Magnitude and influencing factors of respiration-induced liver motion during abdominal compression in patients with intrahepatic tumors
Hu et al. Radiation Oncology
Magnitude and influencing factors of respiration-induced liver motion during abdominal compression in patients with intrahepatic tumors
Yong Hu 0
Yong-Kang Zhou 0
Yi-Xing Chen 0
Zhao-Chong Zeng 0
0 Department of Radiation Oncology, Zhongshan Hospital, Fudan University , 180, Feng Lin Road, Shanghai 200032 , China
Purpose: The purpose of this study was to use 4-dimensional-computed tomography (4D-CT) to evaluate respiration-induced liver motion magnitude and influencing factors in patients with intrahepatic tumors undergoing abdominal compression. Methods: From January 2012 to April 2016, 99 patients with intrahepatic tumors were included in this study. They all underwent 4D-CT to assess respiratory liver motion. This was performed during abdominal compression in 53 patients and during free-breathing (no abdominal compression) in 46 patients. We defined abdominal compression as being effective in managing the breath amplitude if respiration-induced liver motion in the cranial-caudal (CC) direction during compression was ≤5 mm and as being ineffective if >5 mm of motion was observed. Gender, age, body mass index (BMI), transarterial chemoembolization history, liver resection history, tumor area, tumor number, and tumor size (diameter) were determined. Multivariate logistic regression analysis was used to analyze influencing factors associated with a breath amplitude ≤5 mm in the CC direction. Results: The mean respiration-induced liver motion during abdominal compression in the left-right (LR), CC, anterior-posterior (AP), and 3-dimensional vector directions was 2.9 ± 1.2 mm, 5.3 ± 2.2 mm, 2.3 ± 1.1 mm and 6.7 ± 2.1 mm, respectively. Univariate analysis indicated that gender and BMI significantly affected abdominal compression effectiveness (both p < 0.05). Multivariate analysis confirmed these two factors as significant predictors of effective abdominal compression: gender (p = 0.030) and BMI (p = 0.006). There was a strong correlation between gender and compression effectiveness (odds ratio [OR] = 7.450) and an even stronger correlation between BMI and compression effectiveness (OR = 10.842). Conclusions: The magnitude of respiration-induced liver motion of patients with intrahepatic carcinoma undergoing abdominal compression is affected by gender and BMI, with abdominal compression being less effective in men and overweight patients.
Four-dimensional computed tomography; Abdominal compression; Body mass index (BMI); Respiratory liver motion
Liver cancer is much more common in men than in
women. In men, it is the second leading cause of
cancer death worldwide and in less developed countries.
In more developed countries, it is the sixth leading
cause of cancer death among men. An estimated
782,500 new liver cancer cases and 745,500 deaths
occurred worldwide during 2012, with China alone
accounting for about 50% of the total number of
cases and deaths .
Patients with unresectable but limited hepatocellular
carcinoma (HCC) recurrence may undergo
externalbeam radiation therapy (EBRT), but hepatic tumors
move during EBRT because of respiration-induced liver
motion. In order to avoid both inadequate tumor
coverage and unnecessary liver parenchyma irradiation, it is
crucial to determine the internal target volume (ITV).
Abdominal compression (AC) can be used in
conjunction with 4-dimensional computed tomography (4D-CT)
to reduce liver respiratory motion and determine the
ITV . Mid-ventilation is an attractive strategy because
it allows smaller planning target volume (PTV) margins
to account for breathing motion . It seems not crucial
for radiation oncologists to determine the ITV for
patients when using breath-hold techniques, gated
treatment, or tracking techniques, all of which have already
eliminated the influence of breathing motion, but the
reproducibility and accuracy of these techniques should be
included in the PTV margin [3, 4].
The ITV boundary range relies primarily on
respiration-induced liver motion, and if not properly
accounted for, motion of this magnitude could lead to
altered dosimetry because of the use of a static plan
and irradiation of an uncertain volume of normal
tissue [5, 6]. Smaller target volumes can improve dose
distribution in normal liver tissue and provide better target
dose coverage . Concern about toxicity to normal tissue
can be partially addressed by improving the geometrical
targeting accuracy and confidently reducing treatment
margins . Therefore, it is imperative to manage and/or
account for respiratory liver motion.
AC is commonly used for reducing abdominal tumor
motion during radiation therapy [9, 10]. In previous
studies, dosimetric comparison research of liver tumor
radiotherapy was mainly based on the 5 mm expansion
that was added to the gross tumor volume to create the
PTV [7, 11, 12]. Lujan et al.  also reported that static
dose distributions would change significantly when the
amplitude of motion was more than 5 mm.
Respirationinduced liver motion is anisotropic, occurring primarily
in the cranial-caudal (CC) direction [14–18]. Based on
the above observations, we consider AC to be effective if
respiration-induced liver motion is maintained within
5 mm in the CC direction.
In the current study, we used 4D-CT scans to
investigate the magnitude of the reduction of
respiration-induced liver motion achieved and to
identify the influencing factors that would help
predict the effectiveness of AC for patients with
Materials and methods
The patient inclusion criteria were as follows: (1)
confirmed liver hepatic malignancy and plan to receive
EBRT; (2) presence of at least one hepatic tumor; (3)
Child-Pugh A liver function and Karnofsky performance
status > 80; (4) no colostomy or ascites; (5) no history of
chest surgery; (6) regular breathing after basic breath
training; (7) no disease affecting pulmonary function. (8)
AC of the subxiphoid area was possible; and (9)
maximum compression force could be reached.
Between January 2012 and April 2016, 53 consecutive
patients (41 male and 12 female; age range 18–82 years;
46 primary liver cancers and 7 metastatic liver cancers)
diagnosed with liver cancer were included in the study
and underwent 4D-CT scans to assess respiratory liver
motion with AC. Another 46 patients with intrahepatic
carcinoma (32 male and 14 female; age range 40–81
years; 40 primary liver cancers and 6 metastatic liver
cancers) were also included and underwent 4D-CT scans
to assess respiratory liver motion without AC.
All patients received AC using the Body Pro-Lok system
(CIVCO, Orange City, IA, USA), which consisted of a
lightweight carbon fiber platform, a patient customizable
vacuum cushion, an AC bridge, a respiratory plate, and
knee and foot sponges. Each patient underwent basic
respiratory training guided by a radiotherapy oncologist
and therapist before administration of AC. AC was
applied during each patient’s end-expiration until
maximum tolerability was reached, as indicated by the
patient. The AC was applied to the subxiphoid area.
4D-CT image acquisition
4D-CT scans were obtained using a CT-simulation
Scanner (Siemens Somatom CT, Sensation Open; Siemens
Healthcare, Munchen, Germany). Patients were placed
in the supine position with their arms raised above the
forehead and were immobilized using a vacuum cushion.
Patient respiration was detected using the Respiratory
Gating System (AZ-733 V, Anzai Medical, Tokyo, Japan).
The x-ray tube settings were as follows: 120 kV;
400 mA; pitch 0.1; 3-mm reconstructed thickness; and
gantry rotation cycle time 0.5 s for patients without AC
when the respiratory cycle of each patient was ≤5
seconds, and 1 s for patients under AC when the
respiratory cycle of each patient was >5 s to avoid 4DCT
image quality reduction and reconstruction distortion.
The respiratory phase on the respiratory wave was
manually adjusted and confirmed by the CT-simulation
technician prior to CT image reconstruction. 4D-CT
images from raw respiratory data were sorted into a 10 CT
image series (CT0, CT10…CT90) according to the
respiratory cycle, with CT0 being defined as the
endinspiration phase and CT50 as the end-expiration phase
. Datasets for 4D-CT scans were then transferred to
Nucletron Oncentra’s treatment planning software
Version 4.3(NUCLETRON B.V., Veenendaal, Netherlands),
and all liver contours were drawn by an experienced
observer (HY) and confirmed by a single physician (YKZ).
Liver displacement acquisition and analysis
Liver contours were delineated at all CT image
phases and then copied manually to a single plan.
The nine liver contours of CT10, CT20…CT90 were
copied onto the CT0 image and were designated
CopyContour10, CopyContour20…CopyContour90. There
were 10 liver contours (CopyContour10, CopyContour20…
CopyContour90 and liver contours of CT0) on the CT0
image. Then, 0- and 90° digitally reconstructed
radiographic beams were added to the CT0 image. 0- and
90° digitally reconstructed radiographic images were a
set of coronal and sagittal projections. Ten liver
3dimensional (3D) contours could be projected onto
the digitally reconstructed radiographic images in the
directions of 0 and 90°. Overlays of 10 liver contours
were shown on the digitally reconstructed
radiographic images of 0 and 90°. The relative coordinates
of the liver were automatically generated to calculate
the respiratory liver motion in three different
anatomical directions. The position for each liver was
expressed using the left-right (LR), CC, and
anteriorposterior (AP) coordinates of the center of mass
(COM) for each 4D-CT bin. Then, the range in
respiratory liver motion from the COM of each
coordinate was obtained. Maximum range of motion in
each axial direction was calculated by subtracting the
minimum relative coordinate value from the
maximum relative coordinate value.
In this study, we defined that the AC is just effective if
respiration-induced liver motion is less than 5 mm in
Abbreviations: BMI body mass index, CC cranial-caudal, TACE transarterial
chemoembolization. * statistically significant values
Body mass index (BMI) was calculated using weight
(kg) divided by the square of the height (m), according
to the following formula:
BMI ¼ weight=height2
Variations in the LR, CC, AP, and 3D directions are
expressed as mean ± standard deviation. The
Chisquare test was used for univariate analyses (Table 1).
Multivariate logistic regression analysis was used to
analyze the influencing factors associated with breath
amplitude (Table 2). The independent-samples t-test
was used to compare differences in male and female
Table 1 Univariate analyses of factors associated with
effectiveness of abdominal compression
≤ 50 y
≥ 25 kg/m2
Postoperative recurrence, n (%)
≤ 5 cm
Liver tumor location, n (%)
Left and right lobe
Intrahepatic lesions, n (%)
Tumor diameter, n (%)
Abbreviations: BMI body mass index, CI confidence interval, OR odds ratio. *
statistically significant values
mean BMI values, and differences in liver respiratory
motion in the CC direction between male and female
patients without AC. Pearson correlation analysis was
used to detect the correlation between free-breathing
amplitude in the CC direction and BMI for patients
without AC. All calculations were performed using
SPSS 15.0 for Windows (Chicago, Illinois, USA). For
all statistical tests, the p-value for significance was set
at < 0.05.
Respiratory liver motion during abdominal compression
The mean respiration-induced liver motion for patients
undergoing AC in the LR, CC, AP, and 3D vector
directions was 2.9 ± 1.2 mm, 5.3 ± 2.2 mm, 2.3 ± 1.1 mm, and
6.7 ± 2.1 mm, respectively. Figure 1 shows scattered plot
representations of respiratory liver motion in the LR,
CC, and AP directions for patients undergoing AC.
Predictors of effectiveness of abdominal compression
Table 1 summarizes the association between
clinicopathological factors and the effectiveness of AC in the CC
direction. Gender, age, BMI, TACE (transarterial
chemoembolization) history, liver resection history, tumor
area, tumor number, and tumor size (diameter) were
analyzed. In univariate comparisons, gender and BMI were
significantly associated with the effectiveness of AC in
patients with intrahepatic tumors (p < 0.05 of both
factors). Age (p = 0.500), TACE (p = 0.669), postoperative
recurrence (p = 0.659), tumor area (p = 0.691), tumor
number (p = 0.908), and tumor size (diameter) (p =
0.934) were not significantly associated with the
effectiveness of AC in intrahepatic tumor patients. The two
≥ 25 kg/m2
Table 2 Multivariate logistic regression analyses of factors
associated with effectiveness of abdominal compression
Fig. 1 Scatter plots of liver motion in three dimensional directions. Scatter plots illustrating respiration-induced liver motion in the left-right (LR),
cranial-caudal (CC), and anterior-posterior (AP) directions for patients undergoing abdominal compression
associated factors (gender and BMI) were subsequently
used for multivariate analysis.
Table 2 summarizes the association between the
effectiveness of AC management in the CC direction and
patient gender or BMI, as determined by multivariate
analysis. These two factors both remained significant
predictors of the likelihood of ineffective AC: gender (p
= 0.030) and BMI (p = 0.006). There was a strong
correlation between gender and the effectiveness of AC (odds
ratio [OR] = 7.450) and an even stronger correlation
between BMI and the effectiveness of AC (OR = 10.842).
Correlation between body mass index and gender
Among the patients who underwent AC, the mean BMI
was 22.99 ± 3.92 kg/m2 for the females and 23.26 ±
3.44 kg/m2 for the males. There was no significant
difference between these values (p = 0.821). No correlation
was detected between BMI and gender. This supports
Fig. 2 Receiver operating characteristic curve of body mass index
(BMI) and breath amplitude in the cranial-caudal direction
the multivariate analysis findings that BMI and gender
were independent factors influencing the effectiveness of
Respiratory liver motion without abdominal compression
The mean liver respiratory motion in the LR, CC, AP,
and 3D vector directions for 46 intrahepatic carcinoma
patients in the free-breathing state (without AC) were
3.1 ± 1.3 mm, 9.9 ± 2.6 mm, 2.9 ± 1.4 mm, and 11.0 ±
2.4 mm, respectively. Respiration-induced liver motion
was most obvious in the CC direction, ranging from 5.2
to 16.8 mm in these patients who did not undergo AC.
The mean liver respiratory motion in the CC direction
in the absence of AC was 8.9 ± 2.3 mm for females and
10.4 ± 2.6 mm for males. There was no significant
difference between these two values (p > 0.05). There was no
correlation between free-breathing amplitude in the CC
direction and BMI (r = 0.214 and p = 0.153 by Pearson
In this study, we found that gender and BMI were
independent influencing factors associated with the
effectiveness of AC. Females had a lower likelihood of AC being
ineffective than males. This may be attributable to a
more predominant thoracic breathing pattern observed
in females. BMI is a tool used to assess weight status
based on height, which reflects the amount of body fat
to some degree. In this study, no children or athletes
were included because their degree of body fat would
not be accurately described by the BMI. As shown in
Fig. 3, the greater the volume of abdominal adipose
tissue depots, the greater the respiration-induced liver
motion that would occur when AC was provided. The likely
explanation for this finding is that fat accumulating in
the abdomen would act as a cushion attenuating the rise
in abdominal pressure during AC. Indeed, the
waistheight ratio may, at least theoretically, be a more
accurate indicator of abdominal obesity than BMI. However,
the two parameters (BMI and waist-height ratio) would
interfere with each other in multivariate logistic
regression analysis, as there would be a correlation between
them. At first, we only recorded height and weight
values of patients in this study, but not the waistline. We
then attempted to measure the waistline of patient using
CT image, but found it was not a real waistline for
patient under AC because of the compressed abdomen.
We chose BMI as the factor evaluated in this study
primarily also because it was better known to researchers
and readers than the waist-height ratio.
Kitamura et al.  reported that tumor location,
hepatic cirrhosis, and previous hepatic surgery all had an
impact on the intrafractional tumor motion of the liver
in the transaxial direction. Tumor motion of patients
Fig. 3 Overlay of 10 liver contours rendered on a digitally reconstructed radiographic image showing the relationship between body mass index
and breath amplitude in the 3-dimensional directions from a qualitative perspective. The image in a1 is a tight overlay of 10 liver contours for a
patient with a normal body weight (a2), and the image in b1 is a loose overlay for an overweight patient (b2)
with liver cirrhosis was significantly larger than that of
patients without liver cirrhosis in the LR and AP
directions (p < 0.004) . We did not evaluate liver cirrhosis
as a possibly influencing factor in our study for two
main reasons. First, most (70% to 90%) primary liver
cancers occurring worldwide are HCC, and most of
these tumors arise in patients with liver cirrhosis prior
to being diagnosed with HCC . Thus, it is quite likely
that the majority of patients in our study had some
degree of cirrhosis. Furthermore, there are no diagnostic
signs specific for early stage liver cirrhosis according to
CT imaging, so we were unable to accurately determine
the exact number of patients with liver cirrhosis in this
Varying forces on the abdomen may inhibit liver
motion to different degrees. For example, using 4D-CT,
Heinzerling et al.  demonstrated significantly
improved control of liver tumor motion with strong AC
compared to medium AC. Likewise, varying AC plate
positions may inhibit liver motion to different degrees;
the further away from the subxiphoid area the
compression is applied, the greater the magnitude of liver motion
. In the current study, AC was applied during each
patient’s end-expiration until maximum tolerability was
reached, as indicated by the patient. We found that
abdominal breathing clearly switched to thoracic breathing
with satisfactory AC, especially in male patients, and
forced shallow breathing also occurred . However,
forced shallow breathing was difficult to detect in male
patients with severe obesity.
Our results suggest that an overweight man
undergoing AC may have a high risk of ineffective control of
respiration-induced liver motion. Based on our findings,
radiation oncologists should predict the effectiveness of
AC for patients with intrahepatic tumors by considering
their gender and BMI (the independent influencing
factors) and chose another respiratory management for
patients if they have a high likelihood of the breath
amplitude being > 5 mm in the CC direction. However,
with current advancements in precision radiotherapy,
controlling organ motion continues to be critical for
successful treatment in complex cases involving higher
doses of radiation. In these instances, it may be more
suitable to use a respiratory gating technique to deliver
radiation only to the tumor during part of the
respiratory cycle [22–24] or active breathing control (ABC),
which achieves temporary and reproducible inhibition of
respiration-induced motion by monitoring the patient’s
breathing cycle and implementing a breath hold at a
predefined stage of respiration and air flow direction [25, 26].
Zhao et al.  investigated the feasibility and
effectiveness of utilizing ABC in 3D-conformal radiation
therapy (3D-CRT) for HCC; they concluded that using ABC
in 3D-CRT for HCC is feasible and reduces normal liver
irradiation. Xi et al.  reported that respiratory-gated
radiotherapy can further reduce target volumes to spare
more surrounding tissue and allow dose escalation,
especially for patients with > 1 cm tumor mobility. Cyber
Knife  should also be considered as a good treatment
choice for some patients. Compared with
intensitymodulated radiation therapy, helical tomotherapy is one
of the techniques for overcoming the effects of
respiration during abdominal tumor radiotherapy [30, 31].
Liver deformable registration can be evaluated using
MORFEUS, a finite element model (FEM)-based
multiorgan deformable image registration method developed by
RayStation TPS (RaySearch Laboratories AB, Stockholm,
Sweden) [9, 32]. Because of our lack of access to a
deformable registration device, we could not use liver deformable
registration to enrich our conclusions. Motion artifacts
occur frequently in 4D-CT images because of breathing
irregularities, which may affect the robustness of
measurements. Each patient in the current study underwent basic
respiratory training guided by a radiotherapy oncologist
and therapist before 4D-CT. The panel “Trigger” of the
4D-CT application software allows visualization of the
respiratory waveform, and we were able to observe the
respiratory wave immediately prior to the 4D-CT scanning.
Although patients were taught to breathe as regularly as
possible, we are considering the use of audio-visual
feedback to improved breathing regularity in our future
The magnitude of respiration-induced liver motion in
patients with intrahepatic carcinoma undergoing AC is
affected by gender and BMI. Caution must be taken
when trying to reduce respiration-induced liver motion
with AC, especially in males and overweight patients
with intrahepatic tumors. It may be better for
overweight male patients with intrahepatic tumors to select
other motion management strategies during external
Authors contribution were as follows: 1) Z-CZ contributed to the conception
and design of the study, revising the article critically for important intellectual
content; 2) YH contributed to collecting 4DCT images, gathering data and
drafting the article; 3) All liver contours were drawn by YH and confirmed by
Y-KZ; 4) YH, Y-KZ and Y-XC analyzed and interpreted data; 5) All authors gave
their final approval to the version and Z-CZ took the responsibility for
submitting the manuscript for publication.
Ethics approval and consent to participate
The study was approved by the Ethics Committee of Zhongshan Hospital,
Fudan University (Ethics Approval No:2011-235).
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