Version of Record: https://www.sciencedirect.

com/science/article/pii/S1120179722019792
Manuscript_e962d562d97aaa45e197503300975187

Stoichiometric CT number calibration using three-parameter fit model

for ion therapy

Minoru Nakao1,2, Masahiro Hayata1, Shuichi Ozawa1,2, Hideharu Miura1,2, Kiyoshi Yamada1,
Daisuke Kawahara2, Kentaro Miki3, Takeo Nakashima4, Yusuke Ochi4, Shintaro Tsuda4,
Mineaki Seido5, Yoshiharu Morimoto5, Atsushi Kawakubo6, Hiroshige Nozaki7, Kosaku Habara7,
Yasushi Nagata1, 2

1
Hiroshima High-Precision Radiotherapy Cancer Center, 3-2-2, Futabanosato, Higashi-ku,
Hiroshima 732-0057, Japan
2
Department of Radiation Oncology, Graduate School of Biomedical & Health Sciences, Hiroshima
University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
3
Department of Medical Radiological Technology, Faculty of Health Sciences, Kyorin University,
5-4-1 Shimorenjaku, Mitaka-shi, Tokyo 181-8612, Japan.
4
Radiation Therapy Section, Department of Clinical Support, Hiroshima University Hospital, 1-2-3
Kasumi, Minami-ku, Hiroshima 734-8551, Japan
5
Department of Radiology, Hiroshima Prefectural Hospital, 1-5-54, Ujinakanda, Minami-ku,
Hiroshima 734-8530, Japan
6
Radiation Therapy Department, Hiroshima City Hiroshima Citizens Hospital, 7-33, Motomachi,
Naka-ku, Hiroshima 730-8518, Japan
7
Division of Radiology, Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, 1-9-6,
Senda, Naka-ku, Hiroshima 730-8619, Japan

Corresponding Author: Minoru Nakao, PhD

Mailing address: Hiroshima High-Precision Radiotherapy Cancer Center, 3-2-2, Futabanosato,
Higashi-ku, Hiroshima, Hiroshima Prefecture, 732-0057, Japan
Email: nakao@hiprac.jp

Conflict of interest statement:

The authors have no conflicts of interest.

Short running title: CT number calibration for ion therapy

© 2022 published by Elsevier. This manuscript is made available under the Elsevier user license
https://www.elsevier.com/open-access/userlicense/1.0/
ABSTRACT (235 / 250 words)

Purpose: Treatment planning for ion therapy involves the conversion of computed tomography

number (CTN) into a stopping-power ratio (SPR) relative to water. The purpose of this study was to

create a CTN-to-SPR calibration table using a stoichiometric CTN calibration model with a

three-parameter fit model for ion therapy, and to demonstrate its effectiveness by comparing it with a

conventional stoichiometric CTN calibration model.

Methods: We inserted eight tissue-equivalent materials into a CTN calibration phantom and used six

CT scanners at five radiotherapy institutes to scan the phantom. We compared the theoretical

CTN-to-SPR calibration tables created using the three-parameter fit and conventional models to the

measured CTN-to-SPR calibration table in three tissue types: lung, adipose/muscle, and

cartilage/spongy bone. We validated the estimated SPR differences in all cases and in a worst-case

scenario, which revealed the largest estimated SPR difference in lung tissue.

Results: For all cases, the means ± standard deviations of the estimated SPR difference for the

three-parameter fit method model were -0.1 ± 1.0%, 0.3 ± 0.7%, and 2.4 ± 0.6% for the lung,

adipose/muscle, and cartilage/spongy bone, respectively. For the worst-case scenario, the estimated

SPR differences of the conventional and the three-parameter fit models were 2.9% and -1.4% for the

lung tissue, respectively.

Conclusions: The CTN-to-SPR calibration table of the three-parameter fit model was consistent with

that of the measurement and decreased the calibration error for low-density tissues, even for the

worst-case scenario.

Keywords: Treatment planning, CT number calibration, Stoichiometric method, Quality assurance

2
1. INTRODUCTION

In radiotherapy treatment planning systems (RTPSs), the conversion from computed

tomography number (CTN) into an estimate of the stopping-power ratio (SPR) relative to water is

one of the main methods to calculate the dose distribution for ion therapy [1,2]. In particular, the

accuracy of CTN-to-SPR conversion affects the estimated position of the Bragg peak [3,4] which is

determined by the ion beam and the estimated SPR of the body tissues. An inaccurate estimated

SPR of the body tissues leads to a beam overshoot/undershoot because the real position of the

Bragg peak is different from the estimated position with RTPS [5,6].

A stoichiometric CTN calibration proposed by Schneider et al. [5] (Schneider96 model) is

widely accepted as the gold standard to convert CTN to SPR in human tissue. Several

stoichiometric CTN calibration models have been developed based on the parameterization of the

Schneider96 model [7–10]. The stoichiometric CTN calibration models have been compared to

verify the characteristics of each model [11,12].

Schneider et al. [7] established stoichiometric CTN calibration with a two-parameter fit model

(Schneider00 model) based on the same cross-section model [13] in the human body. The

Schneider00 model has also been used to create a CTN-to-SPR calibration table for ion therapy

because the CTNs is converted into mass densities (MDs) and elemental weights. Recently, a new

stoichiometric CTN calibration [14] with a three-parameter fit model (Nakao20 model) was

established by modifying the Schneider00 model [7]. The Nakao20 model improved the agreement

between the theoretical and measured CTNs for air and lung tissue.

The purpose of this study was to create a CTN-to-SPR calibration table using the Nakao20

model for ion therapy, and to demonstrate its effectiveness by comparing it with the Schneider96 [5]

and the Schneider00 [7] models.

3
2. MATERIAL AND METHODS

2.1. CT scan

2.1.1. CT scan phantom

To compare the theoretical CTN-to-SPR calibration table using the stoichiometric method

with a measured CTN-to-SPR calibration table, we scanned a CTN calibration phantom to acquire

CT image sets (Figure 1). The phantom body size was 330 mm × 270 mm × 50 mm, and its body

consisted of a water-equivalent material (Plastic Water; CIRS Model 062M electron density phantom,

CIRS, Inc., Norfolk, VA, USA). We inserted eight tissue-equivalent materials (TEMs)—lung (inhale),

lung (exhale), adipose, breast 50/50, muscle, bone 200 mg/cm3 (CIRS Model 062M electron density

phantom, CIRS, Inc., Norfolk, VA, USA), tough lung, and tough bone (Kyoto Kagaku, Kyoto,

Japan)—into the inner circle so that the centers of the circle and phantom coincided to avoid the

influence of beam hardening and beam-hardening corrections[15–17].

The estimated SPRs of the plugs were calculated using the Bethe–Bloch formula [5,11,12], as

shown in Eq. (1):

= (1)

Here, SPRm denotes the estimated SPR of the material. nm and nw denote the electron densities of the

material and water, respectively; me and c denote the electron mass and speed of light, respectively; β

denotes the velocity of the charged particle relative to c; and Im and Iw denote the mean excitation

energies of the material and water, respectively. The Bragg additivity rule was considered in the

estimated SPR calculation model. The ionization energy of a material, Im, is calculated as follows:

! ! &
In = ∑ "
ln $ % ∑ "
% (2)

Here, i denotes the element index; wi, Ai, Zi, and Ii denote the elemental weight, atomic mass, atomic

number, and ionization energy of index i, respectively; and the ionization energy Ii for each element

was obtained from the International Commission on Radiation Units and Measurements Report 37

4
[18]. To calculate the estimated SPR using Eq. (1), a proton kinetic energy of 100 MeV, in which

used by other authors for proton therapy, was assumed [11,19].

2.1.2 MD and elemental weight

Stoichiometric CTN calibration requires accurate MD values and elemental weights. The MD

and elemental weight of the TEMs in the CIRS Model 062M were provided by the manufacturer.

Table 1 summarizes the MDs, estimated SPRs, and element weights for the six TEMs of the CIRS

Model 062M. We calculated the MDs and elemental weights for tough lung and tough bone by

analyzing the elemental composition using the following four methods:

• Carbon, hydrogen, and nitrogen (CHN) element analysis

• Inductively coupled plasma atomic emission spectroscopy (ICP-AES)

• Ion chromatography

• X-ray fluorescence spectrometry

To calculate the MDs, we divided the weight by the volume according to ISO 845–2006 [20].

We quantitatively analyzed the elemental weights of H, C, and N using a CHNS-O 2400II

elemental analyzer (PerkinElmer, Inc., Waltham, USA). The limit of detection is 0.3 wt% for the

CHN element analysis. The weight percent differences were verified using a standard sample

(acetanilide : C8H9NO).

We followed three steps to analyze the elemental weights of Al, Si, P, and Ca:

1. We used acid digestion procedures to dissolve the samples of the tough lung and tough

bone.

2. We used an alkali fusion to filter and decompose the residue left after acid digestion.

3. The acid digestion filtrate, along with the final solution of alkali fusion, underwent a

quantitative analysis using an inductively coupled plasma atomic emission spectrometer

(ICPS-7510, Shimadzu, Kyoto, Japan).

5
The element weights of the solutions generated by the acid digestion and alkali fusion were

determined using a calibration curve between the signal intensity and element weight. The

correlation coefficients of Al, Si, P, and Ca were calculated using the standard sample.

We analyzed the elemental weight of Cl using the following three steps:

1. We ignited samples of the tough lung and tough bone by heating a wire, and burned them

with oxygen and water in a combustion chamber.

2. We dissolved the generated gas in water.

3. To analyze water-soluble chloride ions quantitatively, we used an ion chromatograph system

(pump, LC-10ADvp; column, Shin-pack IC-A3, Shimadzu, Kyoto, Japan).

The element weights were determined using a calibration curve. The correlation coefficients for Cl

were calculated using the standard sample.

To analyze the elemental weights of Mg, S, K, Fe, and Sr semi-quantitatively, we used an X-ray

fluorescence spectrometer (ZSX Primus, Rigaku, Akishima, Japan). The analysis was performed

three times, and the standard deviation (SD) was calculated.

We calculated the elemental weight of O as the residual weight by defining the total weight as

100%, because we could not calculate the elemental weight with the above four analysis methods.

All four analysis methods were carried out at the Hiroshima Prefectural Technology Research

Institute.

2.1.3. Tissue equivalency of TEMs

The tissue equivalency was verified by comparing the effective atomic number between eight

TEMs and the adult reference computational phantom data from the International Commission on

Radiological Protection publication 110 (ICRP-110) [21]. The effective atomic numbers were

defined as
&- &-
).+, /.,)
'( = ∑$ " '$).+, % and '. = ∑$ " '$/.,) % (3)

6
 Here, ZR and Zp denotes the effective atomic number for the Rayleigh and photoelectric

coefficients, respectively [13,22].

2.1.4. CT scanners and scan conditions

Six CT scanners located at five radiotherapy institutes were used to analyze the uncertainty

between CT scanner types. Table 2 presents the scanning conditions which were the same as those

used for a treatment planning CT scan. In addition to those conditions, we used four tube voltages

(80, 100, 120, and 140 kV) for the CT scan at Institute D. There were 14 combinations of all scan

conditions. To acquire the average CTNs of the plugs, we averaged the CTNs in the region of interest

(ROI) from one CT slice, using a diameter for the ROI circle smaller than that of the plug. The

phantom was scanned again with the tough lung sample removed to acquire the CTNs of air inside

and outside of the phantom.

2.2. Parametrizations of three stoichiometric CTN calibration models

We compared three stoichiometric CTN calibration models: the Schneider96, Schneider00, and

Nakao20. The stoichiometric CTN calibration procedure consisted of three steps.

1. Conduct CT scans of a set of materials with known MDs and elemental weights.

2. Perform a multi-parameter fit between the MDs, elemental weights, and measured CTNs.

3. Calculate the theoretical CTNs using the resultant parameters, known MDs, and elemental

weights.

In the first step, the CTN calibration phantom was scanned with six CT scanners. In the second

step, different multi-parameter fits were performed for each stoichiometric CTN calibration model.

In the third step, three theoretical CTN-to-SPR calibration tables were created by calculating the

theoretical CTNs of the biological tissue model.

Following the three stoichiometric CTN calibration models, we defined the common-scaled

CTN. Eq. (4) shows the CTNs defined for attenuation relative to water.

7
 56
4
01 = 1000 57 8
4
−1 (4)

Here, Hx denotes the CTN of the material, :̅1 and :̅< = denote the photon linear attenuation

coefficients of the inserted material and water, respectively, averaged over the X-ray spectrum.

2.2.1. Schneider 1996 (Schneider96) model

The linear attenuation coefficient of the Schneider96 model is defined as

:̅1 = >?,1 A BC 'D1E.,) + A GHC 'I1&.+, + A JK (5)

Here, >?,1 denotes the electron density of the material; 'D1 and 'I1 denote the effective atomic

numbers; Kph, Kcoh, and KKN denote constants that characterize the photoelectric effect, coherent

scattering, and Klein-Nishina cross sections, respectively, and are free parameters of the Schneider96

model. Note that

!
>?,1 = >1 LM ∑ (6)
"

'D = N∑ O$ '$E.,) P&/E.,) and 'I = N∑ O$ '$&.+) P&/&.+) (7)

and
! !
O$ = "
-∑ "
(8)

Here, ρx denotes MD; NA denotes Avogadro’s number; λi denotes fraction of electrons attributed

to atoms of index i. Measured CTNs for materials were shown in Eq. (4). Eq. (9) shows the

least-squares fit of Eq. (4) and (5), as follows:

)
Sℎ UVℎ AL
A ,A ,A
56
4 W6
∑ R % − + 1% Y (9)
5
4 7 8 &XXX

Here, n denotes the material index, where a set of materials with known MDs and elemental

weights were used for the least-squares fit. The theoretical CTNs were calculated by substituting the

resultant values of Kph, Kcoh, and KKN into Eq. (10):

J \] !D6^._ `J a] !b6 .c_ `J de
[ ,6
0Z = 1000 − 1000
[ ,7 8 J \] !D7 b7.c_
^._ `J a] ! (10)
8 `J
de
8

Here, Ht is the theoretical CTN.

8
9
2.2.2. Schneider 2000 (Schneider00) model

The linear attenuation coefficient of the Schneider00 model is defined as

56
4 [6 ∑ -" % ! `! .c_ i `! j._ i
fg& , g) h = (11)
57 8
4 [7 8
"7 %f&`i `i h` `+j._ i h
7- 8- .c_ i
"8 %f+`+

>1
Here, ->< =
denotes the ratio of the MD relative to water; wH and wO denote the elemental

weights of hydrogen and oxygen, respectively; AH and AO are the atomic masses of hydrogen and

oxygen, respectively; and k1 and k2 denote the two free parameters. Eq. (12) shows the least-squares

fit of Eq. (4) and (11), as follows:

)
56
4 W6
∑ k fg& , g) h − + 1% l (12)
5
4 7 8 &XXX

The theoretical CTNs were calculated by substituting the resultant values of k1 and k2 into Eq. (13):

[6 ∑ -" % ! `! .c_ i `! j._ i

0Z = 1000 m[ − 1n (13)
"7 %f&`i `i h` `+j._ i h
7- 8- .c_ i
7 8 "8 %f+`+

2.2.3. Nakao 2020 (Nakao20) model

The theoretical CTNs of air for the Schneider96 and Schneider00 models use the nominal CTN

(−1000 HU) and theoretical SPR (0.001) for air. However, in some CT scanners, the CTN for air is

not −1000 HU [23,24]. Therefore, we established a three-parameter fit model [14] that improved the

agreement between theoretical and measured CTNs for air and lung tissue by adding one free

parameter (α) to Eq. (4). The free parameter α denotes the scaling correction of the CTN, and the

CTNs of water and air were calculated as 0 and −1000α, respectively.

For the three-parameter fit model, Eqs. (4) and Eq. (12) can be rewritten as follows:
56
4
01 = 1000o 57 8
−1 (14)
4

)
56
4 W6
∑ k fg& , g) h − + 1% l (15)
5
4 7 8 &XXXp

In these equations, k1, k2, and α denote the free parameters experimentally determined by applying a

10
least-squares fit to the measured CTNs. The initial values for k1, k2, and α were set to 1.24 × 10-3,

3.06 × 10-5, and 1.0, respectively. After performing this least-squares fit, we calculated the theoretical

CTNs by substituting the resultant values for k1, k2, and α into Eq. (16):

[6 ∑ -" % ! `! .c_ i `! j._ i

0Z = 1000o m − 1n. (16)
[7 8
"7 %f&`i `i h` `+j._ i h
7- 8- .c_ i
"8 %f+`+

We used the programming language Python and the open-source SciPy (http://www.scipy.org) to

automatically apply the least-squares fits while minimizing Eqs. (9), (12), and (15).

The three theoretical CTN-to-SPR calibration tables, namely Schneider96, Schneider00, and

Nakao20 models, were created with the 11 representative tissues defined by Kanematsu et al. [10]

The 11 representative tissues were defined according to the adult reference computational phantom

data of ICRP-110. The human body consists of six major elements, M = {H, C, N, O, P, Ca}; thus,

the residual weight and its mean residual atomic number of all other minor elements (Na, Mg, S, Cl,

K, Fe, and I) were calculated as follows in Eq. (17):

qr?s = ∑t∉v qt and ̅ = ∑w∉x !w

'r?s w
(17)
y z

Here, wres is the weight of the residual element; wr and Zr are the weight and atomic number of

the residual element r, respectively; and '̅r?s is the mean atomic number of the residual elements.

The SPRs of 11 representative tissues were calculated with Eq. (1) and (2) for a proton kinetic energy

of 100 MeV. Table 3 summarizes the MDs, estimated SPRs, major element weights, residual element

weights, and mean residual atomic numbers for the 11 representative tissues. The atomic mass of the

̅
residual element, Ares, in Eq. (13) and Eq. (16) was approximately 2.1×'r?s in the human body [14].

2.3. Comparison between measured and theoretical CTN-to-SPR calibration tables

Three theoretical CTN-to-SPR calibration tables of the 11 representative tissues were

created using Schneider96, Schneider00, and Nakao20 models, based on CTNs of eight TEMs. A

measured CTN-to-SPR calibration table was also created using of CTNs and SPRs of eight TEMs.

Each theoretical CTN-to-SPR calibration table was compared with the measured CTN-to-SPR
11
calibration table. The estimated SPR differences were calculated by subtracting the estimated SPRs

of the measured CTN-to-SPR calibration table from those of the theoretical CTN-to-SPR calibration

table for each CTN. We then compared the results for each tissue type based on the MD range. We

classified the lung, adipose/muscle, and cartilage/spongy bone based on the defined MD ranges of

0.2–0.8, 0.9–1.07, and 1.07–1.25 g/cm3, respectively [14].

We validated the estimated SPR differences in a typical scenario, a worst-case scenario, and

all cases for multiple CT scanner types and scan conditions (Table 2). The typical scenario is one of

the scan conditions. The worst-case scenario is that the estimated SPR differences is the largest for

lung tissue. All cases include all the estimated SPR differences for multiple CT scanner types and

scan conditions.

For the worst-case scenario, the range error caused by the estimated SPR differences was

estimated as the water equivalent thickness (WET) [25]. Eq. (18) calculates the WET as follows:

∆WETf•h = ∆SPR × • (18)

Here, ΔWET(t) is the estimated WET error, ΔSPR is the average value of the estimated SPR

difference in the MD range of each tissue type, and t is the tissue thickness.

3. RESULTS

3.1. MD and elemental weight

The estimated SPRs, MDs, and elemental weights are shown in Table 4.

For CHN analysis, the weight percent differences between analysis and theoretical values were

verified with the standard sample as 0.02 wt%, 0.85 wt%, and 0.21 wt% for H, C, and N,

respectively.

For ICP-AES and ion chromatography, the correlation coefficients were calculated using the

standard sample. The correlation coefficients of the calibration curves were r = 0.9998, r = 0.99965, r

= 0.99997, r = 0.99993, and r = 1.00 for Al, Si, P, Ca, and Cl.

12
 For the X-ray fluorescence spectrometer, the SD of the analysis values was calculated using

tough lung and tough bone. The SDs were 2.49 × 10-3 wt%, 1.37 × 10-3 wt%, 4.74 × 10-3 wt%, 2.65 ×

10-4 wt%, and 5.86 × 10-4 wt% for Mg, S, K, Fe, and Sr, respectively.

3.2. Tissue equivalency of TEMs

Figure 2 shows relative electron density as a function of ZR and Zp for TEMs and biological

tissues. Figure 3 shows SPR as a function of the theoretical CTN for TEMs and biological tissues

using the the resultant value of the least-squares fit based on the measured CTNs of 80 kV and 140

kV at Institute D.

3.3. Comparison between CTNs of air inside and outside of the phantom

Figure 4 shows the CTNs of air inside and outside of the phantom. The CTNs of air outside the

phantom weren’t measured when a field of view (FOV) was smaller than 270mm. Figure 5 compared

the measured and theoretical CTNs of TEMs using CTNs of air inside or outside of the phantom for

parameter fit. The root-mean-square error (RMSE) between the measured and theoretical CTNs by

averaging across six CT scanners were 6.0 HU and 8.1 HU for inside and outside of the phantom,

respectively.

3.4. Comparison between measured and theoretical CTN-to-SPR calibration tables

Figure 6(a) and (b) show the typical and worst-case scenarios, respectively. The measured and

theoretical CTN-to-SPR calibration tables of the Toshiba Aquilion LB CT scanner with a large FOV

of 400 mm at Institute C are shown as a typical scenario. For the typical scenario, the theoretical

CTN-to-SPR calibration tables obtained using the three methods were consistent with the measured

CTNs of TEMs.

For the worst-case scenario, the largest difference was found for the GE LightSpeed RT 16 CT

13
scanner at Institute A. For this CT scanner, with a small FOV of 250 mm, the measured CTN of air

was −923 HU. The theoretical CTN-to-SPR calibration table obtained using the Nakao20 model

were consistent with the measured CTN for air, lung (inhale), and tough lung. However, the

theoretical CTN-to-SPR calibration tables with the Schneider96 and Schneider00 models varied from

the measured CTNs. For adipose/muscle (0.9–1.07 g/cm3) and cartilage/spongy bone (1.07–1.25

g/cm3), the three theoretical CTN-to-SPR calibration tables were consistent with the measured CTNs

for adipose, breast 50/50, muscle, bone 200 mg / cm3, and tough bone even for the worst-case

scenario.

Figure 7 shows the estimated SPR differences boxplots for the lung (0.2–0.8 g/cm3),

adipose/muscle (0.9–1.07 g/cm3), and cartilage/spongy bone (1.07–1.25 g/cm3) in the worst-case

scenario and all cases. Table 5 summarizes the mean ± SD (minimum–maximum) [RMSE] in the

estimated SPR differences for the lung, adipose/muscle, and cartilage/spongy bone. For all cases of

the Nakao20 model, the mean ± SDs of the difference in the estimated SPR were -0.1 ± 1.0%, 0.3 ±

0.7%, and 2.4 ± 0.6% for the lung, adipose/muscle, and cartilage/spongy bone, respectively. The

estimated SPR difference includes the difference in composition between TEMs and biological

tissues. For the worst-case scenario, the estimated SPR difference for the lung tissue was larger than

that for the other tissue types. The theoretical CTN calculated by the Nakao20 model was more

consistent with the measured CTN for lung tissue than those calculated by the Schneider96 and

Schneider00 models. The mean values of the estimated SPR difference in lung tissue were 2.9%,

2.9%, and -1.4% for Schneider96, Schneider00, and Nakao20, respectively. The estimated SPR

difference in % is relative to water (e.g. even if SPR is 0.3 for lung tissue and if the estimated SPR

difference is 0.03, the estimated SPR difference in % is 3%). When the treatment beam passes

through 10 cm-thickness lung tissues for ion therapy, the WET error for Schneider96, Schneider00,

and Nakao20 were estimated as 2.9 mm, 2.9 mm, and -1.4 mm in Eq. (18), respectively.

14
4. DISCUSSION

For tissue equivalency of TEMs, if a set of TEMs containing high atomic number (Z > 20) or

not containing phosphorus and calcium were used for parameter fit, the theoretical CTNs differed

from the actual biological tissues [12,14,22]. We showed in Figure 2 and 3 that the eight TEMs used

in this study were representative of real tissues [22]. High-density TEMs of CIRS, namely bone 800

mg/cm3 and bone 1250 mg/cm3, were not used for stoichiometric CTN calibration model comparison

because these two materials contain barium (Z=56). Barium is not a natural component of human

tissues, and its high Z and pronounced K-edge transitions could potentially affect the fitting process

of the models [12,26]. We have closely tissue equivalent materials, and thus the measured

CTN-to-SPR calibration table would likely be the optimal choice for calibration technique. However,

this also gave us an opportunity to verify how closely stoichiometric CTN calibration models were

able to reproduce the measured CTN-to-SPR calibration table.

We showed the difference between the measured and theoretical CTNs performing the

parameter fit with CTN of air inside and outside of phantom. Because air calibration was performed

daily for all CT scanner and CTNs of air outside of the phantom were close to -1000 HU than those

inside of the phantom, the image reconstruction algorithm type could cause the deviation from

-1000HU [23]. The RMSE slightly increased by using the CTN of air outside of phantom because

the CTN difference of air affected the fitting process.

We used three characteristic free parameters (k1, k2, and α) of the Nakao20 model for the

least-squares fit. Here, k1 and k2 are related to the cross-sectional parameterization of the

Schneider00 model, whereas α is related to the scaling correction of the CTN-to-SPR calibration

table [14]. In a previous study [12], fit models that contained either one, two, or three parameters

have been compared to investigate the robustness to theoretical CTN deviations in the calibration

process. The fit models were modified to reduce the number of free parameters and simplify the fit

model. In contrast, the Nakao20 model added one free parameter to the Schneider00 model. In

15
addition to the scaling correction, an offset correction can be useful to improve the consistency

between the theoretical and measured CTNs for water. However, as the CTN accuracy is lower than

0 ± 5 HU for water [27], the CTN variation of water is smaller than that of air (Figure 4). Therefore,

the scaling correction is more effective than the offset correction for parameter fit. The Nakao20

model was established with adding only the scaling correction (α) to the Schneider00 model because

it is possible that the robustness of stoichiometric CTN calibration model could be decreased by

adding excess free parameter of the offset correction [12].

For the typical scenario (Figure 6(a)), the measured and three theoretical CTN-to-SPR

calibration tables were in agreement. However, for the worst-case scenario (Figure 6(b)), only the

theoretical CTN-to-SPR calibration table obtained using the Nakao20 model was consistent with the

measured CTN for air and lung equivalent materials, although the measured CTN of air was –923

HU. We calculated the theoretical CTN for air as –920 HU for the Nakao20 model because the

resultant value of the least-squares fit result α = 0.92 was substituted in −1000α. Furthermore,

theoretical CTN-to-SPR calibration table of the Nakao20 model was consistent with that of the

Schneider00 models from soft tissue to tooth tissue. Therefore, the Nakao20 model is equal to or

better than the Schneider00 model.

For the worst-case scenario, the estimated SPR difference for the lung tissue was larger than

that for the other tissue types (Figure 7). The WET errors for Schneider96 and Schneider00 were

estimated as 2.9 mm and 2.9 mm in Eq. (18), respectively. These errors are comparable to a range

uncertainty of 3.0 - 3.5%, which are clinically used in proton therapy, and total range uncertainty

including other source of range uncertainty can exceed the clinical range uncertainty level [1–3]. As

the WET errors lead to even larger range errors in lung tissue, the Nakao20 model can improve

current clinical practice. For both the worst-case scenario and all cases, the theoretical CTN-to-SPR

calibration table with the Nakao20 model is consistent with the measured CTN of each TEMs.

Therefore, we demonstrated the effectiveness of the Nakao20 model for ion therapy.

16
 Because of the close tissue equivalence, the stoichiometric CTN calibration is unnecessary

when using the set of eight TEMs and the measured CTN-to-SPR calibration table could be used

instead. However, other institutes could have a less optimal set of TEMs available, and in that case,

we suggest that the Nakao20 model should be preferred over the Schneider96 and Schneider00

models due to it providing better fitting in the lung region.

5. CONCLUSION

We compared three CTN calibration models, namely the Schneider96, Schneider00, and

Nakao20 models, for ion therapy. The CTN-to-SPR calibration tables obtained using the three

models agreed for the typical scenario. Only the CTN-to-SPR calibration table that used the Nakao20

model was consistent with the measured CTN of air and lung tissue, even in the worst-case scenario.

We demonstrated the effectiveness of the Nakao20 model in low-density tissues by comparing it with

the Schneider96 model and the Schneider00 model for ion therapy.

ACKNOWLEDGMENTS

We thank Hiroto Munetsuna, Ph.D., and Shuji Matsushita, Ph.D., from the Hiroshima Prefectural

Technology Research Institute for their technical support in elemental weight measurements. This

work was supported by AMED under Grant Numbers 2031526 and JSPS KAKENHI Grant Numbers

19K17269 and 19K12865.

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21
Figure 1. CTN calibration phantom.

Figure 2. Relative electron density as a function: (a) ZR; (b) Zp for lung (inhale), lung (exhale),
adipose, breast 50/50, muscle, bone 200 mg/cm3, tough lung, tough bone, and biological tissues.

Figure 3. SPRs as a function of the calculated CTN for lung (inhale), lung (exhale), adipose, breast
50/50, muscle, bone 200 mg/cm3, tough lung, tough bone, and biological tissues. The CTNs were
calculated using the resultant value of the least-squares fit based on the measured CTNs of (a) 80 kV
and (b) 140 kV at Institute D.

Figure 4. Measured CTNs of air inside and outside of the phantom.

Figure 5. Comparison of the measured and theoretical CTNs using CTNs of air inside or outside of
the phantom for parameter fit.

Figure 6. Comparison between the measured and three theoretical CTN-to-SPR calibration tables:
(a) typical scenario; (b) worst-case scenario when the measured CTN of air was −923 HU.

Figure 7. The estimated SPR difference boxplots for lung (MD range: 0.2–0.8 g/cm3),
adipose/muscle (MD range: 0.9–1.07 g/cm3) and cartilage/spongy bone (MD range: 1.07–1.25
g/cm3) for Schneider96, Schneider00, and Nakao20 in the worst-case scenario and all cases.

22
1 Table 1. Summary of - , MDs, and element weights for six TEMs of CIRS Model 062M.
„

Name
-
ρ wH wC wN wO wP wCl wCa
„ [g/cm3] [%] [%] [%] [%] [%] [%] [%]

Lung (inhale) 0.193 0.195 8.8 67.5 3.5 18.6 - 1.6 -

Lung (exhale) 0.502 0.507 8.9 66.0 2.4 20.4 - 0.6 1.7

Adipose 0.967 0.960 10.0 71.4 1.8 16.4 - 0.2 0.3

Breast 50/50 0.993 0.991 9.6 70.3 1.9 17.0 - 0.2 0.9

Muscle 1.055 1.062 9.1 69.8 2.1 16.8 - 0.1 2.2

Bone 200 mg/cm3 1.108 1.160 7.0 56.3 2.0 22.7 3.3 0.2 8.5

2 TEM, tissue-equivalent material; - denotes the ratio of the stopping-power ratio relative to water for a proton kinetic energy of 100MeV.
„

23
Table 2. Summary of CT scanner type and scan conditions for multiple institutes.

Tube Slice
Tube Acquisition Reconstruction Reconstruction
Institute CT scanner current thickness Case
voltage (kV) FOV (mm) FOV (mm) filter
(mA) (mm)
A GE LightSpeed RT 16 120 210 2.5 250 250 STANDARD Worst case
120 200 2.5 500 500 STANDARD
B Toshiba Asteion TSX-021A 120 200 2.0 320 320 FC10
120 200 2.0 500 480 FC10
C Toshiba Aquilion LB 120 350 2.0 240 240 FC21
120 350 2.0 320 320 FC21
120 350 2.0 400 400 FC21 Typical case
D GE Optima CT 580 W 80 400 2.5 500 600 STANDARD
100 400 2.5 500 600 STANDARD
120 400 2.5 500 600 STANDARD
140 400 2.5 500 600 STANDARD
E GE HiSpeed NXI 120 110 3.0 500 500 STD+
GE Optima CT 580 W 120 333 1.25 500 300 STANDARD
120 128 2.5 500 500 STANDARD
CT, computed tomography; FOV, field of view

24
Table 3. Summary of MDs, - , major element weights, residual element weight, and mean residual atomic numbers for 11 representative tissues.
„

Name
- Z†r?s
ρ wH wC wN wO wP wCa wres
[g/cm3] „ [%] [%] [%] [%] [%] [%] [%]

Air 0.001 0.001 0.00 0.01 75.52 23.17 0.00 0.00 1.30 18.0

Lung 0.384 0.380 10.3 10.7 3.2 74.6 0.2 0.0 1.0 15.9

Extra Lung 0.8 0.793 10.3 10.7 3.2 74.6 0.2 0.0 1.0 15.9

Fat 0.9 0.931 11.96 76.87 0.00 11.17 0.00 0.00 0.00 -

Adipose / Marrow 0.950 0.971 11.40 58.92 0.74 28.64 0.00 0.00 0.30 14.7

Muscle / General 1.049 1.041 10.25 14.58 3.20 70.87 0.21 0.02 0.87 16.8

Miscellaneous 1.090 1.079 9.94 20.90 3.84 63.73 0.45 0.27 0.87 15.5

Heavy Spongiosa 1.136 1.115 9.30 39.15 2.22 41.71 2.36 4.60 0.66 14.9

Mineral Bone 1.92 1.696 3.6 15.9 4.2 44.8 9.4 21.3 0.8 13.1

Tooth 2.75 2.345 2.2 9.5 2.9 42.1 13.7 28.9 0.7 12.0

Hydroxyapatite 3.156 2.558 0.20 0.00 0.00 41.14 18.50 39.89 0.00 -

MD, mass density; - denotes the ratio of the stopping power ratio relative to water for a proton kinetic energy of 100MeV;
„

wres, residual element weight; Z†r?s , mean residual atomic number

25
Table 4. - , MDs, and elemental weights for tough lung and tough bone.
„

Tough lung Tough bone Method

- 0.355 1.386 -
„

ρ [g/cm3] 0.374 1.510 a

wH [%] 5.74 5.05 b
wC [%] 62.87 42.14 b
wN [%] Not detect 0.64 b
wO [%] 29.58 31.40 f
wMg [%] Not detect 0.06 e
wAl [%] 0.29 0.02 c
wSi [%] 1.39 0.03 c
wP [%] 0.01 6.54 c
wS [%] 0.01 0.01 e
wCl [%] 0.03 0.05 d
wK [%] 0.05 Not detect e
wCa [%] 0.02 14.05 c
wFe [%] 0.01 Not detect e
wSr [%] Not detect 0.01 e

- denotes the ratio of the stopping-power ratio relative to water for a proton kinetic
„

energy of 100MeV
MD, mass density
The values are determined by
a : ISO 845–2006
b : Carbon, hydrogen, and nitrogen (CHN) element analysis
c : Inductively coupled plasma atomic emission spectroscopy (ICP-AES)
d : Ion chromatography
e : X-ray fluorescence spectrometry
f : We calculated the elemental weight as the residual weight.

26
Table 5. Summary of the estimated SPR differences for three tissue types—namely, lung, adipose/muscle, and cartilage/spongy bone. The worst-case

scenario is that the estimated SPR differences is the largest for lung tissue. All cases included the estimated SPR differences for all scan conditions

(Table 2).

SPR difference (worst-case scenario) SPR difference (all cases)

Tissue type ρ
Mean ± SD (Min - Max) [ RMSE ] (%) Mean ± SD (Min - Max) [ RMSE ] (%)

[g/cm3] Nakao20 Schneider96 Schneider00 Nakao20 Schneider96 Schneider00

-1.4 ± 1.0 2.9 ± 2.0 2.9 ± 2.0 -0.1 ± 1.0 -0.1 ± 1.9 -0.1 ± 1.9

Lung 0.2–0.8 (-3.8 – 0.1) (-1.4 – 6.4) (-1.3 – 6.4) (-3.8 – 2.5) (-5.9 – 6.4) (-5.9 – 6.4)

[ 1.7 ] [ 3.5 ] [ 3.5 ] [ 1.0 ] [ 1.9 ] [ 1.9 ]

0.2 ± 0.7 -0.1 ± 0.5 0.3 ± 1.0 0.3 ± 0.7 0.4 ± 0.5 0.6 ± 0.9

Adipose/muscle 0.9–1.07 (-0.9 – 2.1) (-0.8 – 1.0) (-1.1 – 2.7) (-1.0 – 2.6) (-0.8 – 2.7) (-1.1 – 3.3)

[ 0.8 ] [ 0.5 ] [ 1.1 ] [ 0.7 ] [ 0.7 ] [ 1.1 ]

2.1 ± 0.4 2.1 ± 0.6 1.8 ± 0.5 2.4 ± 0.6 2.6 ± 0.6 2.4 ± 0.6

Cartilage/spongy bone 1.07–1.25 (0.4 – 2.8) (0.2 – 2.8) (-0.1 – 2.5) (0.3 – 4.0) (0.2 – 4.4) (-0.1 – 4.1)

[ 2.1 ] [ 2.2 ] [ 1.9 ] [ 2.4 ] [ 2.7 ] [ 2.5 ]

SPR, stopping-power ratio; CTN, computed tomography number; SD, standard deviation; Min, minimum; Max, maximum; RMSE, root-mean-square

error;
27
 Kyoto Kagaku
Tough lung CIRS
CIRS Muscle
Lung (Exhale)

CIRS
CIRS Breast 50/50
Bone 200mg/cc

CIRS CIRS
Lung (Inhale) Kyoto Kagaku Adipose
Tough bone
 (a) (b)
3.0 3.0
Biological tissues Biological tissues
Tissue-equivalent materials Tissue-equivalent materials
2.5 2.5
Relative electron density

Relative electron density

2.0 2.0

1.5 1.5

1.0 1.0

0.5 0.5

0.0 0.0
3 4 5 6 7 8 2 2.5 3 3.5 4 4.5
Zp ZR
 (a) (b)
2.5 2.5

2.0 2.0
Stopping-power ratio

Stopping-power ratio
1.5 1.5

1.0 1.0

0.5 0.5
Biological tissues Biological tissues
Tissue-equivalent materials Tissue-equivalent materials
0.0 0.0
-1000 0 1000 2000 3000 4000 -1000 0 1000 2000 3000
CT number(HU) CT number(HU)
 -900
-920
-940

CT number (HU)
-960
-980
-1000
-1020
-1040
-1060
-1080
-1100
Inside Outside
 1000
Outside
Inside

CT number (Calculation)
500

-500

-1000
-1000 -500 0 500 1000
CT number (Measurement)
 (a) (b)
2.7 2.7
Measurement Measurement
2.4 Schneider96 2.4 Schneider96
Schneider00 Schneider00
2.1 Nakao20 2.1 Nakao20
Stopping-power ratio

Stopping-power ratio
1.8 1.8
1.5 1.5
1.5 1.5
1.2 1.2 1.2
1
0.9 0.9
0.9
0.6
0.5
0.6 0.6 0.3
0.3 0 0.3 0
-1000 -400 200 800 -1000 -400 200 800
0 0
-1000 0 1000 2000 3000 4000 -1000 0 1000 2000 3000 4000
CT number (HU) CT number (HU)
 7.5%

Stopping-power ratio difference

5.0%

2.5%

0%

- 2.5%

- 5.0%

- 7.5%
Lung Adipose/muscle Cartilage/spongy-bone