Setup uncertainties and appropriate setup margins in the head-tilted supine position of whole-brain radiotherapy (WBRT).

Various applications of head-tilting techniques in whole-brain radiotherapy (WBRT) have been introduced. However, a study on the setup uncertainties and margins in head-tilting techniques has not been reported. This study evaluated the setup uncertainties and determined the appropriate planning target volume (PTV) margins for patients treated in the head-tilted supine (ht-SP) and conventional supine position (c-SP) in WBRT. Thirty patients who received WBRT at our institution between October 2020 and May 2021 in the c-SP and ht-SP were investigated. The DUON head mask (60124, Orfit Industries, Wijnegem, Belgium) was used in the c-SP, and a thermoplastic U-Frame Mask (R420U, Klarity Medical & Equipment Co. Ltd., Lan Yu, China) was used in the ht-SP. Daily setup verification using planning computed tomography (CT) and cone-beam CT was corrected for translational (lateral, longitudinal, and vertical) and rotational (yaw) errors. In the c-SP, the means of systematic errors were -0.80, 0.79, and 0.37 mm and random errors were 0.27, 0.54, and 0.39 mm in the lateral, longitudinal, and vertical translational dimensions, respectively. Whereas, for the ht-SP, the means of systematic errors were -0.07, 0.73, and -0.63 mm, and random errors were 0.75, 1.39, 1.02 mm in the lateral, longitudinal, and vertical translational dimensions, respectively. The PTV margins were calculated using Stroom et al.'s [2Σ+0.7σ] and van Herk et al.'s recipe [2.5Σ+0.7σ]. Appropriate PTV margins with van Herk et al.'s recipe in WBRT were <2 mm and 1.5° in the c-SP and <3 mm and 2° in the ht-SP in the translational and rotational directions, respectively. Although the head tilt in the supine position requires more margin, it can be applied as a sufficiently stable and effective position in radiotherapy.

Introduction

Radiotherapy for patients with brain tumours are based on various factors, such as the size, location, and cell type of the primary tumour. Whole-brain radiotherapy (WBRT) is a commonly used effective technique to relieve neurological symptoms, improve the quality of life, and prolong survival [.

In our previous study [, we have demonstrated that head-tilting techniques can be effectively used to reduce radiation exposure of normal tissues, such as the hippocampus, lens, and parotid gland, using volumetric arc therapy (VMAT). Moreover, the radiation conformity and dose distribution in tumours simultaneously improved.

Recently, various studies using a head-tilting baseplate in radiotherapy have been published. Miura et al. [ compared the potential of the use of tomotherapy in the dose distribution improvement of the planning target volume (PTV) and reduction of exposure time of normal organs, such as the hippocampus and lens, with and without the head-tilting baseplate in hippocampal-sparing WBRT. Tilted hippocampal-sparing WBRT reportedly reduced the radiation exposure time by more than 10% of normal organs such as the hippocampus and lens.

Shimizu et al. [ used the four-field box technique in WBRT to examine the best head-tilt angle that could reduce the parotid gland dose while maintaining a safe level of lens dose. Since the parotid dose is inversely proportional to the lens dose, it was concluded that the orbitomeatal plane angle required to reduce the maximum lens dose to less than 10 Gy and minimise the parotid gland dose was 14°.

Lin et al. [ investigated the various head flexion angles in hippocampal-sparing WBRT in VMAT. This study demonstrated that at least 15° should be implemented in clinical practice, and for better dose coverage and uniformity of whole-brain PTV and dose reduction in critical organs, a head angle of ≥25° is recommended.

Therefore, the application of the head tilt in WBRT has several advantages. However, data on the setup uncertainties in head-tilting techniques in WBRT and the clinical target volume (CTV) to PTV setup margins has not been reported. Although the head-tilt technique has several advantages in radiotherapy, if the setup uncertainties are excessively large, the PTV margin becomes large and the dose delivered to the normal organs, such as the hippocampus, parotid, and lens, increases; thus, the existing advantages of the head-tilt technique may be negated. Therefore, it is necessary to study the exact setup uncertainties and PTV margins for the head-tilt technique compared to that of the existing supine setup.

Hence, this study evaluated the setup uncertainties and determined the appropriate PTV margins for patients treated in the conventional supine position (c-SP) and head-tilted supine position (ht-SP) using a head-tilting baseplate in WBRT.

Materials and methods

Study overview

This retrospective data analysis of the 30 patients who underwent WBRT enrolled in this study was approved by the Institutional Review Board of the Yeungnam University Medical Center (YUMC 2021-07-033). Informed consent was specially waived under the approval of the institutional review board, given that patient anonymity was ensured.

Patient selection

All patients who received WBRT between October 2020 and May 2021 at our institution were included in the study. Thirty patients who received radiotherapy in the c-SPs and ht-SP fixed with a thermoplastic mask were investigated. The patient radiotherapy techniques and treatment schedules included in this study are described in Table 1. Of the 30 WBRT patients, 15 were treated in the c-SP and 15 in the ht-SP. Patients treated in the c-SP had one patient who received 25 Gy in 10 fractions, and 14 patients who received 30 Gy in 10 fractions for a total fraction number of 150. Meanwhile, among the patients treated in the ht-SP, one patient received 25 Gy in 10 fractions, and 14 patients received 30 Gy in 10 fractions for a total fraction number of 150.

Table 1

Characteristics of the patients and treatment included in this study.

	c-SP	Ht-SP
Number of patients	N = 15	N = 15
Number of fractions	n = 150	n = 150
Median age (Range)	59(35–83)	62(37–86)
Sex (%)
Female	9(60)	7(46.7)
Male	6(40)	8(53.3)
Radiotherapy techniques (%)
3DRT	2(13)	15(100)
VMAT	13(87)	0(0)
Fraction schemes (%)
25 Gy in 10 fractions	1(7)	1(7)
30 Gy in 10 fractions	14(93)	14(93)

3D = three-dimensional radiotherapy; VMAT = volumetric-modulated arc therapy.

Immobilisation and CT simulation

Fig 1 shows the setup position of the patient in the supine and the head-tilted supine position with a thermal mask before radiotherapy in the radiation treatment room. A thermal plastic mask was used in all the patients to minimise the inter- and intra-fractional variations of radiotherapy. In the traditional c-SP, the DUON head mask (60124, Orfit Industries, Wijnegem, Belgium) was fixed at 2.4-mm mask thickness. For the ht-SP, a tilting acrylic supine baseplate (MedTec, USA) was used to elevate the patient’s head to up to 40° according to our institution’s protocol, and a thermoplastic U-Frame Mask (R420U, Klarity Medical & Equipment (GZ) Co. Ltd., Lan Yu, China) with 2.4-mm mask thickness was used. All the computed tomography (CT) simulation images were obtained using a Brilliance Big Bore CT simulator (Philips Inc., Cleveland, OH) with a thickness of 2.5–5 mm.

Fig 1

Patient setup position for radiotherapy.

(A) supine position, (B) head-tilted supine position.

Treatment planning and delivery techniques

We performed delineation of CT and MRI images of T2-weighted and gadolinium contrast-enhanced T1-weighted sequences using a rigid fused MRI-CT image set. The CTV of the whole brain was defined as the parenchyma and the spinal cord up to the lower level of the atlas. In the three-dimensional radiotherapy (3DRT) and volumetric-modulated arc therapy (VMAT) techniques, the PTV was created with an extension of 5 mm in all directions from the CTV. An anisotropic analytic algorithm (AAA Varian Eclipse TPS, version 15.6.05) was used for all the radiation treatment plans as reported in previous studies [6,10]. The Novalis-Tx (Varian Medical System, CA, USA and BrainLAB, Feldkirchen, Germany) linear accelerator system with a high-definition multi-leaf collimator and 6 degrees of freedom (DOF) robotic couch (BrainLAB, Feldkirchen, Germany) was used. However, cone-beam CT (CBCT) images in the translational (lateral, longitudinal, and vertical) and rotational (yaw) directions applicable to 4DOF were used. Photon energy of 6 MV was used in all radiation treatment planning. 3DRT used a beam arrangement in 0°, 90°, 180°, and 270° directions, and the VMAT used two coplanar full-arc beams with clockwise (CW) and counter clockwise (CCW) gantry rotation. The collimator of the VMAT was rotated around 290° for CW and 25° for CCW to minimize the tongue-and-groove effect.

Image registration and setup protocol

The image registration using planning CT and CBCT in the c-SP and the ht-SP is shown in Figs 2 and 3, respectively. Daily setup verification images were obtained for all 30 patients who received WBRT using CBCT (Varian Medical Systems, Palo Alto, CA, USA) before treatment. The X-ray tube voltage and current used for CBCT imaging were 100 kV and 80 mA, respectively. Figs 2A and 3A show the planning CT images in transverse, frontal, and sagittal directions, and Figs 2B and 3B were obtained with CBCT in pre-treatment. Figs 2C and 3C show the registration images between the planning CT and CBCT images in the translational and rotational directions. To match the planning CT and CBCT during image registration, an experienced therapist adjusted the window level appropriately. Also, in the image registration, a clip box was used to include PTV. Image registration between the planning CT and CBCT image was performed using bony anatomy auto-matching. There is no institutionally accepted shift tolerance, and all radiation treatment patients were treated with radiation by correcting the translational and rotational directions based on the differences in the planning CT and pre-treatment CBCT. The automatic corrections of the couch on the setup differences in the translational and rotational directions were recorded.

Fig 2

Image registration using the planning computed tomography (CT) and cone beam CT (CBCT) in the c-SP.

(A) Planning CT, (B) CBCT, and (C) registration image.

Fig 3

Image registration using the planning computed tomography (CT) and cone beam CT (CBCT) in the ht-SP.

(A) Planning CT, (B) CBCT, and (C) registration image.

Analysis of the setup uncertainties between the planning CT and CBCT

A one-sample Kolmogorov–Smirnov test was performed to verify the normal distribution of all the recovered setup corrections. A non-parametric Mann–Whitney U-test was performed to compare the systematic and random setup errors of the two independent groups between the c-SP and the ht-SP. The mean values of the random and systematic errors are denoted as mean±standard deviation. All the statistical tests were performed using the SPSS statistical software version 22 (SPSS Inc., Chicago, IL, USA), and a p-value <0.05 was considered statistically significant.

Van Herk et al. introduced a method to analyse the random (σ) and systematic errors (Σ) using setup correction values for setup verification and have been applied in several papers [11-13]. During the image registration process, the differences in four directions, translational (lateral, longitudinal, and vertical) and rotational (yaw) directions, were analysed between the planning CT and CBCT images. Several studies [11-20] have already been conducted on the appropriate PTV margin recipe through expansion from CTV. In this study, the PTV margin was calculated using the methods of Stroom et al. [14] and Van Herk et al. [15].

Stroom et al. [14] assumed a 95% dose, on an average of 99% of the CTV tested in a practical setting. However, this study has only been demonstrated in prostate, cervix, and lung cancers. Conversely, Van Herk et al. [15] assumed that the minimum dose for the CTV was 95% for 90% of the patients using the analytical solution for perfect conformation. However, Van Herk et al. reported that because the margin excludes rotational errors and shape deviations, this recipe must be considered as a lower limit for safe radiotherapy. where Σ is the systematic errors, and σ is the random errors.

We also compared the 3D vector values between the c-SP and ht-SP. The 3D vector values can be calculated as follows: where x, y, and z are the errors in the lateral, longitudinal, and vertical directions, respectively.

Results

Figs 4 and 5 show the histograms and normal distribution curves of the setup errors in translation (lateral, longitudinal, and vertical) and rotation (yaw) in the c-SP and ht-SPs, respectively.

Fig 4

Histograms and normal distribution curves of the setup errors in the translation and rotation for the supine position (c-SP).

Setup errors in the (A) lateral, (B) longitudinal, (C) vertical, and (D) yaw directions.

Fig 5

Histograms and normal distribution curves of the setup errors in the translation and rotation for the head-tilted supine position (ht-SP).

Setup errors in the (A) lateral, (B) longitudinal, (C) vertical, and (D) yaw directions.

Table 2 shows the systematic (Σ) and random errors (σ) in the translational and rotational directions for the c-SPs and ht-SPs. In the c-SP, the mean values of the systematic error in the lateral, longitudinal, vertical, and yaw directions were -0.80±0.47 mm, 0.79±0.34 mm, 0.37±0.54 mm, and 0.17°±0.56, respectively. The mean values of the random errors were 0.27±0.24 mm, 0.54±0.31 mm, 0.39±0.20 mm, and 0.35°±0.17, respectively. The mean values of the systematic error in the lateral, longitudinal, vertical, and yaw directions in the ht-SP were -0.07±1.10 mm, 0.73±0.97 mm, -0.63±0.83 mm, and -0.01°±0.69, respectively. The mean values of the random errors were 0.75±0.16 mm, 1.39±0.42 mm, 1.02±0.28 mm, and 0.57°±0.26, respectively.

Table 2

Systematic errors (Σ) and random errors (σ) in the translational (lateral [x-axis], longitudinal [z-axis], and vertical [y-axis]) and rotational (yaw [y-axis]) directions.

	c-SP				Ht-SP
Setup errors	Systematic errors (Σ)		Random error (σ)		Systematic errors (Σ)		Random errors (σ)
	Mean (mm)	S.D	Mean (mm)	S.D	Mean (mm)	S.D	Mean (mm)	S.D
Translational
Lateral (x-axis) (mm)	-0.80	0.47	0.27	0.24	-0.07	1.10	0.75	0.16
Longitudinal(z-axis) (mm)	0.79	0.34	0.54	0.31	0.73	0.97	1.39	0.42
Vertical (y-axis) (mm)	0.37	0.54	0.39	0.20	-0.63	0.83	1.02	0.28
Rotational
Yaw (y-axis) (°)	0.17	0.56	0.35	0.17	-0.01	0.69	0.57	0.26

SD = standard deviation.

Fig 6 shows the results of the box plot and Mann–Whitney U-test in translation and rotation for the setup errors between the c-SP and ht-SPs. All the data were not normally distributed in any direction. There was a statistically significant difference in the lateral and vertical directions, and there was no significant difference in the longitudinal (p-value = 0.941) and yaw (p-value = 0.109) directions.

Fig 6

Boxplot and p-value of the Mann–Whitney U-test in the translation and rotation be-tween the c-SP and ht-SP.

Setup errors in the (A) lateral, (B) longitudinal, (C) vertical, and (D) yaw directions.

The results of the box plot and Mann–Whitney U-test for the 3D vector between the c-SP and ht-SP are shown in Fig 7. The p-value was <0.001, indicating a significant difference.

Fig 7

Boxplot and p-value of the Mann–Whitney U-test in the three-dimensional radiotherapy (3D) vector between the c-SP and ht-SPs.

Table 3 shows the CTV to PTV margin calculated by Stroom et al.’s and van Herk et al.’s margin recipe for systematic (Σ) and random errors (σ). In the c-SP, the CTV to PTV margin was 1.1 mm, 0.9 mm, 1.2 mm, and 1.2° with Stroom et al.’s recipe for lateral, longitudinal, vertical, and yaw directions, and 1.3 mm, 1.1 mm, 1.5 mm, and 1.5° with van Herk et al.’s recipe, respectively. The CTV to PTV margin in the ht-SP was 2.3 mm, 2.2 mm, 1.9 mm, and 1.6° with Stroom et al’s recipe, and 2.9 mm, 2.7 mm, 2.3 mm, and 1.9° with van Herk et al’s recipe, respectively. In the CTV to PTV margin, the ht-SP was larger than c-SP in all directions.

Table 3

Clinical target volume (CTV) to planning target volume (PTV) margin calculations calculated by Stroom et al.’s [14] and van Herk et al.’s [15] margin recipe for systematic (Σ) and random errors (σ).

Studies	Setup position	Imaging modalities	Recipe	PTV margin
				Translational			Rotational
				Lateral(mm)	Longitudinal(mm)	Vertical(mm)	Yaw(°)
Oh et al. [18]	Supine	CBCT	Van Herk et al	3.73	3.45	3.24
Zhou et al [19]	Supine	MVCT	Stroom et al	4.8	5.0	1.5
Oh et al. [12]	Supine	ExacTrac	Stroom et al	1.7	3.5	2.3	1.9
Present Study	Supine	CBCT	Stroom et al	1.1	0.9	1.2	1.2
			Van Herk et al	1.3	1.1	1.5	1.5
	Head tilt supine		Stroom et al	2.3	2.2	1.9	1.6
			Van Herk et al	2.9	2.7	2.3	1.9

*Used formula: Stroom et al.’s recipe[14] = 2Σ+0.7σ, Van Herk et al.’s recipe [15] = 2.5Σ+0.7σ.

CBCT = cone-beam computed tomography; MVCT = megavoltage computed tomography.

Discussion

In this study, the setup uncertainties and appropriate PTV margins were determined by analysing the setup errors of CBCT images of patients before radiotherapy in the c-SP (N = 15) and ht-SP using a head-tilting baseplate (N = 15) in WBRT.

According to the results of our recent study [, the conformity and homogeneity indices of the target were improved upon using the head-tilting baseplate VMAT in hippocampal-sparing WBRT, and the mean dose to normal tissues, such as the hippocampus, parotid, and right and left lenses, were significantly reduced. However, one of the limitations of the previous study was that the dose delivered to the lens was relatively higher in the supine VMAT than in the head-tilted VMAT because the treatment plan was optimised to maximise target coverage and spare the hippocampus. Therefore, it would have been difficult to preserve the hippocampus in the supine VMAT plan because the lens constraint was a high priority.

In another study, Miura et al. reported [ that a tilted hippocampus-sparing WBRT with tomotherapy while sparing healthy organs, including the hippocampus and lens, could reduce the treatment time by more than 10%. However, their study had the limitation of a small sample size of five; therefore, a larger cohort study should be conducted. Furthermore, because they used two pairs of CT images on the same day, they were able to evaluate two CT images and construct a useful deformable image registration algorithm.

Several studies have reported the advantages of the ht-SP in radiotherapy [; however, no studies have reported on the uncertainties and PTV margins for this setup. The PTV should be extended from the CTV with an appropriate margin. However, less expansion of the CTV could lead to an increase in the uncertainty of the radiation dose to the PTV resulting in undesired radiation treatment outcomes. However, if the margin of the CTV is expanded too large, a sufficient radiation dose can be delivered to the CTV; however, at the same time, normal tissues may be exposed [. Therefore, radiation treatment positions, such as the c-SP and ht-SP, which can affect setup uncertainty in radiotherapy, should be investigated for appropriate margin calculations.

Oh et al. [ analysed the setup uncertainties in 21 (438 fractions) cases of brain tumours using daily CBCT. The patient was immobilised in the c-SP using a thermoplastic fixation mask, and the registration procedure between the acquired CBCT and the planning CT image was performed according to the bony anatomy. They used van Herk et al.’s recipe [ to calculate the PTV margin, which was 3.73 mm, 3.45 mm, and 3.24 mm in the lateral, longitudinal, and vertical directions, respectively.

Similar to their study, the PTV margin in the present study using the image tool of CBCT in the c-SP was 1.3 mm, 1.1 mm, 1.5 mm, and 1.5° with van Herk et al.’s recipe [, and 1.1 mm, 0.9 mm, 1.2 mm, and 1.2°, in the lateral, longitudinal, vertical, and yaw directions with Stroom et al.’s recipe [, respectively. Whereas the PTV margins in the ht-SP were 2.9 mm, 2.7 mm, 2.3 mm and 1.9° with van Herk et al.’s recipe., and 2.3 mm, 2.2 mm, 1.9 mm, and 1.6° with Stroom et al.’s recipe, respectively.

Therefore, when the ht-SP was compared to the c-SP in WBRT, it was observed that the PTV should be further expanded by 1.2 mm, 1.3 mm, 0.7 mm, and 0.3° in the lateral, longitudinal, vertical, and yaw directions, respectively, as per Stroom et al.’s recipe. Moreover, according to van Herk et al.’s recipe, the PTV should be expanded further by 1.5, 1.6, 0.8, and 0.4°, respectively. In our study, although a little more margin was required in the ht-SP than in the c-SP. Therefore, further research is needed to reduce the setup margin in WBRT treatment in the c-SP and ht-SP in the future.

Appropriate CTV to PTV margin analysis through systematic and random error analysis can be evaluated using various image tools, such as CBCT [18], megavoltage CT [19], and ExacTrac [12], and the results can be compared as shown in Table 3. The factors causing the differences in the setup uncertainties in the translational and rotational directions according to the setup position in WBRT should be evaluated. As shown in Table 2, it seems that the mask was unable to fix the position of the patient and the baseplate in the ht-SP compared to in the c-SP. Therefore, random error is considered larger in the ht-SP. Although the head-tilt in the supine position requires a little more margin, it can be utilized as a safe and effective position in radiotherapy. Therefore, additional studies are needed on the advantages of sparing organs at risk and the disadvantages of a little more margin in the head-tilt supine position.

This study has some limitations. First, the patients who received radiotherapy in the c-SP and ht-SP did not use the same mask. This is because the treatment position and mask were determined according to our institution’s setup protocol since the setup accuracy varied based on the thermoplastic mask [. Second, our study analysed images using rigid image registration in the image analysis between the planning CT and pre-treatment verification CBCT. The use of deformable image registration could yield varying results [. Third, since this study was calculated considering only inter-fractional variation, the PTV margin could be different if intra-fractional variation was included [. Fourth, since we used only 40° to elevate the patient’s head according to our institution’s protocol, this study could not demonstrate the effect of different angles on setup uncertainties.

Conclusions

This study analysed the setup error of 15 patients treated in the c-SP and 15 in the ht-SP using a head-tilting baseplate in WBRT. In the c-SP, the means of systematic errors were -0.80, 0.79, and 0.37 mm and random errors were 0.27, 0.54, and 0.39 mm in the lateral, longitudinal, and vertical translational dimensions, respectively. Whereas, for the ht-SP, the means of systematic errors were -0.07, 0.73, and -0.63 mm, and random errors were 0.75, 1.39, 1.02 mm in the lateral, longitudinal, and vertical translational dimensions.

Appropriate PTV margins with van Herk et al.’s recipe in WBRT were <2 mm and 1.5° in the c-SP, and <3 mm and 2° in the ht-SP in the translational and rotational directions, respectively. Although the head tilt in the supine position requires a little more margin, the head-tilt can be applied as a safe and effective position in radiotherapy.

18 Apr 2022

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Reviewer #1: Whole brain radiotherapy (WBRT) is one of the most effective radiotherapy-based approaches to treat patient with brain metastasis. Due to the complex anatomical structures within the treatment fields, more conformal treatment is essential to provide good local control rates with less late toxicity. There are some published literatures reported the use of a head-tilting baseplate in WBRT and its advantages in comparison with conventional supine position setup. Typical CTV-PTV margins are 3-5 mm (Ann Barrett, Jane Dobbs et al, 2009) to eliminate the systematic and random errors. To date, there is lack of publications discussing the setup uncertainties and CTV-PTV margins with regards to the head-tilting baseplate setup technique. Therefore, this study is relevance and able to provide general interest to the readers of the journal.

This study performed image registration on planning CT and cone beam CT in order to determine the setup uncertainties; and adapted the methods proposed by Stroom et al. [2Σ+0.7σ] and van Herk et al. [2.5Σ+0.7σ] to estimate the CTV-PTV margins. The authors found that the head-tilting baseplate setup technique was sufficiently stable and able to provide effective position in WBRT, while proposing the CTV-PTV margins of <3 mm. In general, I found that this paper is well structured. Nevertheless, there is lack of detailed elaborations for some of the descriptions or important points. With that in view, I suggest that a minor revision should be considered and the authors should address the comments as detailed below:

Major comments:

(1) The objectives of the study were to evaluate the setup uncertainties and determine the appropriate CTV-PTV margins for patients treated with or without a head-tilting baseplate. It is recommended that the abstract and conclusion sections should also include the summaries of setup uncertainty.

(2) The authors have chosen Stroom et al. and van Herk et al. recipes in estimating CTV-PTV margins. Please mention the rational and limitation (if any) of these selections. For instance, van Herk et al.’s (2000) method was excluding rotational errors and shape deviations, and considered as a lower limit for safe radiotherapy. Stroom et al.’s (1999) method was initially applied to prostate, cervix, and lung cancer case.

(3) Page 14, line 260: The authors have mentioned that the CTV-PTV margins that applied in the clinic were 5 mm. However, the study revealed that the margin should expand further compared to the conventional supine position. Please elaborate further in the discussion section how these findings have changed the current clinical practice if any?

Minor comments:

(4) Table 1: Please check the table settings (merge/unmerge) of each column titles to avoid confusion.

(5) Page 6, lines 101: Please check the angle of beam directions.

(6) Page 8, line 131 and page 9, line 155: The symbols () and () denote different parameter in this manuscript, i.e. random error, systematic error and its standard deviation. Please make necessary amendment in this manuscript to avoid confusion.

(7) Page 8, line 137: Suggest to move the sentence “All the data were not normally distributed in any direction” to Result section.

(8) Page 9, line 158 & line 170-181: Please rephrase the paragraphs as some of them were repeatedly mentioned in the text as well as figures 4&5 or Table 2.

(9) Table 2’s caption: Please check whether pitch [x-axis] and roll [z-axis] were included in your data set.

(10) Table 3: Data for “vertical” should be under “translational” column.

(11) Table 3: Please check the value for “vertical-Stroom recipe- Head tilt supine”, 1.9 instead of 1.8.

(12) Page 15, line 272: Repetition of conclusion “In conclusion, …effective position in radiotherapy.”

(13) Figure 4-7: the font size of the axis labels was too small.

(14) Reference: Please ensure the reference formatting is in line with the journal requirements, for instance:

a. Reference 1: Use the abbreviation “Surg. Neurol. Int.”

b. Reference 13: Use the abbreviation “Int. J. Radiat. Oncol. Biol. Phys.”

Reviewer #2: This work focused on PTV margin calculated from daily setup errors in two different patients' treatment setup during whole brain radiotherapy, which may contribute to the scientific knowledge in radiotherapy field. However, the inability of the authors to present proper and accurate analysis and discussion, hence producing low quality of scientific manuscript. Each sections needs to be re-write in scientific article style in order for higher appreciation of the data presented in this study. This manuscripts suffers from the lack review of related literatures in addition to the inability of the authors to perform varieties of analysis with the available data and also the inability to calculate the margin according to the well-known Van Herk or Stroom formulas. It is hope that the author would revise and re-analyze all data pertaining to this work in order to achieve the objective of the study. It would be my pleasure to review again the revised manuscript, should the author performed a proper and correct data analysis as this study do has significant contribution to radiotherapy field.

Reviewer #3: The study investigates the uncertainties of whole brain radiotherapy in a head-tilt position. The manuscript has described the work in sufficient details. The following can be considered to improve the manuscript

1. The write-up has too many short paragraphs of single/two sentences that can be combined with other paragraphs.

2. Abstract: The motivation of using head-tilting technique can be briefly highlighted in the abstract

3. Line 23: Please rephrase the sentence. The sentence is describing the image correction not the radiotherapy delivery. “Radiotherapy was performed by correcting the translational (lateral, longitudinal, and vertical) and 24 rotational (yaw) errors based on the differences in computed tomography (CT) and cone-beam CT.”

4. Suggest to compare results obtained with recently published margin, e.g., http://doi.org/10.1002/acm2.13291

5. Line 272, In discussion, although the head tilt gives larger margin, perhaps authors can comment on how the benefit of sparing OAR, can justify the use of head-tilt? This can be included in the conclusion briefly.

6. Perhaps authors can discuss how the head-tilt technique can be improved, to reduce the uncertainties.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: HM Zin

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Submitted filename: Headtilt_manuscript (1)_ZJreview.docx

Click here for additional data file.

30 May 2022

we attached point by point responses to all reviewers and editor.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

23 Jun 2022

Setup uncertainties and appropriate setup margins in the head-tilted supine position of whole-brain radiotherapy (WBRT)

PONE-D-22-03374R1

Dear Dr. Se An Oh ,

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,

Ngie Min Ung

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Please address the remaining minor corrections in the current draft.

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: All comments have been addressed

Reviewer #3: All comments have been addressed

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thanks to the authors who had revised the manuscript accordingly. However, further improvement should be made to address several minor corrections. With that in view, I suggest that a minor revision should be considered and the authors should address the comments as detailed below:

Minor corrections:

1. Page 3, line 41 & Page 17, line 312: Please tally the c-SP random errors results with data presented in Table 2.

2. Page 7, line 128: Suggest to revise the manufacturer’s details “The Novalis-Tx (Varian Medical System, CA, USA) linear accelerator system with a high-definition multi-leaf collimator and 6 degrees of freedom (DOF) robotic couch (BrainLAB, Feldkirchen, Germany) was used.”

3. Page 8, line 141: mA

4. Figure 4: Please enlarge the font size of the labels in the figure.

5. Table 3: The caption of the table didn’t reflect its contents which includes the comparison data with other studies. Please revise.

6. Page 15, line 282: Please double check the value for vertical which supposed to be 0.8 mm.

7. Page 15, line 284-288 & page 295, line 295-298: Please rephrase and consolidate the sentences to avoid repetition.

8. Acknowledgement: Please include acknowledgements wherever appropriate.

Reviewer #2: The revised version has strengthened the manuscript. I strongly recommend it for publication with minor correction (as suggested in the attached document) to enhanced the quality of published manuscript.

Reviewer #3: The paper has improved and addressed concerns from the reviewers. The pape can be accepted for publication.

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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.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Hafiz Zin

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27 Jul 2022

PONE-D-22-03374R1

Setup uncertainties and appropriate setup margins in the head-tilted supine position of whole-brain radiotherapy (WBRT)

Dear Dr. Oh:

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

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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