Investigation of intrafractional spinal cord and spinal canal movement during stereotactic MR-guided online adaptive radiotherapy for kidney cancer

Takaya Yamamoto; Shohei Tanaka; Noriyoshi Takahashi; Rei Umezawa; Yu Suzuki; Keita Kishida; So Omata; Kazuya Takeda; Hinako Harada; Kiyokazu Sato; Yoshiyuki Katsuta; Noriyuki Kadoya; Keiichi Jingu

doi:10.1371/journal.pone.0312032

. 2024 Oct 30;19(10):e0312032. doi: 10.1371/journal.pone.0312032

Investigation of intrafractional spinal cord and spinal canal movement during stereotactic MR-guided online adaptive radiotherapy for kidney cancer

Takaya Yamamoto ^1,^*, Shohei Tanaka ¹, Noriyoshi Takahashi ¹, Rei Umezawa ¹, Yu Suzuki ¹, Keita Kishida ¹, So Omata ¹, Kazuya Takeda ¹, Hinako Harada ¹, Kiyokazu Sato ¹, Yoshiyuki Katsuta ¹, Noriyuki Kadoya ¹, Keiichi Jingu ¹

Editor: Minsoo Chun²

PMCID: PMC11524472 PMID: 39475854

Abstract

Background and purpose

This study aimed to investigate the intrafractional movement of the spinal cord and spinal canal during MR-guided online adaptive radiotherapy (MRgART) for kidney cancer.

Materials and methods

All patients who received stereotactic MRgART for kidney cancer between February 2022 and February 2024 were included in this study. Patients received 30–42 Gy in 3-fraction MRgART for kidney cancer using the Elekta Unity, which is equipped with a linear accelerator and a 1.5 Tesla MRI. MRI scans were performed at three points during each fraction: for online planning, position verification, and posttreatment assessment. The spinal cord was contoured from the upper edge of Th12 to the medullary cone, and the spinal canal was contoured from Th12 to L3, using the first MRI. These contours were adjusted to the second and third MR images via deformable image registration, and movements were measured. Margins were determined via the formula “1.3×Σ+0.5×σ” and 95% prediction intervals.

Results

A total of 22 patients (66 fractions) were analyzed. The median interval between the first and third MRI scans were 38 minutes. The mean ± standard deviation of the spinal cord movements after this interval were −0.01 ± 0.06 for the x-axis (right–left), 0.01 ± 0.14 for the y-axis (caudal–cranial), 0.07 ± 0.05 for the z-axis (posterior–anterior), and 0.15 ± 0.08 for the 3D distance, respectively. The correlation coefficients of the 3D distance between the spinal cord and the spinal canal was high (0.92). The calculated planning organ at risk volume margin for all directions was 0.11 cm for spinal cord. The 95% prediction intervals for the x-axis, y-axis, and z-axis were −0.11–0.09 cm, −0.23–0.25 cm and −0.14–0.03 cm, respectively.

Conclusions

Margins are necessary in MRgART to compensate for intrafractional movement and ensure safe treatment delivery.

Introduction

The concept of planning organ at risk volume (PRV) was introduced in ICRU Report No. 62 to account for its anatomical and geometrical variability [1]. Since then, interfractional anatomical and geometrical movements of the spinal cord and various other sites have been investigated to determine the appropriate PRV margin [2–5]. In the abdominal region, interfractional setup errors are significantly greater than those in the skull, brain and head and neck regions [6]. An investigation in esophageal cancer patients reported that positioning errors in the spinal cord were larger in the abdominal area than in the neck area [2]. Clinically, narrow PRV margins with fiducial marker matching in pancreatic cancer have been associated with higher rates of Grade 3–4 late gastrointestinal toxicity [7].

If interfractional anatomical and geometrical errors were negligible, how should PRV margins be applied to organs? The emergence of MR-Linac has enabled MR-guided online adaptive radiotherapy (MRgART), but the need for PRV margins in MRgART is not well understood. MRI allows for precise visualization of structures such as the spinal cord, which are difficult to identify with electronic portal imaging devices or cone beam CT (CBCT) of conventional Linacs. Consequently, deriving PRV margins from older data is challenging. Nevertheless, we must address a significant concern: intrafractional movement during the longer treatment times required for MRgART. In a human feasibility study of MRgART, the median duration of treatment was 32 minutes [8]. The median durations for the pelvis, upper abdomen, and lung were 46 minutes, ranging from 31 to 113 minutes; 66 minutes, ranging from 38 to 114 minutes; and 41 minutes with a 5-95th percentile ranging from 34 to 58 minutes, respectively [9,10]. Despite the advantage of eliminating interfractional errors, intrafractional movement over such long treatment times must be considered. In this study, we focused on intrafractional movement of the spinal cord and spinal canal, which is not significantly affected by peristalsis, the movement of food, feces and gases, respiration, or medication. Therefore, intrafractional movement of the spinal cord and spinal canal is suitable for determining the need for the PRV margin. We investigated the intrafractional movement of the spinal cord and spinal canal during MRgART of stereotactic radiotherapy (SRT) for kidney cancer.

Materials and methods

Patient selection and ethics

Patients who received SRT for kidney cancer via MRgART between February 2022 and February 2024 were identified from the database, which was accessed in March 2024. All of these patients included in the analyses. The authors had access to information that could identify individual participants during and after data collection.

This study was approved by the Ethics Committee of Tohoku University Hospital (reference number: 2023-1-960). Informed consent was waived because of the retrospective design. All patients were guaranteed the opportunity to opt out of participation in this study by receiving information about this study via the internet. Written informed consent as a form of general consent for the utilization of treatment data was obtained from all patients. All of the methods were performed in accordance with the Declaration of Helsinki.

SRT procedure, MRI scan and contouring for spinal cord and spinal canal

The MR-Linac used in this study was the Elekta Unity (Elekta AB, Stockholm, Sweden), which is equipped with a 1.5 Tesla MRI scanner and a linear accelerator. Unity 1.5 Tesla MRI and CT scans (SOMATOM Definition AS+, Siemens Medical, Iselin, NJ) were performed for radiotherapy planning. For scanning and radiotherapy, patients were immobilized in the supine position with or without a waist abdominal compression belt (Beruetto; Taketora, Kanagawa, Japan) to control respiratory movement of the tumor. Our MRgART workflow with Elekta Unity has been described previously [11]. In the MRgART workflow, a fat-suppressed T2-weighted MRI scan with a breathing navigator was performed with the following parameters: TR 2100 ms, TE 252 ms, acquired voxel size 2.0×2.0×2.4 mm³, reconstructed voxel size 0.79×0.79×1.2 mm³, and FOV 360 (anterior-posterior) × 455 (left-right) × 280 (cranial-caudal) mm³. MRI scans were performed three times: an initial scan for online delineation and planning (the first MRI), a second scan for position verification which was performed immediately before beam-on (the second MRI), and a third scan for posttreatment assessment, which was performed immediately after beam-off (the third MRI). Irradiation for kidney cancer patients was administered at doses of 30–42 Gy in 3 fractions via the intensity-modulated radiotherapy (IMRT) technique (step-and-shoot method) with 7 MV flattening-filter-free photons.

The spinal cord and spinal canal were contoured on the first MRI using Monaco v5.51.11 (Elekta AB, Stockholm, Sweden). In this study, the spinal cord was contoured from the upper edge of Th12 to the medullary cone using the first MRI. The spinal canal was contoured from the upper edge of Th12 to the lower edge of L3, and structures for the entire spinal canal (Th12–L3) as well as each vertebral body level (Th12, L1, L2, L3) were created using the first MRI. If the scanning area was not large enough to delineate the entire spinal canal or spinal cord, delineable parts of the spinal canal were created at each level. All the “transformation data” values were subsequently reset to zero, and the delineations were adjusted to the second and third MR images via deformable image registration (DIR) through the “Adapt Anatomy” function in Monaco. To confirm the accuracy of the DIR, manually rigid registration with or without manual modification of structure contouring (manual registration) was also performed by a radiation oncologist with 14 years of experience.

Calculation of margins and statistical analysis

Three-dimensional coordinates of each structure were obtained from the “center of structure” option of Monaco; the coordinates consisted of the x-axis, y-axis and z-axis, which were the lateral axis, craniocaudal axis and vertical axis, respectively, with three-dimensional coordinates in centimeters.

The intrafractional movement of each structure was calculated via subtraction between the first and second MR images and between the first and third MR images. The movements of the x-axis, y-axis and z-axis were expressed as X, Y and Z, respectively, and the 3D distance was calculated using the following formula: $\sqrt{X^{2} + Y^{2} + Z^{2}}$ . To evaluate the correlation, Pearson’s correlation coefficients were computed between the 3D distances calculated via DIR and those obtained via manual registration. Additionally, Pearson’s correlation coefficients were calculated to assess the discrepancy in 3D distances between the spinal cord and the spinal canal, in order to determine whether the movement of the spinal cord originates from the patient’s movement or from spinal cord itself within the spinal canal.

The concept, methodology and formula reported by McKenzie et al. and Suzuki et al. were used for the PRV margin calculation [12,13]. In MRgART with the adapt-to-shape method, which allows radiation oncologists to modify the contouring of the tumor and organs via on-line MRI, interfractional structure movement is modified at the time of the first MRI, effectively reducing interfractional setup margins to zero [14]. Therefore, we calculated the margins solely for the intrafractional movements by analyzing the three-dimensional coordinate shift of each structure point via the “center of structure” option. The intrafractional random error and systematic error were calculated from the intrafractional data, which included the patient-specific factors such as back pain, spinal stenosis, and muscle tension. While continuous and linearly increasing motion allows for margin approximation, the movements of the spinal cord and spinal canal do not drift and are not assumed to follow a linear pattern [15]. Therefore, the first, second, and third MRI were used to calculate the intrafractional random error and systematic error.

Intrafractional systematic error (Σ-intra): The average structural movements at each fraction were calculated by using the 3D distance from the first MRI to the second MRI (Distance1) and from the first MRI to the third MRI (Distance2). The overall mean ± standard deviation (SD) of these average movements for each fraction was then calculated across all patients. The resulting SD is termed SD1, representing Σ-intra (intrafractional systematic error).
Intrafractional random error (σ-intra): The mean ± SD between Distance1 and Distance2 was calculated for each fraction, and the SD for each fraction was determined (SD2). The root mean square of SD2 across all patients and fractions was then calculated and used as σ-intra, representing intrafractional random error.

Finally, the PRV margin was calculated using the following formula: 1.3×Σ-intra+0.5×σ-intra (hereafter referred to as the PRV margin). For reference, the margin formula for planning target volume (PTV) was also calculated using the following formula: 2.5×Σ-intra+0.7×σ-intra [16] (hereafter referred to as the Reference margin).

In addition to these margin formulas, 95% prediction intervals were also calculated via two-sided tests because asymmetrical structural movement can occur [17]. JMP v. 17.1.0 (SAS Institute, Cary, NA) was used for prediction interval calculations.

When the difference between Distance1 and Distance2 for each patient was compared, a two-sided paired t test was performed with EZR v1.54 [18]. The significance level was set to 5%.

Results

A total of 22 patients were identified, and all patients completed 3-fraction SRT for kidney cancer (Table 1). None of the patients had vertebral lesions, including spine metastases, symptomatic hernias or symptomatic spinal stenosis. The median interval between the first MRI scan and the second MRI scan was 14 minutes (interquartile range 12–18 minutes, range 8–28 minutes), and the median interval between the first MRI scan and the third MRI scan was 38 minutes (interquartile range 34–43 minutes, range 21–61 minutes).

Table 1. Patients characteristics and treatment information.

Category	Median (range) or distribution
Number of patients and treatment	22 patients and 66 treatments
Age	75 years (47–83 years)
Sex	Male: 17, Female: 5
Actual radiotherapy dose	42 Gy: 20, 30 Gy: 2
Waist belt	Yes: 18, No:4
Vertebral lesion	No: 22
Location of medullary cone	L1: 16, L2: 5, L3: 1^*
Intervals between the first MRI and the second MRI	14 minutes (8–28 minutes)
Intervals between the first MRI and the third MRI	38 minutes (21–61 minutes)
Intervals between beam on and beam off	12 minutes (8–23 minutes)

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*Patient whose medullary cone was located at the L3 level had six lumbar vertebrae.

The movement of the centers of the structures via the DIR method is summarized in Table 2 for Distance1 and in Table 3 for Distance2. Among the three directions, the absolute mean value of the z-axis (vertical direction) was the highest, indicating a preference for movement in the posterior direction. In contrast, the SD of the y-axis (craniocaudal direction) was the highest, indicating relatively large movement in the craniocaudal direction without a preference for the cranial or caudal direction. The 3D distances are also summarized in the tables. The correlation coefficients between DIR and manual registration via Distance1 and Distance2 were 0.76 (p<0.01) and 0.83 (p<0.01) for the spinal cord and 0.89 (p<0.01) and 0.88 (p<0.01) for the spinal canal, respectively. The correlation coefficients of the 3D distance from the DIR between the spinal cord and the spinal canal using Distance1 and Distance2 were 0.88 (p<0.01) and 0.92 (p<0.01), respectively. As a result, it was determined that the movement of the spinal cord originates from the patient’s movement. Additionally, the individual values of 3D distances for Distance1 and Distance2 of the spinal cord for each patient are plotted in Fig 1A and 1B, respectively. The overall mean of the average 3D distance across 3 fractions for each patient was 0.10 cm for Distance1 and 0.15 cm for Distance2 (p<0.01). The mean variance of the 3-fraction 3D distance for each of the 22 patients was 0.0021 cm for Distance1 and 0.0010 cm for Distance2 (p = 0.33). As shown in Fig 1, two patients (No. 10 and No. 18) exhibited larger values derived from spinal cord. The mean movements of Distance2 for Patient No. 10 along the x-axis, y-axis, z-axis, and 3D distance were 0.01 cm, −0.26 cm, −0.09 cm and 0.28 cm, respectively. For Patient No. 18, the corresponding values were 0.01 cm, −0.42 cm, 0.01 cm and 0.42 cm, respectively. Patient No. 10 reported increasing back pain over time while in the supine position, while no specific reason could be identified for the other patient. Examples of the MR images of these patients are shown in Figs 2 and 3.

Table 2. Movement of the center of the structures between the first and second MR images with deformable image registration.

	Axis^*	No.	Mean (cm)	SD	Range (cm)
Spinal canal	X	57†	<±0.01	0.04	−0.10, 0.09
(Th12–L3)	Y		<±0.01	0.09	−0.36, 0.12
	Z		−0.02	0.02	−0.09, 0.04
	3D distance		0.08	0.06	0.01, 0.36
Spinal cord	X	59	<±0.01	0.04	−0.12, 0.07
(Th12–cone)	Y		0.01	0.10	−0.36, 0.12
	Z		−0.04	0.03	−0.12, 0.02
	3D distance		0.10	0.07	0.01, 0.36
Th12	X	61	<±0.01	0.04	−0.10, 0.07
	Y		0.01	0.10	−0.36, 0.12
	Z		−0.03	0.03	−0.13, 0.02
	3D distance		0.09	0.07	0.01, 0.36
L1	X	61	<±0.01	0.04	−0.10, 0.08
	Y		<±0.01	0.10	−0.36, 0.12
	Z		−0.02	0.02	−0.11, 0.05
	3D distance		0.09	0.07	0.01, 0.36
L2	X	63	<±0.01	0.04	−0.12, 0.08
	Y		<±0.01	0.09	−0.36, 0.12
	Z		−0.02	0.03	−0.09, 0.05
	3D distance		0.08	0.07	0.01, 0.36
L3	X	61	<±0.01	0.04	−0.13, 0.11
	Y		−0.01	0.09	−0.36, 0.12
	Z		−0.02	0.03	−0.10, 0.06
	3D distance		0.08	0.07	0.01, 0.36

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*Positive directions of the x-axis (lateral axis), y-axis (craniocaudal axis) and z-axis (vertical axis) are the left, cranial and anterior directions, respectively. †The number 57 indicates that 57 MRI series included the scanning area from the upper edge of Th12 to the lower edge of L3 in both the first and second MRIs, and the spinal canal movement in these 57 MRI series was measured.

Abbreviations: No.: Number of measurable MRI series; SD: Standard deviation.

Table 3. Movement of the center of the structures between the first and third MR images with deformable image registration.

	Axis	No.	Mean (cm)	SD	Range (cm)
Spinal canal	X	52	<±0.01	0.06	−0.14, 0.10
(Th12–L3)	Y		−0.01	0.13	−0.42, 0.18
	Z		−0.05	0.05	−0.14, 0.09
	3D distance		0.13	0.09	0.02, 0.43
Spinal cord	X	55	−0.01	0.06	−0.14, 0.09
(Th12–cone)	Y		<±0.01	0.14	−0.42, 0.24
	Z		−0.07	0.05	−0.19, 0.05
	3D distance		0.15	0.08	0.02, 0.42
Th12	X	56	<±0.01	0.06	−0.13, 0.10
	Y		0.01	0.13	−0.42, 0.24
	Z		−0.05	0.04	−0.17, 0.06
	3D distance		0.14	0.08	0.01, 0.42
L1	X	58	<±0.01	0.05	−0.14, 0.10
	Y		<±0.01	0.14	−0.48, 0.18
	Z		−0.05	0.05	−0.15, 0.10
	3D distance		0.14	0.10	0.02, 0.49
L2	X	60	<±0.01	0.05	−0.16, 0.10
	Y		−0.01	0.14	−0.48, 0.18
	Z		−0.05	0.06	−0.19, 0.16
	3D distance		0.13	0.10	0.03, 0.50
L3	X	57	<±0.01	0.06	−0.21, 0.13
	Y		−0.02	0.13	−0.48, 0.18
	Z		−0.04	0.06	−0.20, 0.18
	3D distance		0.14	0.10	0.02, 0.51

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Abbreviations are the same as those in Table 2.

Fig 1 — (A) shows the movement from the planning MRI scan to the position verification MRI scan, and (B) shows the movement from the planning MRI scan to the posttreatment assessment MRI scan. The movements during the first, second, and third treatment fractions are plotted using circles, triangles, and squares, respectively.

Fig 2 — **10.** A and C show the contouring of the spinal cord (yellow) and spinal canal (pink) via the first MRI. B and D show the third MR image with the contouring of the spinal cord and spinal canal on the first MR image. On the third MRI (B and D), movement in the caudal and posterior directions was observed. There was relatively large movement in the caudal direction; however, a relatively small portion was out of the contour due to the cylindrical shape of the structures.

Fig 3 — The sagittal, axial, and coronal views in a checkerboard format comparing the first and third MRI scans are shown in A, B, and C, respectively. C shows that the movement of the vertebrae in the craniocaudal direction was easy to observe, and relatively large movements were observed in this direction.

The results of the PRV and Reference margin calculations are shown in Table 4. The calculated PRV margin for all directions of expansion was 0.11 cm for the spinal canal and the spinal cord. When asymmetrical PRV margins were considered, the 95% prediction intervals for the x-axis (positive direction is left), y-axis (positive direction is cranial), and z-axis (positive direction is anterior) were −0.10–0.10 cm, −0.23–0.22 cm and −0.12–0.04 cm for the spinal canal, respectively, and −0.11–0.09 cm, −0.23–0.25 cm and −0.14–0.03 cm for the spinal cord, respectively.

Table 4. The result of planning organ at risk volume margin calculation from the movement of the center of structures via MRI for adaptive planning, position verification and posttreatment assessment with deformable image registration.

	Axis	No.	Mean (cm)	SD	Range (cm)	95% prediction intervals^*	PRV / Reference margin from the formula
Spinal canal	X	109	<±0.01	0.05	−0.14, 010	−0.10, 0.10	0.07 / 0.13
(Th12–L3)	Y		<±0.01	0.11	−0.42, 0.18	−0.23, 0.22	0.16 / 0.30
	Z		−0.03	0.04	−0.14, 0.09	−0.12, 0.04	0.11 / 0.20
	3D		0.11	0.08	0.01, 0.43	0.25	0.11 / 0.21
Spinal cord	X	114	<±0.01	0.05	−0.14, 0.09	−0.11, 0.09	0.07 / 0.14
(Th12–cone)	Y		<±0.01	0.12	−0.42, 0.24	−0.23, 0.25	0.17 / 0.32
	Z		−0.05	0.04	−0.19, 0.05	−0.14, 0.03	0.06 / 0.11
	3D		0.12	0.08	0.01, 0.42	0.26	0.11 / 0.22
Th12	X	117	<±−0.01	0.05	−0.13, 0.10	−0.11, 0.10	0.07 / 0.14
	Y		0.01	0.12	−0.42, 0.24	−0.22, 0.25	0.17 / 0.31
	Z		−0.04	0.04	−0.17, 0.06	−0.12, 0.03	0.05 / 0.10
	3D		0.11	0.08	0.01, 0.42	0.25	0.11 / 0.21
L1	X	119	<±0.01	0.05	−0.14, 0.10	−0.10, 0.09	0.07 / 0.13
	Y		<±0.01	0.12	−0.48, 0.18	−0.25, 0.25	0.17 / 0.33
	Z		−0.04	0.04	−0.15, 0.10	−0.12, 0.04	0.05 / 0.10
	3D		0.11	0.09	0.01, 0.49	0.27	0.13 / 0.24
L2	X	123	<±0.01	0.05	−0.16, 0.10	−0.10, 0.10	0.05 / 0.10
	Y		−0.01	0.12	−0.48, 0.18	−0.25, 0.22	0.17 / 0.32
	Z		−0.03	0.05	−0.19, 0.16	−0.14, 0.06	0.06 / 0.12
	3D		0.11	0.09	0.01, 0.50	0.26	0.13 / 0.24
L3	X	118	<±0.01	0.05	−0.21, 0.13	−0.10, 0.11	0.07 / 0.14
	Y		−0.01	0.11	−0.48, 0.18	−0.25, 0.21	0.16 / 0.30
	Z		−0.03	0.05	−0.20, 0.18	−0.14, 0.07	0.07 / 0.13
	3D		0.11	0.09	0.01, 0.51	0.26	0.13 / 0.24

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*Prediction intervals for the x-axis, y-axis and z-axis were calculated via two-sided tests, and those for the 3D distance were calculated via a one-sided test for the upper limit.

Abbreviations: No.: Number of measurable MRI series, SD: Standard deviation, PRV: Planning organ at risk volume,: 3D: 3D distance.

Discussion

This study revealed intrafractional movement and recommended margins during MRgART. The strength of this study was the use of MRI for delineation. Unlike previous studies that relied on bony landmarks, MRI enabled the direct contouring of the spinal cord and spinal canal. From this perspective, this study is the first to directly measure the movement of these structures during radiotherapy [13,19]. As a result, the movement of the spinal cord itself within the spinal canal was not observed, and the movement of the spinal cord resulted from the patient’s movement. Our motivation was to reduce the PRV margin to 0 cm using MRgART with the adapt-to-shape method because the spinal cord and spinal canal are minimally affected by respiratory motion and organ movement during MRgART. However, the results indicated that there was some movement originated from the patient’s movement, including muscle relaxation or postural adjustments. According to dosimetric analysis of reirradiation via stereotactic radiotherapy (SRT) for the thoracic spine, MRgART with the adapt-to-shape method using on-line MRI increases the minimum dose to the gross tumor volume (GTV) in most cases while maintaining spinal cord doses similar to those in reference radiotherapy plans (clinical plans) [20]. In contrast to the adapt-to-shape method, previous studies reported that all plans using the adapt-to-position method, which provides only a shift of the plan to the patient using on-line MRI, presented a 10% or greater increase in the near maximum dose to the spinal cord. Overall, even with MRgART, it was difficult to reduce the PRV margin to 0 cm.

Because bony anatomical matching has long been in use, investigations of the PRV margin and clinical evidence for the PRV margin for the spinal cord have already been reported. Suzuki et al. reported PRV margins of 0.22–0.24 cm for the cervical vertebrae, which were calculated from interfractional and intrafractional errors [13]. They measured intrafractional organ movement via 2D films recorded every 3 minutes over a 15-minute period on an X-ray simulator. In a randomized phase 2/3 trial comparing 20 Gy in 5 fractions with 24 Gy in 2 fractions (SRT) for spinal metastases, no cases of radiation-induced myelopathy were documented using a 0.15–0.20 cm PRV margin for the spinal cord, with SRT showing superiority in pain relief [21]. This safety was achieved with the caution that an additional intrafractional scan for positioning was performed if the treatment length exceeded 30 minutes. This necessity for an additional intrafractional scan was confirmed in our study, which revealed that the intrafractional movement of the spinal cord (representing the patient’s movement) significantly increased over time, with the mean intrafractional movement reaching 0.15 cm at the third MRI (Fig 1 and Table 3). In contrast, radiation-induced myelopathy occurred in 1 out of 86 patients when a 0 cm margin was used for the PRV and PTV via bony anatomical matching [22]. In a prospective trial comparing 8 Gy in 1 fraction with 16–18 Gy in 1 fraction (SRT) using a similar margin concept for the PRV and PTV, the incidence of spinal cord signal changes on MRI at 24 months after radiotherapy was reported to be 3.6% in the 16–18 Gy arm and 1.7% in the 8 Gy arm [23]. Although late spinal cord complications were not reported, superiority in pain relief with SRT was not obtained in the trial. Excessive shrinkage of the PRV margins could lead to results similar to those suggested by our study although the adapt-to-shape method was available in MRgART.

In MRgART, margins have been the focus of investigation primarily for PTV. The investigation of PTV margin via MRgART for pelvic oligometastases reported that only a 2 mm PTV margin achieved a minimum of 95% GTV coverage while reducing the dose to the bowel [24]. The validity of PTV margin reduction is often evaluated by GTV dose coverage via online planning MRI and posttreatment MRI (the first and third MR images, respectively, in this study) [25,26]. For example, margin assessments for rectal cancers have investigated the prescribed dose coverage of 95% of the GTV in 90% of patients [26]. In intracranial MRgART, a 3 mm PTV margin was recommended to cover 98% of the clinical target volume in 95% of the fractions in 95% of patients [27]. Although the standard to set the PTV margin for maintaining target dose coverage was not established, one of the standards would be 90% confidence of coverage of the clinical target volume by the 95% isodose, which used to create the Van Herk formula. As MR-Linac is a relatively new modality, more data are needed for the PTV margin and the PRV margin in MRgART.

The difficulty in reducing the PRV and PTV margins in MRgART lies in the challenge of minimizing treatment time. First, the adapt-to-shape method, which requires more time than the adapt-to-position method, is essential because the latter provides only plan shifts in the x-, y-, and z-axis directions (three degrees of freedom) [28]. The adapt-to-shape method ensures greater accuracy than the 6-axis correction in six degrees of freedom. Second, optimization recalculation is needed for each treatment fraction in MRgART. Third, Elekta Unity uses 7 MV flattening-filter-free photons, but the dose rate is fixed at 425 monitor units per minute [29]. Compared with 2400 monitor units per minute of conventional Linac, Elekta Unity requires longer treatment times [30]. Finally, Elekta Unity does not yet perform volumetric modulated arc therapy, which would shorten treatment times compared with intensity-modulated radiotherapy [31]. A comparison of beam-on times for MR-based IMRT using Co-60 sources, MR-Linac IMRT and volumetric modulated arc therapy via conventional Linac for spine SRT reported mean beam-on times ± SDs of 49.7± 11.1 minutes, 27.6±5.1 minutes and 4.0±1.1 minutes, respectively [32]. As a result, long treatment times are needed for MRgART. In this situation, proper optimization recalculation using the second MRI might contribute to reducing PTV margins if intrafractional movement is detected and corrected [26].

The PRV margins for the spinal cord and the spinal canal in this study were 0.11 cm and 0.11 cm, respectively. The results of the PRV margins are relatively smaller than the PRV margins from prospective trials of conventional Linac; however, these margins may appear insufficient for the y-axis (craniocaudal direction) [21]. This is because the formula is designed to avoid underestimating the high-dose components of serial structures in 90% of cases [12]. As a result, the effect of movement in the craniocaudal direction is considered relatively small due to the cylindrical shape of the spinal canal and spinal cord (Fig 2). Therefore, the calculated PRV margin is considered valid. However, it should be noted that the variations also reported that the multiplying value of sigma ranged from 1.2×Σ to 1.8×Σ and from −0.2×σ to 0.6×σ [33]. Further margin information, including 95% prediction intervals, was reported in this study. Relatively small prediction intervals were observed in the left, right, and anterior directions, all within ±0.11 cm. In the z-axis (vertical direction), the calculated margins in the posterior direction were larger than those in the anterior direction, suggesting that adding asymmetrical margins could be an option.

This study was subject to several limitations. Because MR-Linac is a relatively new modality, patient immobilization methods are still being developed. Proper body fixation, such as a vacuum cushion can reduce intrafractional movement [34]. Moreover, the retrospective nature of this study is associated with inherent limitations. The intervals between the first MRI and the second or third MRI varied, and the areas of the MRI scans also varied, leading to some missing data. In this study, SRT was performed in only 3 fractions. Using the margin formula in such cases is limiting because the formula assumes an infinite number of fractions [19].

In conclusion, the PRV margin for the spinal cord is necessary even if MRgART with the adapt-to-shape method is used. Based on the PRV margin formula and 95% prediction intervals, the 3D symmetric PRV margins are 0.11 cm and 0.26 cm, respectively, for the spinal cord and 0.11 cm and 0.25 cm, respectively, for the spinal canal. This study also suggested that directional preferences exist for movement; therefore, asymmetric PRV margins for the spinal cord and the spinal canal might be an option.

Supporting information

S1 File. Detailed patient information and three-dimensional coordinates of structures for each fraction.

(XLSX)

pone.0312032.s001.xlsx^{(43.6KB, xlsx)}

Acknowledgments

We thank to the radiation technologists at Tohoku University Hospital who contributed to the acquisition of MRI data.

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

TY received the JSPS KAKENHI [Grant Number 24K10879]. URL: https://www.jsps.go.jp/english/ The funder had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0312032.r001

Decision Letter 0

Minsoo Chun

6 Aug 2024

PONE-D-24-26533Investigation of intra-fractional spinal cord and spinal canal movement during stereotactic MR-guided online adaptive radiotherapy for kidney cancerPLOS ONE

Dear Dr. Yamamoto,

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Additional Editor Comments:

Both reviewers pointed out several English grammer errors.

Provide types of the MRgRT machine, and prescription information in Abstract.

There are several previous researches regarding need for PRV margin in MRgRT for other treament site, please search and add them in Introduction.

Provide CT scan information in M&M.

Arrange Table line for better understanding.

In Fig 1, label x and y axis, and mark with different shape to distinguish each point.

In Fig 2, describe what a, b, and c means.

[Note: HTML markup is below. Please do not edit.]

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Reviewer #1: Partly

Reviewer #2: Partly

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Reviewer #2: Yes

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Reviewer #2: No

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Reviewer #2: No

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Reviewer #1: Authors investigated intrafractional spinal cord movement and it is well written and might be beneficial to medical physics community. Here are my comments.

Introduction section - " P3L52-53, " How shold RV margins be applied to organs?" please rephrase with proper grammar.

Method section - P4L74-77, " why is the letter size not uniform?

in P4L87, "The MR-Linac of this study was the Elekta Unity. please rephrase with proper grammar.

in P5L106, how did use DIR in Monaco, did you use VOI?

in P6L122, what do you mean by inter-fraction errors were modified?

in P6132-135, can you justify your method of considering Distance2 as interactional errors even though two MRIs are only 38 min apart?

Result section -

in P7L139, can you also compare with Van Herk's margin recipe (2.5 Big Sigma +0.7 little sigma)?

in Table2, please clarify what No. (57) is?

It seems redundant and excessive in data display between Table2-5, did you use DIR at all for manual contouring?

in P11L193-196 I cannot agree with author's speculation.

Discussion section - the 1.6mm motion of spine cord is from movement of patient or from cord itself inside of spinal canal?

Reviewer #2: The authors investigated the intrafractional movement of spinal cord and spinal canal during MR-guided stereotactic radiotherapy for kidney cancer. This study is of interest in the field of radiation oncology. However, it’s not ready for publication in its current state. The English need to be checked. A few details still need to be clarified, and the data need to be presented in a clearer manner.

Line 123. Explain what is “the average structure movement”. Is it an average of certain points in the structure, or all points in the structure?

Line 123-136. It’s hard to understand the calculations. Please check English to make them clear to understand. Is SD1 calculated for Distance 1 or Distance 2, or both? What does it mean “average movement between Distance 1 and Distance 2”. Similar questions to those in Secondly…, and Thirdly…

Line 139. PRV margin formula needs to be made easy to read, e.g., “Σ - intra2” change to (Σ-intra)2. Please provide more detail about the margin calculation model used and comment on its appropriateness for hypofractionated or SBRT situations.

Table 4-5, too many raw data tables of the distances. Suggest that authors summarize or just show/plot the difference of results using manual registration from those using deformable image registration. This can tell the accuracy of deformable image registration.

Table 2 and 3 and Figure 1 showed two patients had larger Y direction movement. Please explain or discuss the outliers?

Figure 2. please add space between images. also explain what are (A), (B), (C) presenting. Are they for different patients (specify patient No.). Please use the same contrast to show cord/canal and vertebra discs as in (B) so we can see craniocaudal shifts. Also suggest to show the spinal ord/canal contours on one of the images.

Table 6. suggest to calculate margins for each direction of X, Y, and Z. Authors mentioned that the shift was high in vertical direction, and the expectation of PRV margin reduction to 0cm. Authors also concluded at the end that “there are directional preference for movement”. So it’s better to provide margin in each direction, so we can know the minimal margin to apply in different direction when treating kidney cancer with MRgRT.

Line 266. Should it be “48.82±10.44 minutes and 3.95±1.13 minutes” for IMRT and VMAT, respectively?

Minor comments:

Suggest use 3D instead of “straight-line”.

Change “at the timing of” to “at the time of”.

Line 52: how “should” PRV margins…

Line 95: “post-treatment planning” should be “post-treatment”?

Line 134: was calculated “for” each “patient”…

Line 135: was calculated from all patients’ “” average data…

Line 255: “shift in the x, y, and z-axis direction” – why this is “four” degrees of freedom?

Line 269: suggest remove “unfortunately”

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Reviewer #2: No

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PLoS One. 2024 Oct 30;19(10):e0312032. doi: 10.1371/journal.pone.0312032.r002

Author response to Decision Letter 0

20 Aug 2024

The following response was also provided in Response to Reviewers.docx

file.

Response to additional editor comments:

Both reviewers pointed out several English grammer errors.

Response:

Thank you for your comments. We improved the English using professional proofreading. We enclosed certification of English professional proofreading.

Provide types of the MRgRT machine, and prescription information in Abstract.

Response:

Thank you for your advice. We added the information about MRgRT machine and prescription information in Abstract.

There are several previous researches regarding need for PRV margin in MRgRT for other treament site, please search and add them in Introduction.

Response:

Thank you for your suggestion. We searched for relevant papers and found several studies that discuss PRV margins in the context of PTV margin reduction in MRgRT for other treatment sites. After considering the overall structure and flow of the manuscript, we have added a discussion of these findings in the Discussion section.

Provide CT scan information in M&M.

Response:

Thank you for your advice. We added the information about CT scan in M&M.

Arrange Table line for better understanding.

Response:

Thank you for your suggestion. We reviewed the tables and made modifications to improve clarity and understanding.

In Fig 1, label x and y axis, and mark with different shape to distinguish each point.

In Fig 2, describe what a, b, and c means.

Response:

Thank you for your advice. We modified Fig 1 and 2.

Response to Reviewers

For Reviewer #1

Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: No

Response:

Thank you for your comments. We improved the English using professional proofreading. We enclosed certification of English professional proofreading.

1) Introduction section - " P3L52-53, " How shold RV margins be applied to organs?" please rephrase with proper grammar.

Response:

Thank you for your advice. We modified the sentence.

“How should PRV margins be applied to organs?”

2) Method section - P4L74-77, " why is the letter size not uniform?

Response:

Thank you for pointing this out. We have now standardized the letter size to ensure consistency throughout the manuscript.

3) in P4L87, "The MR-Linac of this study was the Elekta Unity.” please rephrase with proper grammar.

Response:

Thank you for your suggestion. We modified the sentence.

“The MR-Linac used in this study was the Elekta Unity.”

4) in P5L106, how did use DIR in Monaco, did you use VOI?

Response:

Thank you for your question. We did not use VOI; instead, we utilized the “Adapt Anatomy” function in Monaco to align the first MRI with the second and third MRIs. In the “Adapt Anatomy” function, VOI cannot be used. While VOI could be applied if image fusion were used, but we did not use image fusion. If image fusion was used, we ensured that all values in the “Transformation Data” were reset to zero to accurately measure coordinate deviation. To clarify this, we have added the following explanation to the manuscript:

“All the “transformation data” values were subsequently reset to zero, and the delineations were adjusted to the second and third MR images via deformable image registration (DIR) through the “Adapt Anatomy” function in Monaco.”

5) in P6L122, what do you mean by inter-fraction errors were modified?

Response:

Thank you for question. The sentence meant that the inter-fractional structure changes (shift, rotation or deformation) were modified using ATS method. We modified the terms “inter-fraction errors” as follows:

“interfractional structure movement is modified at the time of the initial scan, effectively reducing interfractional setup margins to zero”

6) in P6L132-135, can you justify your method of considering Distance2 as interactional errors even though two MRIs are only 38 min apart?

Response:

Thank you for your question. As described in the Materials and Methods section, we based our approach on the methodology reported by Suzuki et al. (https://doi.org/10.1016/j.radonc.2006.03.006). In their study, they calculated intrafractional organ motions using an X-ray simulator with images taken only 15 minutes apart from the initial image. Therefore, we believe our method is valid, even with MRIs taken 38 minutes apart. To clarify this, we have added the following information to the Discussion section:

“Suzuki et al. reported PRV margins of 0.22–0.24 cm for the cervical vertebrae, which were calculated from interfractional and intrafractional errors [13]. They measured intrafractional organ movement via 2D films recorded every 3 minutes over a 15-minute period on an X-ray simulator”

7) Result section -

in P7L139, can you also compare with Van Herk's margin recipe (2.5 Big Sigma +0.7 little sigma)?

Response:

Thank you for your proposal. Yes, we can calculate the Van Herk's margin recipe. The formula added the results in method section and in the table 4.

8) in Table2, please clarify what No. (57) is?

Response:

Thank you for your comment. "No. (57)" of spinal canal refers to the 57 MRI series that included the scanning area from the upper edge of Th12 to the lower edge of L3 in both the first MRI and the second MRI. The spinal canal movement in these 57 MRI series was measured. We have added this clarification as a footnote in Table 2:

“†The number 57 indicates that 57 MRI series included the scanning area from the upper edge of Th12 to the lower edge of L3 in both the first and second MRIs, and the spinal canal movement in these 57 MRI series was measured.”

9) It seems redundant and excessive in data display between Table2-5, did you use DIR at all for manual contouring?

Response:

Thank you for your comments and advice. We used rigid registration for manual registration, as described in the method section. We have revised the text in the methods section to clarify this:

“To confirm the accuracy of the DIR, manually rigid registration with or without manual modification of structure contouring (manual registration) was also performed”

We agree that the tables were excessive, and have therefore moved Tables 4 and 5 to the supplemental materials.

10) in P11L193-196 I cannot agree with author's speculation.

Response:

Thank you for your advice. The speculation is not suitable for result section, therefore the sentence removed from figure legends.

11) Discussion section - the 1.6mm motion of spine cord is from movement of patient or from cord itself inside of spinal canal?

Response:

Thank you for your question. We believe the movement is primarily due to patient movement. This conclusion is supported by the high correlation coefficients between the 3D distances of the spinal cord and spinal canal at the second and third MRIs, which were 0.88 (p<0.01) and 0.92 (p<0.01), respectively. These high coefficients suggest that the movements of the spinal cord and spinal canal were closely related, likely reflecting overall patient movement rather than independent movement of the spinal cord within the canal. However, we cannot entirely rule out some intrinsic movement of the cord itself. We have added this information (the correlation coefficients) to the Results section.

For Reviewer #2

1) 3. Have the authors made all data underlying the findings in their manuscript fully available? Reviewer #2: No

A few details still need to be clarified, and the data need to be presented in a clearer manner.

Response:

Thank you for your comments. We apologize for the confusion caused by the previous Excel files. We have now uploaded clearer raw data, including the coordinate points. Thank you again for bringing this to our attention.

2) 4. Is the manuscript presented in an intelligible fashion and written in standard English? Reviewer #2: No

The English need to be checked.

Response:

Thank you for your comments. We improved the English using professional proofreading. We enclosed certification of English professional proofreading.

3) Line 123. Explain what is “the average structure movement”. Is it an average of certain points in the structure, or all points in the structure?

Response:

Thank you for your question. In Monaco, we determine a specific point within the structure using the 'center of structure' option. To clarify this, we have added the following sentence immediately before the sentence in question:

“Three-dimensional coordinates of each structure were obtained from the “center of structure” option of Monaco; the coordinates consisted of the x-axis, y-axis and z-axis, which were the lateral axis, craniocaudal axis and vertical axis, respectively, with three-dimensional coordinates in centimeters.”

4) Line 123-136. It’s hard to understand the calculations. Please check English to make them clear to understand. Is SD1 calculated for Distance 1 or Distance 2, or both? What does it mean “average movement between Distance 1 and Distance 2”. Similar questions to those in Secondly…, and Thirdly…

Response:

Thank you for your question, and we apologize for the lack of clarity in our original explanation. We understand that this paragraph was complex, particularly regarding the calculations involving SD1, Distance1, and Distance2. With the assistance of English proofreading, we have revised this section to improve clarity:

“1. 1. Intrafractional systematic error (Σ-intra): The average structural movements at each fraction were calculated by using the 3D distance from the first MRI to the second MRI (Distance1) and from the first MRI to the third MRI (Distance2). The mean ± standard deviation (SD) of these average movements across all fractions was calculated, with the resulting SD termed SD1, which represents Σ-intra (intrafractional systematic error).

2. Intrafractional random error (σ-intra): The mean ± SD between Distance1 and Distance2 at each fraction was calculated, and the SD for each fraction was determined (SD2). The root mean square of SD2 from all fractions was calculated, which was used as σ-intra, representing intrafractional random error.

3. Interfractional systematic error (Σ-inter): The average Distance2 for each patient was calculated from 3-fraction Distance2 data, and the mean ± SD of these averages across all patients was determined, with the resulting SD termed SD3. SD3 was used as Σ-inter, representing interfractional systematic error.

4. Interfractional random error (σ-inter): For each patient, the mean ± SD was calculated via 3-fraction Distance2 data (SD4) data. The root mean square of SD4 from all patients was calculated, which was used as the σ-inter, representing interfractional random error.”

5) Line 139. PRV margin formula needs to be made easy to read, e.g., “Σ - intra2” change to (Σ-intra)2. Please provide more detail about the margin calculation model used and comment on its appropriateness for hypofractionated or SBRT situations.

Response:

Thank you for your advice. We have revised the formula for clarity, making it easier to read. Additionally, we have provided more details about the margin calculation model in the Methods and Discussion sections. However, we acknowledge that applying this formula to hypofractionated or SBRT situations is a limitation. To address this, we also calculated the 95% prediction intervals and discussed this limitation in both the Discussion section and the limitations paragraph.

We have added the following discussion:.

“This inconsistency partly arises because the formula assumes an infinite number of fractions, which may not be applicable for MRgART with a small number of fractions [16,25]. To account for this assumption, we also examined the 95% prediction intervals, and the results were consistent with the PRV margin formula (Table 4).”

“In this study, SRT was performed in only 3 fractions. Using the margin formula in such cases is limiting because the formula assumes an infinite number of fractions [19].”

6) Table 4-5, too many raw data tables of the distances. Suggest that authors summarize or just show/plot the difference of results using manual registration from those using deformable image registration. This can tell the accuracy of deformable image registration.

Response:

Thank you for your advice. Another reviewer also pointed out the issue of having too many tables. Therefore, we have removed Tables 4 and 5 and included them as supplementary materials. To demonstrate the accuracy of deformable image registration (DIR), we calculated Pearson's correlation coefficients between the 3D distances obtained using DIR and those obtained through manual registration.

Method section: “To evaluate the correlation, Pearson's correlation coefficients were computed between the 3D distances calculated via DIR and those obtained via manual registration.”

Result section: “The correlation coefficients between DIR and manual registration via Distance1 and Distance2 were 0.76 (p<0.01) and 0.83 (p<0.01) for the spinal cord and 0.89 (p<0.01) and 0.88 (p<0.01) for the spinal canal, respectively.”

7) Table 2 and 3 and Figure 1 showed two patients had larger Y direction movement. Please explain or discuss the outliers?

Response:

Thank you for your question. As you pointed out, two patients exhibited larger movements. Upon review, we found that one patient experienced increasing back pain over time while in the supine position, and the other patient, although without complaints, had a body mass index (BMI) of 32, which may have influenced the movement. We have added this information to the Discussion section.

" As shown in Figure 1, two patients (No. 10 and No. 18) exhibited larger spinal cord movements. One patient reported increasing back pain over time while in the supine position, and the other patient, although asymptomatic, had a body mass index (BMI) of 32, which may have influenced the results."

8) Figure 2. please add space between images. also explain what are (A), (B), (C) presenting. Are they for different patients (specify patient No.). Please use the same contrast to show cord/canal and vertebra discs as in (B) so we can see craniocaudal shifts. Also suggest to show the spinal ord/canal contours on one of the images.

Response:

Thank you for your comments. We have addressed your suggestions by splitting Figure 2 into two separate figures: Figure 2 and Figure 3. Figure 2 now shows images from Patient No. 10, including contouring of the spinal cord and spinal canal. Unfortunately, it was challenging to maintain the same contrast for displaying the cord/canal and vertebrae discs due to the fat suppression used in T2-weighted images, as the contrast varies depending on the fat content of the discs. Figure 3 presents images from Patient No. 18 using a checkerboard view for comparison.

9) Table 6. suggest to calculate margins for each direction of X, Y, and Z. Authors mentioned that the shift was high in vertical direction, and the expectation of PRV margin reduction to 0cm. Authors also concluded at the end that “there are directional preference for movement”. So it’s better to provide margin in each direction, so we can know the minimal margin to apply in different direction when treating kidney cancer with MRgRT.

Response:

Thank you for your advice. We calculated the margins for X, Y and Z directions, and the result was added in the table.

10) Line 266. Should it be “48.82±10.44 minutes and 3.95±1.13 minutes” for IMRT and VMAT, respectively?

Response:

Thank you for your pointing this out. Thie sentence meant exactly what you mentioned. We modified this sentence.

“A comparison of intensity-modulated radiotherapy of the Co-60 MR-Linac system with volumetric modulated arc therapy of conventional Linac for spine SRT reported mean beam-on times ± SD of 48.82±10.44 minutes and 3.95±1.13 minutes, respectively.”

11) Suggest use 3D instead of “straight-line”.

Response:

Thank you for your advice. We modified this point using “3D distance” instead of “straight-line”.

12) Change “at the timing of” to “at the time of”.

Line 52: how “should” PRV margins…

Line 95: “post-treatment planning” should be “post-treatment”?

Line 134: was calculated “for” each “patient”…

Line 135: was calculated from all patients’ “” average data…

Line 269: suggest remove “unfortunately”

Attachment

Submitted filename: Response to Reviewers.docx

pone.0312032.s002.docx^{(31.5KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0312032.r003

Decision Letter 1

Minsoo Chun

20 Sep 2024

PONE-D-24-26533R1Investigation of intrafractional spinal cord and spinal canal movement during stereotactic MR-guided online adaptive radiotherapy for kidney cancerPLOS ONE

Dear Dr. Yamamoto,

Please submit your revised manuscript by Nov 04 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Minsoo Chun, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments :

I agree with both reviewers, but the grammar needs clarification.

In Figure 1, for example, there are redundant expressions regarding "first," "second," and "third," which can be interpreted as fractions or scans. Additionally, I find it difficult to agree that the range of plots in Figure 1B is narrower than those in 1A. Please clarify these points.

I also recommend that the figure caption be placed below the figure.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: No

Reviewer #2: No

**********

6. Review Comments to the Author

Reviewer #1: Thank you for the authors' hard work on the revision and responses. The revised manuscript looks much improved and clean. However, English grammar seems still need to be corrected in the entire manuscript. for example,

P3L46 - " planning the organ as risk volume"

P3L61 - " INevertheless"

P4L71 - "PRV margin.."

P19L346 - A Moreover

P19L352 - In conclusion, ta PRV...

And these are minor comments as below.

P5L97 - please describe the detail of T2 MRI protocol used.

As you said in the discussion P17L307, Van Herk's model is calculated for 90% confidence of coverage of CTV by 95% isodose. so, basically 90% of pt population will receive 95% of CTV dose with that margin formular. I have 3 IMPORTANT Qs since this is your key results.

1. How about the formular you used--> 1.3xbigSigma + 0.5xlittleSigma in P8L160? if we use that margin, what statistical meaning does this formular have to do with CTV coverage and pt population?

2. why are there a big discrepancy between 95% prediction intervals (0.26cm) and PRV margin (0.16) from the formular in Table 4?

3. it is hard to understand the rational ("inconsistency") regarding why you chose 95% prediction instead of Van Herk's formular on P17L308-312.

P9L196-197 I still do not agree with authors' interpretation of the results and significance of it.

P10L201-105 please describe more detail like larger movement of two patients and meaning of BMI 32. you mean larger pt tends to move more?

Throughout the paper, please clarify if the motion comes from patient's motion or spinal cord motion itself inside of spinal canal. You mentioned that you saw some specific cord motion, please describe in detail.

Unusually the Figure captions are located in the top of the figures, and it seems confusing, please check the PLOS ONE standard.

P18L325 - 48.82min is beam-on time or total treatment time?

P18L336-338 - it is hard to follow the meaning and significance of these sentences.

In discussion section, it was confusing because "PRV margin" and "PTV margin" were mentioned interchangeably. please clarity them in entire section for readers' better understanding. Thanks.

Reviewer #2: English is better than last version. A few more details still need to be clarified.

Major comments:

Line 143-158: both Distance1 and Distance2 are intrafractional errors. Why there are interfractional systematic error (3) and interfraction random error (4) calculated here (no interfractional structure movement considered in this study as mentioned in line 132-133)? To my understanding, these errors in 3 and 4 are standard intrafractional systematic and random errors calculated using Distance2, which is larger than Distance1. The errors calculated in 1 and 2 are not clear to me. I guess the authors wanted to use the average of Distance1 and Distance2 to calculate the systematic and random error, but I don’t see these errors are for each patient or for all patients. In my opinion, there are only intrafractional errors should be calculated and authors can use either Distance2 only (most conservative), or Distance1 only, or average of Distance1 and Distance2. Combining 1 and 2 with 3 and 4 (formula in line 160 and 163) is not reasonable to me, because they are both intrafractional errors and Distance2 is used in both pairs, thus may overestimate the margins. The authors should provide the reference for error calculation method in 1 and 2, or explain the method if they developed it.

Line 182-193: I think the movement data with manual registration are not needed to be included in this manuscript, since the correlation of DIR and manual are presented in lines 189-193.

Line 196-197: “the absolute values tended to increase from Figure 1A to Figure 1B, whereas the scatter of the plots per patient tended to decrease from Figure 1A to Figure 1B”. I only see 8/22 patients had decreased scatter.

Line 199: define “dispersion” of the 3D distance.

Line 201-203: specify the patient # who reported back pain, and patient who had body mass index of 32.

Line 246: Table 4 listed the PTV margin, but never mentioned PTV motion data.

Line 292 paragraph: PTV margin is not a topic in this study.

Line 354-355: the PRV margins for spinal cord are numbers (0.16cm and 0.26cm), but for spinal canal are ranges (0.16-0.19cm and 0.25-0.27cm)?

Minor comments:

Figure legends should be below the Figures.

Line 29: change “postplan” to “posttreatment” since you use “posttreatment” in the other places.

Line 61: Correct spelling “Nevertheless”.

Line 198: what dose this mean: “The mean 3-fraction mean 3D distance”?

Line 346: remove “A” before “Moreover”.

Line 352: correct “ta PRV”. Do you mean “The PRV”?

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No

**********

PLoS One. 2024 Oct 30;19(10):e0312032. doi: 10.1371/journal.pone.0312032.r004

Author response to Decision Letter 1

24 Sep 2024

We have enclosed the responses to Reviewer 1, Reviewer 2, and the Editor in the 'Revised Manuscript with Track Changes.docx' file.

Attachment

Submitted filename: Response to ReviewersR2.docx

pone.0312032.s003.docx^{(32.3KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0312032.r005

Decision Letter 2

Minsoo Chun

30 Sep 2024

Investigation of intrafractional spinal cord and spinal canal movement during stereotactic MR-guided online adaptive radiotherapy for kidney cancer

PONE-D-24-26533R2

Dear Dr. Yamamoto,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Minsoo Chun, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

I accept this manuscript for publication.

Minor comments should be corrected in the final submission.

1. Unit in Table 2-4.

2. Figure 1: Plot should be larger (or fill and blank) for better visualization, and I think legend is necessary.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: Overall, all comments were addressed, and English was corrected. Please add unit "cm" for data in Table 2-4. No other comments.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No

**********

PLoS One. doi: 10.1371/journal.pone.0312032.r006

Acceptance letter

Minsoo Chun

21 Oct 2024

PONE-D-24-26533R2

PLOS ONE

Dear Dr. Yamamoto,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

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on behalf of

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 File. Detailed patient information and three-dimensional coordinates of structures for each fraction.

(XLSX)

pone.0312032.s001.xlsx^{(43.6KB, xlsx)}

Attachment

Submitted filename: Response to Reviewers.docx

pone.0312032.s002.docx^{(31.5KB, docx)}

Attachment

Submitted filename: Response to ReviewersR2.docx

pone.0312032.s003.docx^{(32.3KB, docx)}

Data Availability Statement

All relevant data are within the manuscript and its Supporting Information files.

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PERMALINK

Investigation of intrafractional spinal cord and spinal canal movement during stereotactic MR-guided online adaptive radiotherapy for kidney cancer

Takaya Yamamoto

Shohei Tanaka

Noriyoshi Takahashi

Rei Umezawa

Yu Suzuki

Keita Kishida

So Omata

Kazuya Takeda

Hinako Harada

Kiyokazu Sato

Yoshiyuki Katsuta

Noriyuki Kadoya

Keiichi Jingu

Roles

Abstract

Background and purpose

Materials and methods

Results

Conclusions

Introduction

Materials and methods

Patient selection and ethics

SRT procedure, MRI scan and contouring for spinal cord and spinal canal

Calculation of margins and statistical analysis

Results

Table 1. Patients characteristics and treatment information.

Table 2. Movement of the center of the structures between the first and second MR images with deformable image registration.

Table 3. Movement of the center of the structures between the first and third MR images with deformable image registration.

Fig 1. Individual 3D distance data of intrafractional movement values derived from spinal cord.

Fig 2. An example of an MRI image of patient no.

Fig 3. MRI images of patient no. 18.

Table 4. The result of planning organ at risk volume margin calculation from the movement of the center of structures via MRI for adaptive planning, position verification and posttreatment assessment with deformable image registration.

Discussion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Minsoo Chun

Roles

Author response to Decision Letter 0

Decision Letter 1

Minsoo Chun

Roles

Author response to Decision Letter 1

Decision Letter 2

Minsoo Chun

Roles

Acceptance letter

Minsoo Chun

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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