Support Care Cancer

DOI 10.1007/s00520-017-3628-5

ORIGINAL ARTICLE

Skeletal muscle loss and prognosis of breast cancer patients

Yoshiko Kubo 1,2 & Tateaki Naito 3 & Keita Mori 4 & Gakuji Osawa 1 & Etsuko Aruga 1

Received: 6 September 2016 / Accepted: 6 February 2017

# Springer-Verlag Berlin Heidelberg 2017

Abstract analyzed. Both the cross-sectional area and MA continued to

Purpose The aim of this study was to clarify the changes in
the cross-sectional area of skeletal muscle and muscle attenu-
ation (MA) during 12-month period before death in breast
cancer patients.
Methods Breast cancer patients who received treatment be-
tween September 2002 and July 2014 at Shizuoka Cancer
Center or between December 2005 and July 2014 at Teikyo
University Hospital were identified. Computed tomography
(CT) scans during the 12-month period before death of con-
secutive female patients who died of breast cancer were
reviewed. Skeletal muscle quantity and quality were evaluated
by a cross-sectional area of skeletal muscle and MA, respec-
tively, on CT scans taken 10–12 months (T1), 7–9 months
(T2), 4–6 months (T3), and within 3 months (T4) prior to
death. Wilcoxon signed rank test was used to compare the
differences between the two-time points with Bonferroni cor-
rection (p = 0.0083).
Results The medical records of 99 patients (median age at
death, 57 years; range, 40–83 years) were retrospectively
* Yoshiko Kubo
kawabehachi@yahoo.co.jp
1
Department of Palliative Medicine, Teikyo University School of
Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo 173-8605, Japan
2
Department of Breast Surgery, Shizuoka Cancer Center, 1007,
Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777,
Japan
3
Division of Thoracic Oncology, Shizuoka Cancer Center, 1007,
Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777,
Japan
4
Clinical Research Center, Shizuoka Cancer Center, 1007,
Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777,
Japan
decrease during 12-month period before death. Statistically
significant differences were observed in the cross-sectional
areas between T1 and T4 (p = 0.0011), T2 and T4
(p = 0.0019), and T3 and T4 (p = 0.0026), as well as in MA
between T2 and T4 (p = 0.0012) and T3 and T4 (p = 0.0061).
Conclusions These results suggest that both quantity and
quality of the skeletal muscle continued to decrease during
12-month period before death in breast cancer patients.
Keywords Breast cancer . Cancer cachexia . Skeletal muscle .
Computed tomography . Muscle attenuation . The
cross-sectional area of skeletal muscle
Introduction
Cancer cachexia is a condition primarily characterized by de-
creased skeletal muscle mass, which is closely correlated with
cancer prognosis and occurs in 15–57% of cancer patients
[1–5]. The 2011 European Palliative Care Research
Collaborative guidelines [1] proposed three stages of cancer
cachexia: pre-cachexia, cachexia, and refractory cachexia.
Signs and symptoms of cachexia, such as decreased muscle
mass, anorexia, and progressive weight loss, are not clear in
the early stage of cancer but become remarkable with disease
progression [1]. In the first stage (i.e., pre-cachexia), interven-
tions, such as nutritional therapy, medication, or rehabilitation,
can possibly prevent or delay the progression of cancer ca-
chexia [1].
The evaluation of skeletal muscle by computed tomogra-
phy (CT) has two aspects: skeletal muscle quantity assessed in
a cross-sectional area at the third lumber vertebrae (L3) level
and skeletal muscle quantity assessed by muscle attenuation
(MA). Previous study has shown that low skeletal muscle

mass is associated with shorter overall survival in respiratory
and gastrointestinal cancer [6]. Low MA is also associated
with poor prognosis in ovarian cancer [7] and melanoma [8].
In patients with hepatocellular carcinoma, both low skeletal
muscle mass and low MA are predictive of mortality [9].
Regarding patients with breast cancer, low skeletal muscle
mass was associated with an increased risk of overall mortality
[10], chemotherapy toxicity, and tumor progression [11].
Change in skeletal muscle mass and MA during the period
near death was rarely reported in breast cancer patients.
According to a recent longitudinal observational study, being
within 90 days from death was the principal risk factor for
muscle decreased in patients with lung, colorectal, and pan-
creatic cancer, as well as cholangiocarcinoma [12]. However,
no previous study has evaluated the longitudinal changes in
skeletal muscle mass and MA in patients with breast cancer
during 12-month period before death.
The primary aim of this study was to clarify the changes in
skeletal muscle mass and MA during 12-month period before
death in breast cancer patients.
Patients and methods
Patient selection
The patient cohort included consecutive female patients with
breast cancer who received treatment and died between
September 2002 and July 2014 at Shizuoka Cancer Center
or between December 2005 and July 2014 at Teikyo
University Hospital. At least two CT scans that included L3
conducted during 12-month period before death were required
for the study entry. Because breast cancer is common in wom-
en and there are sex differences in muscle mass between men
and women, the study population was limited to women. The
exclusion criteria were as follows: (1) a neuromuscular disor-
der and (2) paralysis or motor dysfunction of the extremities.
Patients who experienced changes in muscle by diseases not
related to breast cancer were excluded. The data were re-
trieved from the medical records of all included patients. On
the basis of body weight in the 12 months before death, pa-
tients who experienced body weight loss of >5% over the past
6 months were evaluated as Bweight loss^ [1]. Measurements
were made from the date of diagnosis of weight loss until the
date of death. In this study, oral and intravenous injections of
systemic chemotherapeutic agents were targeted. Therefore,
local radiation and hepatic arterial infusion therapies were
excluded. Performance status (PS) was classified according
to the Eastern Cooperative Oncology Group criteria. Breast
cancer stage was evaluated according to the TNM classifica-
tion of the Union for International Cancer Control (7th edi-
tion). Response to chemotherapy was evaluated using the
Response Evaluation Criteria in Solid Tumors version 1.1
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[13], and adverse events were assessed according to the
Common Terminology Criteria for Adverse Events version
4.0.
The study protocol was approved by the Institutional
Review Boards and the Ethics Committees of Shizuoka
Cancer Center and Teikyo University.
CT image analysis
Muscle analysis was performed using at least two digitally
stored CT images obtained for evaluation of therapy or patient
follow-up during routine clinical practice during 12 months
before death. Spiral CT scans with 5 mm-thick slices, with or
without contrast agents, at an imaging tube voltage of
120 kVp were used for evaluation in all cases. The Aquilion
ONE Vision Edition, Aquilion ONE Global Standard Edition,
and Aquilion 16 M (Toshiba Medical Systems Corporation,
Tochigi, Japan) CT scanners were used at the Shizuoka Cancer
Center, and the Aquilion 64 (Toshiba Medical Systems
Corporation), LightSpeed VCT (GE, Fairfield, CT, USA),
and SOMATOM Definition Flash (Siemens AG, Munich,
Germany) CT scanners were used at Teikyo University
Hospital.
Cross-sectional area of skeletal muscle and MA
Two consecutive axial CT images that included L3 were se-
lected for analysis. First, in each image, the border of the
skeletal muscle was traced and the extent of the
cross-sectional area was determined. The cross-sectional area
(cm2) and MA (Hounsfield units: HU) of the skeletal muscle
were quantified within a range of −29 to 150 HU [14] using
SYNAPSE VINCENT version 3 (FUJIFILM Medical
Systems, Nishiazabu, Minato, Japan) at the Shizuoka Cancer
Center and AZE VirtualPlace RAIJIN Anatomia version
3.5006 (AZE; Marunouchi, Chiyoda, Japan) at Teikyo
University Hospital. Calculations of the two consecutive im-
ages were made, and the average of these values was used for
analysis.
Each CT scan used for comparison was measured by a
single physician. The cross-sectional area of skeletal muscle
at the L3 level is known to be correlated with whole body
skeletal muscle mass [15]. Skeletal muscle mass measurement
using this method is an established technique to analyze mus-
cle mass in cancer patients [15]. Skeletal muscle at the L3
level included the following muscles: the psoas, erector
spinae, quadratus lumborum, transversus abdominis, external
and internal obliques, and rectus abdominis [15].
MA represents the ratio of muscle to water and air, which
have an attenuation of 0 and −1000 HU, respectively.
Decreased MA corresponds closely to muscle lipid content
and loss of muscle function and reflects the pathological infil-
tration of adipose tissue into muscle [4, 16, 17]. MA is used to
Support Care Cancer

evaluate the quality of skeletal muscle even when muscle

mass is measured to have the same cross-sectional area, be-
cause MA decreases when adipose tissue (−190 to −30 HU),
which has a low attenuation, infiltrates between the muscles
[4, 16, 17]. Furthermore, when estimating the skeletal muscle
mass using CT imaging, MA is known to be affected by
movement of body fluids by changes in posture [18] or edema.
Attenuation of body fluid as the cause of edema is higher than
that by water (0 HU). Therefore, when edema appears intra-
muscularly, MA increase. In the CT images, when edema was
observed in the entire subcutaneous fat, we judged as sever
edema.

Statistical analysis

The primary end point was the cross-sectional area of

skeletal muscle measured by CT scan. The secondary end-
points were MA and body weight. Data are expressed as
medians and ranges (minimum to maximum) or
mean ± standard error (SE) for continuous variables, and
as overall percentages (%) for categorical variables. Time
points of the CT scans were classified by the time before
death as 10–12 months (T1), 7–9 months (T2), 4–
6 months (T2), and within 3 months (T4). Wilcoxon
signed rank test was performed for paired comparison of
the cross-sectional area of skeletal muscle and MA. For
multiple comparison (6 pairs for 4 time points), signifi-
cance level was defined as a probability (p) value of
0.0083 after Bonferroni correction. The Pearson’s
product-moment correlation coefficient was used to iden-
tify correlations between two quantitative variables. All
statistical analyses were performed using JMP Pro soft-
ware version 12 for Windows (SAS Institute, Inc., Cary,
NC, USA).
Fig. 1 Selection of patients
stopping chemotherapy.^ Although some patients had no
metastasis at 12 months before death, all patients devel-
oped metastasis before death.
During the 12-month period prior to death, body weight
loss occurred at a median of 115 days (range, 8–285 days)
prior to death, chemotherapy was discontinued at a median
of 52 days (range, 7–650 days) prior to death, and PS was
decreased to 3 at a median of 30 days (range, 4–145 days)
prior to death.
Changes in average cross-sectional area of skeletal muscle
and average MA over time to death

A total of 306 CT scans for 99 patients were evaluable for

Results
Patient characteristics
Of the 5141 patients who received breast cancer treatment at
the Shizuoka Cancer Center or Teikyo University Hospital, 99
were included for analysis in this study (Fig. 1).
The basic characteristics of the study participants are
shown in Table 1. For the 69 patients who underwent
surgery, the number of chemotherapy regimens after re-
lapse, excluding preoperative/postoperative chemothera-
py, was calculated. In the remaining 30 patients (stage 4
or unknown) who did not undergo surgery, all regimens
were counted from the initial visit. The number of regi-
mens was considered zero in patients who received only
local therapy for brain or bone metastases. Therefore,
these patients were classified as Bother reason for
skeletal muscle analysis during the study period. Figure 2
shows changes in the average skeletal muscle cross-sectional
area during the time until death. Figure 3 shows changes in
the average MA during the time until death. The median
number of evaluable CT scans for a patient during the study
period was 3 (range, 2–4) scans. The number of evaluable
CT scans at each time point were 73 scans at T1, 72 scans at
T2, 98 scans at T3, and 62 scans at T4, respectively. The
number of pairs of evaluable CT scans were 47 between T1
and T4, 50 between T2 and T4, 61 between T3 and T4, 71
between T2 and T3, 72 between T1 and T3, and 46 between
T1 and T2. Statistically significant differences in the
cross-sectional areas of skeletal muscle were found between
T1 and T4 (p = 0.0011), T2 and T4 (p = 0.0019), and T3
and T4 (p = 0.0026). Statistically significant differences in
MA were found between T2 and T4 (p = 0.0012) and T3
and T4 (p = 0.0061).
 Support Care Cancer

Table 1 Patient characteristics

N = 99 no. of patients (%)

Age at death (years) 57 (40–83)

Height (cm)a 153 (132–170)
Body mass indexa 20 (13–29)
Estrogen receptor status
Positive 52 52
Negative 47 48
HER-2 status
Positive 18 18
Negative 78 79
Unknown 3 3
Stage
I 5 5
II 38 38
III 26 26
IV 27 27
Unknown 3 3
Number of CT scans 306
Number of CT scans/patienta 3.0 (2–4)
CT scan interval (days) 98 (28–210)
Number of metastasis sites in the 12 months preceding deatha 2 (0–6)
Number of chemotherapy regimensa 4 (0–13)
PS3 to death (days)a 30 (4–145)
Reason for discontinuing chemotherapy
Progressive disease 62 63
Declined general condition
Adverse events (grade 3/4) 24 24
Performance Status 3–4 4 4
Other (hematemesis, cerebral hemorrhage, etc.) 5 5
Other (e.g., refusal, local therapy only) 4 4
N = 96
Time from systemic chemotherapy completion to death (days)a 52 (7–650)
N = 44
Body weight loss (days)a 115 (8–286)
a
Median (minimum to maximum)
PS performance status, CT computed tomography

MA and edema in CT images
Representative CT images demonstrating changes in mus-
cle mass at the L3 level in the same patient during a
10-month period from month 2 to month 12 (death) are
shown in Fig. 4. This image (Fig. 4b) showed severe
edema. It is evident that subcutaneous adipose tissue,
skeletal muscle mass, and visceral adipose tissue all mark-
edly decreased, but MA increased.
The results show the number of data showing severe edema
in CT image (T1, n = 9/73 [12%]; T2, 12/72 [17%]; T3, 30/98
[31%]; and T4, 38/62 [61%]). As death approached, the fre-
quency of edema increased.
Correlations of a cross-sectional area of skeletal muscle
and MA with body weight
Correlations between body weight and the cross-sectional
area of skeletal muscle or MA are shown in Fig. 5. Body
weight was measured within 1 month before and after
measurements of the cross-sectional area of skeletal mus-
cle and MA. The results showed a correlation between
Support Care Cancer

Change in average cross-sectional area of skeletal muscle (cm2)

Fig. 2 Changes in the average 95
cross-sectional area of skeletal
muscle during the time until
death. MA muscle attenuation,
HU Hounsfield units, n number of
data points. Error bars indicate
standard error of mean. Data
points represent mean change
over intervals of patients who 90
were evaluated using computed
tomography within the cross-
sectional area of skeletal muscle
T1 (10–12 months), T2 (7–
9 months), T3 (4–6 months), and
T4 (<3 months) prior to death
(n = 73, 72, 98, 62, respectively)
85

80
T1 T2 T3 T4
Time until death

body weight and cross-sectional area of skeletal muscle. Discussion

The cross-sectional area of skeletal muscle increased with
body weight (Fig. 5a, n = 226, Pearson’s r = 0.689098, In our study, we retrospectively clarified longitudinal changes
p = 0.0001). On the other hand, there was a poor corre- in the cross-sectional area of skeletal muscle and MA in breast
lation between body weight and MA, as MA did not in- cancer patients. We found that both quantity and quality of
crease with body weight (Fig. 5b, n = 226, Pearson’s skeletal muscle continued to decrease during 12-month period
r = −0.29617, p = 0.0001). before death in breast cancer patients.

Fig. 3 Changes in average 38

muscle attenuation during the
time until death. MA muscle
attenuation, HU Hounsfield units,
Change in average muscle attenuation(HU)

n number of data points. Error

bars indicate standard error of
mean. Data points represent mean 36
change over intervals of patients
who were evaluated using
computed tomography within
muscle attenuation T1 (10–
12 months), T2 (7–9 months), T3
(4–6 months), and T4
(<3 months) prior to death 34
(n = 73, 72, 98, 62, respectively)

32

31
T1 T2 T3 T4
Time until death

Fig. 4 Computed tomography images at the L3 vertebral level of one
patient a 12 months before death and b 2 months before death. a Cross-
sectional area of skeletal muscle, 89 cm2; muscle attenuation, 47 HU. b
Cross-sectional area of skeletal muscle, 76 cm2; muscle attenuation,
54 HU. This image shows severe edema of the subcutaneous adipose
tissue, skeletal muscle, and visceral adipose tissue. HU Hounsfield units
The risk of overall mortality was greater in patients with
breast cancer with low skeletal muscle mass as compared to
patients without low skeletal muscle mass [10]. Lieffers et al.
reported longitudinal changes of skeletal muscle mass ana-
lyzed by CT scans in their retrospective study for metastatic
colorectal cancer. They showed that skeletal muscle mass de-
creased during the 12 months prior to death [19]. In a prospec-
tive study, Prado et al. also reported that skeletal muscle mass
decreased with approaching death in patients with lung, colo-
rectal, and pancreatic cancer, as well as cholangiocarcinoma
[12]. They also showed that being within 90 days from death
was the principal risk factor for muscle loss [12]. Similarly,
this study showed that skeletal muscle mass of breast cancer
patients decreased with approaching death.
In regard to changes in muscle quality measured by MA,
the prognosis of pancreatic cancer patients with low MA on
preoperative CT images was poorer than for those without low
MA [20]. The presence of low MA was also reported as a
strong preoperative prognostic factor in ovarian cancer pa-
tients [7]. In lung and gastrointestinal cancer, MA was report-
ed to decrease with approaching death [16]. These results were
consistent with our results, suggesting that skeletal muscle
quantity and quality may decrease with approaching death in
Fig. 5 Correlations of the cross- a b
sectional area of skeletal muscle
Cross-sectional area of skeletal muscle (cm2)
(a) and muscle attenuation (b)
with weight. HU Hounsfield units
Body weight (kg)
Support Care Cancer
breast cancer patients. However, MA increased with sever
edema just prior to death (Fig. 4b). However, the effect of
edema should be considered when measuring MA, because
edema frequently develops in patients with breast cancer, es-
pecially in the progressive phase, which renders accurate mus-
cle analysis rather difficult. We also found that body weight
was well correlated with muscle quantity. Similar results were
patients with advanced non-small-cell lung cancer [21].
There were some limitations to the current study that
should be addressed. First, this was a retrospective study; thus,
the possibility of unintentional bias in patient selection could
not be fully excluded. Second, we did not plan to regularly
perform CT imaging and measure weight loss. Hence, there
were missing data in each period, as indicated in Figs. 2 and 3.
Third, the study period was limited to 12 months prior to
death, in accordance with other cancer studies. Although the
loss of muscle mass was also evaluated over the 12 months
prior to death, we were unable to determine the point in time
when the decrease in muscle mass began. Therefore, the study
period of 12 months may have been insufficient. Fourth, the
study population was small; so, it was not possible to evaluate
the impact of other factors, such as medical history, use of
therapeutic drugs, or subjective symptoms, such as anorexia.
However, the shortcomings of this study can be addressed in
future studies. This study will serve as a small exploratory
survey for future studies to investigate changes in skeletal
muscle over time in breast cancer patients. The present chal-
lenges should be addressed in a future large-scale study.
In conclusion, both quantity and quality of the skeletal
muscle continued to decrease during 12-month period before
death in breast cancer patients. If the course of change in
skeletal muscle of breast cancer patients until death becomes
clear, there is a possibility that it can help clarify the clinical
course of cancer cachexia. Further prospective large-scale co-
hort surveys are needed to clarify the role of skeletal muscle
changes and to establish optimal supportive care for breast
cancer patients.
Muscle attenuation (HU)
r = 0.6891 r = −0.2961
p < .0001 p < .0001
Body weight (kg)
Support Care Cancer
Acknowledgments We would like to thank Dr. Hisao Imai (Department
of Respiratory Medicine, Gunma Prefectural Cancer Center), Dr. Norihiko
Seki (Department of Medical Oncology, Teikyo University School of
Medicine), and Dr. Satoshi Ohno, (Teikyo Academic Research Center,
Teikyo University) for constructive advice regarding this study. We wish
to thank Dr. Tomonori Kanda (Department of Radiology, Teikyo
University School of Medicine), for technical assistance, and Dr. Kaoru
Takahashi and Dr. Seiichiro Nishimura (Department of Breast Surgery,
Shizuoka Cancer Center), for patient information. We greatly appreciate
Dr. Tadashi Ikeda (Department of Surgery, Teikyo University School of
Medicine), for the encyclopedia of breast cancer. We are particularly thank-
ful to Dr. Kenji Eguchi (Health Science on Supportive Medicine for
Intractable Disease, Teikyo University School of Medicine) for providing
expertise and helping to prepare this manuscript. This study was funded by
the Promotion Plan for the Platform of Human Resource Development for
Cancer. The authors would like to thank Enago (www.enago.jp) for the
English language review.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Ethical standards All procedures involving human participants were
performed in accordance with the ethical standards of the institutional
and/or national research committee and the 1964 Helsinki declaration
and its later amendments or comparable ethical standards. For this type
of study, formal consent is not required.
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