Karube M, et al. Dosimetric impact of 4dct artifact in carbon-ion scanning beam treatment: worst case analysis in lung and liver treatments. Phys Med 2016;32:787–94. [6] Mori S, Wolfgang J, Lu H-M, et al. Quantitative assessment of range fluctuations in charged particle lung irradiation. Int J Radiat Oncol Biol Phys 2008;70:253–61. [7] Ohno T, Kanai T, Yamada S, et al. Carbon ion radiotherapy at the gunma university heavy ion medical center: new facility set-up. Cancers 2011;3:4046–60. [8] Tashiro M, Ishii T, J-i Koya, et al. Technical approach to individualized respiratory-gated carbon-ion therapy for mobile organs. Radiol Phys Technol 2013;6:356–66. [9] Irie D, Saitoh JI, Shirai K, et al. Verification of dose distribution in carbon ion radiation therapy for stage i lung cancer. Int J Radiat Oncol Biol Phys 2016;96:1117–23. [10] Soukup M, Sohn M, Yan D, et al. Study of robustness of impt and imrt for prostate cancer against organ movement. Int J Radiat Oncol Biol Phys 2009;75:941–9. [11] Abe S, Kubota Y, Shibuya K, et al. Fiducial marker matching versus vertebral body matching: dosimetric impact of patient positioning in carbon ion radiotherapy for primary hepatic cancer. Phys Med 2017;33:114–20. [12] Miyamoto T, Baba M, Sugane T, et al. Carbon ion radiotherapy for stage i nonsmall cell lung cancer using a regimen of four fractions during 1 week. J Thorac Oncol 2007;2:916–26. [13] Chang J, Mageras GS, Yorke E, et al. Observation of interfractional variations in lung tumor position using respiratory gated and ungated megavoltage conebeam ct. Int J Radiat Oncol Biol Phys 2007;67:1548–58. [14] Mori S, Lu HM, Wolfgang JA, et al. Effects of interfractional anatomical changes on water-equivalent pathlength in charged-particle radiotherapy of lung cancer. J Radiat Res 2009;50:513–9. [15] Sonke JJ, van Lebesque J, Herk M. Variability of four-dimensional computed tomography patient models. Int J Radiat Oncol Biol Phys 2008;70:590–8. [16] Kim TH, Cho KH, Pyo HR, et al. Dose-volumetric parameters for predicting severe radiation pneumonitis after three-dimensional conformal radiation therapy for lung cancer. Radiology 2005;235:208–15. [17] Kong F-M, Hayman JA, Griffith KA, et al. Final toxicity results of a radiationdose escalation study in patients with non–small-cell lung cancer (nsclc): predictors for radiation pneumonitis and fibrosis. Int J Radiat Oncol Biol Phys 2006;65:1075–86. [18] Mery CM, Pappas AN, Bueno R, et al. Similar long-term survival of elderly patients with non-small cell lung cancer treated with lobectomy or wedge resection within the surveillance, epidemiology, and end results database. Chest 2005;128:237–45. [19] Raz DJ, Zell JA, Ou SHI, et al. Natural history of stage i non-small cell lung cancer: implications for early detection. Chest 2007;132:193–9.
Please cite this article in press as: Sakai M et al. Robustness of patient positioning for interfractional error in carbon ion radiotherapy for stage I lung cancer: Bone matching versus tumor matching. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.10.003