European Journal of Oncology Nursing 53 (2021) 101943

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European Journal of Oncology Nursing

journal homepage: www.elsevier.com/locate/ejon

The prevalence of sarcopenia and relationships between dietary intake and

muscle mass in head and neck cancer patients undergoing radiotherapy: A
longitudinal study
Yiwei Cao a, Qian Lu a, *, Bing Zhuang a, Lichuan Zhang a, Yujie Wang a, Shuai Jin a,
Shaowen Xiao b, Sanli Jin a, Baomin Zheng b, Yan Sun b, **
a
Division of Medical & Surgical Nursing, School of Nursing, Peking University, #38 Xueyuan Road, Haidian District, Beijing, 100191, China
b
Department of Radiation Oncology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, #52 Fucheng Road,
Haidian District, Beijing, 100142, China

A R T I C L E I N F O A B S T R A C T

Keywords: Purpose: Our study aims to investigate dietary intake characteristics and their association with skeletal muscle
Dietary intake mass in head and neck cancer patients treated with radiotherapy.
Radiotherapy Methods: From March 2017 to August 2018, patients with head and neck cancer who received radiotherapy at our
Skeletal muscle mass
affiliated hospital were enrolled. Dietary intake was assessed through 24-hr dietary recall and skeletal muscle
Sarcopenia
mass was evaluated by bioelectrical impedance analysis at three-time points. Appendicular skeletal muscle mass
Women
was adjusted for height squared defined sarcopenia and correlated with dietary intake by generalized estimating
equations (GEE).
Results: This study sample comprised 287 patients [median age: 54 years; 187 (65.2%) men]. Median dietary
intake at post-treatment was 14.95 kcal/kg/day energy and 0.63 g/kg/day protein. Skeletal muscle mass
decreased significantly in all patients. The prevalence of sarcopenia increased from 24.4% before treatment to
46.7% at the end of treatment. Exploratory univariate GEE analysis revealed that radiotherapy time-point, male-
gender, age ≥60 and decreased dietary energy intake significantly impacted on muscle loss represented by the
appendicular skeletal muscle index. After controlling covariates, dietary energy intake was only positively
associated with muscle loss in women (P = 0.013, 95% CI = 0.003–0.027) but not in men (P = 0.788, 95% CI =
− 0.007–0.009).
Conclusion: While the loss in skeletal muscle is more prevalent in men receiving radiotherapy, the effects of
dietary energy intake were only associated with women. A prospective randomized clinical trial is required to
identify the appropriate amount of dietary energy supplement by gender in cancer patients treated with
radiotherapy.

1. Introduction
Worldwide, head and neck cancer (HNC) are together the seventh
most common malignancy, with an estimated number of 350 thousand
new cases and 171 thousand deaths from oral cavity and lip cancers in
2018 (Bray et al., 2018; Chow, 2020). Approximately 60% of patients
are diagnosed locally or regionally, at advanced stages. For the majority
of these patients, radiotherapy is a mainstay option (Strojan et al.,
2017). Although modern radiotherapy has markedly improved overall
survival rates, it also adversely affects patients’ quality of life and is
associated with an increased risk of side effects. These effects include
dysphagia, mucositis, and dysgeusia, all of which have detrimental ef­
fects on dietary intake and treatment efficacy. (Bressan et al., 2016;
Silander et al., 2013).
Loss of skeletal muscle mass, also termed sarcopenia, is an under­
appreciated condition in patients during anticancer therapy and a
prognostic factor in various cancer patients treated with radiotherapy
(Ganju et al., 2019; Kiss et al., 2019; Nishikawa et al., 2018; Takeda

* Corresponding author.
** Corresponding author.
E-mail addresses: luqian@bjmu.edu.cn (Q. Lu), lisaysun@139.com (Y. Sun).

https://doi.org/10.1016/j.ejon.2021.101943
Received 15 July 2020; Received in revised form 8 March 2021; Accepted 11 March 2021
Available online 20 March 2021
1462-3889/© 2021 Elsevier Ltd. All rights reserved.
Y. Cao et al.
et al., 2018). Depending on advanced techniques in oncology practice,
reliable quantification of skeletal muscle mass as a prognostic tool of
HNC is possible (Ganju et al., 2019). However, studies that investigate
the evolution of skeletal muscle mass loss over time in HNC patients are
limited. Furthermore, evidence suggests that the majority of HNC pa­
tients do not meet recommended dietary intakes and nutritional status
deteriorates during radiotherapy (Citak et al., 2019; Nejatinamini et al.,
2018; Silander et al., 2013). Based on the current knowledge, the rela­
tionship between skeletal muscle mass and dietary intake in head and
neck cancer patients during radiotherapy is lacking. Only one study
indicated protein and energy-dense nutritional supplements helped in­
crease perioperative lean body mass in patients with HNC (Weed et al.,
2010). However, there are several reports that attempt to decipher this
relationship in other disease conditions. For example, results from
bladder cancer patients were inconclusive with regards to the associated
diet with skeletal muscle mass and sarcopenia (Wang et al., 2019).
Meanwhile, overweight women had larger reductions in fat-free mass
than men when responding to a low-energy diet (Christensen et al.,
2018) and the association between protein intake and grip strength was
only observed among women (Mishra et al., 2018). These studies which
focused on the interaction between nutrition and sarcopenia or skeletal
muscle mass showed favorable but inconsistent effects of dietary quality
(Bloom et al., 2018; Lambell et al., 2018; Millward, 2012).
Besides these inconsistencies, little is known about the relationship
between the change of dietary intake and muscle mass decrease in HNC
patients during treatment, and that hinders the precise application of
dietary supplementation. Therefore, the primary aim of this study was to
examine the longitudinal changes in dietary intake and skeletal muscle
mass during radiotherapy and determine their relationship in patients
with HNC. This investigation enabled the assessment of dietary in­
terventions to preserve skeletal muscle mass during radiotherapy.
2. Methods
2.1. Participants and study design
This was a prospective observational study investigating dietary
intake and skeletal muscle mass in consecutive HNC patients treated
with radiotherapy between March 2017 and August 2018 at Peking
University Cancer Hospital. Patients who met the following criteria were
enrolled: (i) age >18 years; (ii) a histological diagnosis of HNC; (iii)
scheduled for intensity-modulated radiation therapy (IMRT) and (iv)
clear state of consciousness and the ability to communicate. Patients
were excluded if (i) they had evidence of other cancers; (ii) distant
metastasis, or (iii) were receiving any nutrition therapy including tube
feeding or total parenteral nutrition. The rule of thumb of ‘10 x number
of variables’ was applied to the power consideration. Subjects under­
went assessments at the three-time point: T1 (baseline), T2 (mid-treat­
ment, median 22 days), and T3 (end-treatment median 38 days). The
study was conducted following the principles of the Declaration of
Helsinki and the study protocol was approved by Human Research
Ethics Committees at Peking University Health Science Center (Regis­
tration number: IRB00001052-17002). All subjects gave written and
informed consent.
2.2. Skeletal muscle mass measurement
At multiple follow-up appointments, skeletal muscle mass was
assessed non-invasively using multifrequency bioelectrical impedance
(BIA) (Inbody Co., LTD, Seoul, Korea), which has previously been
applied to measure sarcopenia and muscle mass in cancer patients (Ida
et al., 2015; Motoori et al., 2018). Briefly, measurements were made at
30s after the patient assumed a supine position using standard protocols
for BIA by a trained professional (Motoori et al., 2018). The BIA vari­
ables are automatically estimated by InBody 120 and total skeletal
muscle mass (SMM), and the skeletal muscle mass of the arms and legs
2
European Journal of Oncology Nursing 53 (2021) 101943
were collected. Appendicular skeletal muscle mass (ASM) was calcu­
lated as the sum of the skeletal muscle mass of the four limbs. For the
purpose of this study, we analyzed appendicular skeletal muscle index
(ASMI = ASM/height2, kg/m2) and defined sarcopenia, as a skeletal
muscle index of <7.0 kg/m2 in men and <5.7 kg/m2 in women ac­
cording to the criteria of the Asian Working Group for Sarcopenia
(AWGS) (Chen et al., 2020).
2.3. Dietary assessment
Given its low respondent burden and cost-effectiveness, a 24-hr di­
etary recall was administered by trained researchers to determine the
patients’ dietary intake in a face-to-face interview at each follow-up.
This method is currently the most utilized method for the collection of
dietary intakes worldwide (Timon et al., 2016). Before the recall, pa­
tients or caregivers were shown 3-dimensional portion size food models
to help them determine their food intake accurately, and then asked by a
trained nurse about their food consumption for each item during the last
24 h. Dietary recall information was entered into the Kang’ai online
dietary record system, which utilizes the Table of Chinese Food Nutri­
ents for analysis of energy (kcal) and protein (g). Nutritional informa­
tion for commercially available foods not included in this system were
also collected and added manually by the researchers. Recalls were
checked for unrealistic quantities and missing foods by two individual
researchers. Standard daily energy intake (stDEI) was calculated as daily
energy intake [kcal] divided by standard weight (height-105) [kg] and
standard daily protein intake (stDPI) was also calculated as daily protein
intake [g] divided by standard weight [kg]. The recommended daily
requirements by the European Society of Parenteral and Enteral Nutri­
tion (ESPEN) of 25–30 kcal/kg/day energy and 1.0–1.5 g/kg/day pro­
tein were utilized in this study (Arends et al., 2017).
2.4. Covariates
Demographics including age, gender, height, and diabetes history
were assessed at baseline by questionnaires. Data sources of patients’
electronic medical records were reviewed for information on tumor
characteristics and treatment regime, including tumor location, tumor
stages, radiotherapy type, and dosage before treatment. Cancer classi­
fication and stage were defined according to American Joint Committee
on Cancer -Eighth Edition (Huang and O’Sullivan, 2017).
2.5. Statistical analyses
Distributions of continuous variables were examined for normality
and are presented as mean ± standard deviation (SD). Dietary intake,
age, radiotherapy time and dosage had a skewed distribution, which was
expressed as a median with an interquartile range (IQR). Categorical
variables are presented as a number and percentage. Differences in di­
etary intake through the process of radiotherapy were analyzed using
generalized estimating equation (GEE) or trend chi-square, wherever
appropriate. Comparisons on muscle mass among time-points were
analyzed using GEE and the prevalence of sarcopenia was compared
using trend chi-square. GEE is a popularly applied statistical method for
processing longitudinal data and provide stable estimators of regression
coefficients under weak assumptions in order to describe the association
pattern within the subject (Zeger et al., 1988). Strikingly, the results
from GEE have already adjusted for multiple comparisons by SPSS
software. The exploratory analysis of the association of dietary intake
change or ASMI with (i) treatment parameters (radiotherapy time-point,
radiotherapy type) (ii) patients characteristic (gender, age, diabetic
history) and (iii) dietary intake (stDEI, stDPI) were tested using uni­
variate GEE. Subsequently, variates were added as confounders to the
multivariable analyses of the correlation of the variable with ASMI,
which had a P-value lower than 0.1. In multivariable analysis, a P-value
lower than 0.05 is considered as statistically significant. Subsequently,
Y. Cao et al. European Journal of Oncology Nursing 53 (2021) 101943

we categorized patients with below daily dietary energy (stDEI-b) or Table 1

protein intake (stDPI-b) and above daily dietary energy (stDEI-a) or Demographics and clinical characteristics.
protein intake (stDPI-a) based on ESPEN criterion by average of the All patients (n = 287)
intake from T1 to T3 and then created dietary intake categories into four
Age, years-median (IQR) 54 (44–63)
different groups: stDEI-a + stDPI-a; stDEI-a + stDPI-b; stDPI-a + stDEI-b; Gender, no (%)
and stDEI-b + stDPI-b. We next plotted ASM and ASMI trends with four Men 187 (65.2)
groups of patients, men, and women by GraphPad Prism 6.0 (GraphPad Women 100 (34.8)
Software, San Diego, CA, USA). All analyses were duplicated and per­ Diabetic on diagnosis, no (%) 31 (10.8)
Tumor location, no (%)
formed with IBM SPSS Statistics for Windows (Version 24.0 IBM Corp. Oral 89 (31.0)
Armonk, NY, USA). Nasopharyngeal 75 (26.1)
Salivary gland 22 (7.7)
Oropharyngeal 19 (6.6)
3. Results
Sinonasal 15 (5.2)
Lymphoma 15 (5.2)
3.1. Patient characteristics Laryngeal 12 (4.2)
Thyroid 11 (3.8)
A total of 430 patients were screened for inclusion in the study; Hypopharyngeal 10 (3.5)
Esophageal 5 (1.7)
however, 143 were ineligible due to loss to follow-up, having missing
Othersa 14 (4.9)
variables in their medical records due to non-local residency. Therefore, Tumour stage, no (%)
287 patients were included in the analysis (Fig. 1). I 13 (4.5)
The baseline characteristics of the included patients are summarized II 36 (12.5)
III 60 (20.9)
in Table 1. Patients were treated with IMRT for a median of 38 days to a
IV 153 (53.3)
median dose of 63 Gy. Sixty-five percent of the patients were male, and Unclear 25 (8.7)
the median age was 54 years (IQR, 44–63). Oral cancer was the most Radiotherapy received, no (%)
prevalent (31.0%), and the majority of tumors were at stage IV (53.3%). RT alone 36 (12.5%)
All patients were receiving radiotherapy, concurrent chemotherapy was Postoperative RT 114 (39.7)
RT concurrent chemotherapy 85 (29.6)
administered to 137 (47.7%) patients, and 166 (57.8%) patients had
Postoperative 52 (18.1)
received surgery before T1. RT concurrent chemotherapy
Days between T1 and T2, median (IQR) 22 (21–24)
Days between T1 and T3, Median (IQR) 38 (38–41)
3.2. Sarcopenia prevalence and skeletal muscle mass loss over time Radiotherapy dosage (Gy) 63 (63–70)

IQR, interquartile ranges; RT, radiotherapy.

Based on AWGS cut off, 70 patients (24.4%) had sarcopenia before
radiotherapy, with a prevalence of 19.8% in males and 33.0% in fe­
males. The overall prevalence of sarcopenia was present in 134 (46.7%)
of patients (43.9% in men and 52.0% in women) at the end of radio­
therapy treatment.
Table 2 displays detailed information on the available skeletal
muscle mass measures on three evaluated time points. Overall, mean
SMM, ASM, and ASMI were all decreased across the three-time point in
both genders (P < 0.001).
The most skeletal muscle loss (1.98 ± 1.81 kg) was observed in men
treated from T1 to T3., with the least amount reported from women
between T1 and T2 (− 0.36 ± 1.62 kg). Appendicular skeletal muscle
T1 = baseline; T3 = end of radiotherapy.
a
Others (adenoid cystic etc.).
also significantly decreased from T1 (22.02) to T2 (21.36) among men
(P < 0.05), but not in women (T1 = 15.86, T2 = 15.65, P = 0.055). ASMI
was used to evaluate muscle mass adjusted for height in patients. ASMI
at T3 reduced by 6.1% (0.46 ± 0.38 kg/m2, P < 0.001) and 6.5% (0.40
± 0.35 kg/m2, P < 0.001) relative to the initial T1 mean value in men
and women, respectively.
Fig. 2 A-F displays the decreasing trends in ASM and ASMI when
patients were stratified according to dietary energy and protein intake.

Fig. 1. Patient selection flowchart.

3
Y. Cao et al. European Journal of Oncology Nursing 53 (2021) 101943

Table 2
Differences in skeletal muscle parameters and gender -specific sarcopenia cut-off over time.
Parameters All patients (n = 287) Men (n = 187) Women (n = 100)

T1 T2 T3 P value T1 T2 T3 P value T1 T2 T3 P-value

SMM (kg) 26.38 ± 25.65 ± 24.56 ± <0.001 28.85 ± 27.93 ± 26.87 ± <0.001 21.76 ± 21.40 ± 20.24 ± <0.001
5.01bc 4.82ac 4.77ab 3.67bc 3.58ac 3.56ab 3.76bc 3.85ac 3.62ab
△SMM 1.82 ± − 0.73 ± − 1.09 ± 1.98 ± − 0.93 ± − 1.05 ± 1.52 ± − 0.36 ± − 1.16 ±
1.70 1.53 1.62 1.81 1.44 1.47 1.44 1.62 1.88
ASM (kg) 19.87 ± 19.37 ± 18.64 ± <0.001 22.02 ± 21.36 ± 20.67 ± <0.001 15.86 ± 15.65 ± 14.82 ± <0.001
4.16bc 4.02ac 4.00ab 2.84bc 2.80ac 2.78ab 3.14c 3.23c 3.03ab
Arm 5.15 ± 5.01 ± 4.71 ± <0.001 5.80 ± 5.61 ± 5.33 ± <0.001 3.93 ± 3.90 ± 3.54 ± <0.001
1.36bc 1.28ac 1.31ab 1.04bc 0.95ac 1.00ab 1.01c 1.05c 0.99ab
Leg 14.73 ± 14.35 ± 13.92 ± <0.001 16.22 ± 15.75 ± 15.34 ± <0.001 11.93 ± 11.74 ± 11.28 ± <0.001
2.91bc 2.84ac 2.8ab 1.98bc 2.00ac 1.96ab 2.24bc 2.29ac 2.15ab
ASMI (kg/m2) 7.06 ± 6.88 ± 6.62 ± <0.001 7.56 ± 7.33 ± 7.10 ± <0.001 6.12 ± 6.04 ± 5.72 ± <0.001
1.04bc 1.01ac 1.01ab 0.73bc 0.71ac 0.71ab 0.88bc 0.94ac 0.88ab
Sarcopenia no 70 (24.4)c 84 (29.3)c 134 (46.7) <0.001 37 (19.8)c 51 (27.3)c 82 (43.9) <0.001 33 (33.0)c 33 (33.0)c 52 (52.0) 0.006
ab ab ab
(%)

SMM, Skeletal muscle mass; ASM, Appendicular skeletal muscle mass; ASMI, Appendicular skeletal mass index; △SMM, the difference of SMM between T1 to T3, T2 to
T1 and T3 to T2, respectively; Data presented as mean ± SD or a number and (%).
P values are a comparison among groups using analysis of GEE or trend chi-square where appropriate.
a
P < 0.05 vs. baseline by ANOVA-GEE; bP < 0.05 vs. medium-treatment by ANOVA-GEE; cP < 0.05 vs. post-treatment by ANOVA-GEE.

The most muscle loss was observed between middle and end-of-
treatment (T2-T3) and muscle loss patterns differed between four di­
etary intake groups. Patients with more stable muscle mass decreases
(5.0%–6.0%) were more likely to have stDEI above the standard. Those
with adequate stDEI and stDPI patients had the least muscle decrease. In
contrast, patients whose stDEI was below the standard were more likely
to have greater muscle loss (7.6%–8.2%) regardless of protein intake,
especially in women.
3.3. Longitudinal changes in dietary intake
Table 3 shows the main component of dietary intake in T1, T2, and
T3 for all patients. As expected, median DEI, carbohydrate, DPI, and fat
intake attenuation were observed among all three-time points and was
significant (P < 0.001).
Both T2 (18.03) and T3 (14.95) had a significantly lower stDEI than
that of T1 (24.01, P < 0.05). Approximately half (54.0%) of the patients
had lower stDEI than 25 kcal/kg/d at T1 with a prevalence of 79.8% and
85.4% at T2 and T3, respectively. There was statistical significance in
the prevalence of below standard protein intake (stDEI-b) in patients
since the first observation at T1 (P < 0.001). Median daily energy pro­
vided by protein (DPEI/DEI, T1 = 0.15, T2 = 0.16, T3 = 0.17, P < 0.001)
was increased while total DEI and DPI were decreased during
radiotherapy.
3.4. Correlation between skeletal muscle loss and dietary intake change
In univariate GEE analyses (Table 4), those patients who started to
have radiotherapy (T2 & T3) were more likely to have low stDEI (P <
0.001). Patients who had surgery operative before radiotherapy posi­
tively (β = 3.686) related to dietary intake, but gender, age (≥60) and a
history of diabetes did not significantly impact stDEI. It also indicated
that gender, age (≥60), radiotherapy (T2 & T3) and stDEI were signif­
icantly associated with ASMI. The stDPI (P = 0.465) did not show a
significant association with ASMI, neither did the diabetes diagnosis and
RT type.
The correlation between skeletal muscle loss and dietary intake
change by gender are presented in Table 5. In both univariable and
multivariable GEE analyses, stDEI was not associated with ASMI in men.
However, radiotherapy (T2 & T3) and age (≥60) independently lead to
decreases of ASMI in men. In women, radiotherapy from T1 to T2 was
significantly associated with ASMI in univariate analysis (β = − 0.085, P
= 0.045, 95% CI = − 0.167 –0.002) but lost significance in the multi­
variable analysis. stDEI was positively associated with ASMI in both
univariable analysis (β = 0.014, P = 0.046, 95% CI = 0.000–0.027) and
multivariable analysis (β = 0.015, P = 0.013, 95% CI = 0.003–0.027) in
women.
4. Discussion
This longitudinal study provides a unique insight into the association
between the change of dietary intake and skeletal muscle loss in HNC
patients treated with radiotherapy. This study has made an effort to
enhance and extend the results of different studies in the field. Several
studies have tried to correlate sarcopenia with dietary intakes (Beaudart
et al., 2019; Ogawa et al., 2019; Rodriguez-Rejon et al., 2019), however,
the relationship between them is relatively complex and remains
controversial (Okamura et al., 2019; Tanaka et al., 2017; Valenzuela
et al., 2013; Wang et al., 2019). The elderly patients with sarcopenia
consume significantly reduced amounts of macronutrients (Beaudart
et al., 2019), and the risks of a poorer diet were higher in females and
nursing home residents with sarcopenia (Rodriguez-Rejon et al., 2019).
Hence, several reports indicate that dietary energy intake, rather than
protein intake is associated with skeletal muscle mass and sarcopenia
(Tanaka et al., 2017; Valenzuela et al., 2013), especially in patients with
type 2 diabetes (Okamura et al., 2019). Conversely, a research group
from Duke University reported that diet is not associated with skeletal
muscle mass and sarcopenia in patients with bladder cancer. This study
used recall of the diet over a 12 months time period and a number of
exclusions were applied which might have contributed to a biased
sample leading to their inconclusive results (Wang et al., 2019). Given
these complicated results and lack of evidence in patients with HNC, this
longitudinal observation study was performed.
First, we found that along with radiotherapy, the skeletal muscle
mass of patients significantly decreased alongside declines in dietary
intake, including DEI, carbohydrate, DPI, and fat. Specifically, 79.8%
and 85.4% of patients did not achieve their recommended energy intake
at T2 and T3, respectively (Table 2). They only managed protein intake
of 63.0%–75.0% of their recommended requirements. In line with our
findings, there was a significant decrease of daily energy and protein
intake from baseline (27.7 ± 9.4 kcal/kg/day, 1.2 ± 0.6 g/kg/day) to
post-treatment (21.8 ± 0.89 kcal/kg/day, 0.89 ± 0.5 g/kg/day) in HNC
patients elsewhere (Nejatinamini et al., 2018). In parallel, a number of
studies that described energy and protein intake didn’t achieve the
recommendations during treatment (Arribas et al., 2017; Ganzer et al.,
2013; Jager-Wittenaar et al., 2011; Silander et al., 2013). Also, the
impact of time and type of radiotherapy were observed on energy intake
(Table 4) which is in accordance with the previous findings that side

4
Y. Cao et al.
Fig. 2. Change in ASM and ASMI at T1 and T3 for (A–B) all patients, (C–D) men, (E–F) and women with standard stDEI and stDPI (stDEI-a, stDPI-a), patients with
standard stDEI but inadequate protein intake (stDEI-a, stDPI-b), patients with inadequate energy intake but standard stDPI (stDEI-b, stDPI-a), patients with below
standard stDEI and stDPI intake (stDEI-a, stDPI-a).
effects of radiotherapy can affect patients’ ability to consume food. This
is supported by Arribas et al., who reported that 85.0% of the HNC
patients in their study had mucositis during therapy and failed to meet
their nutritional requirements, however, this study had a small sample
size (n = 20) and most of the participants were men, so this finding may
not apply to women (Arribas et al., 2017). This may mean that during
chemotherapy, rates of nausea, anorexia, and food intake might also
significantly worsen over time (Komatsu et al., 2019). We also consid­
ered the effects of concurrent chemotherapy and tumor stages on dietary
intake, however they had less impact in our cohort (Supplementary
Table 1). Compounding this is the ongoing loss of muscle that patients
experienced during radiotherapy, with a significant skeletal muscle loss
of 1.82 ± 1.70 kg, around 6.9% of skeletal muscle within median 38
days (P < 0.001). This is considerably more compared with elderly
healthy individuals, who typically lose muscle at a rate of 1.0%–1.4%
per year (Goodpaster et al., 2006). However, this is comparable with
what is observed in gastric cancer patients (4.1%, range 1.0–13.6%) who
received adjuvant chemotherapy measured by the same method of BIA
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European Journal of Oncology Nursing 53 (2021) 101943
(Aoyama et al., 2015). The prevalence of sarcopenia among locally
advanced esophageal cancer patients, as determined by skeletal muscle
index at the 3rd lumbar vertebra, increased from 29.5% before treat­
ment to 63.9% during neoadjuvant therapy. (P < 0.001) (Panje et al.,
2019) The rate of sarcopenia in our study was from 24.4% prior to
treatment to 46.7% at the end of radiotherapy (P < 0.001). This was
within the range of other reports of sarcopenia in various cancer, which
showed from 28.0% in patients with oropharyngeal cancer to 61.0% in
patients with non-small cell lung cancer assessed by computed tomog­
raphy (CT) scans (Ganju et al., 2019; Kiss et al., 2019; Nishikawa et al.,
2018). Our findings indicate that loss of skeletal muscle is prominent in
radiotherapy patients with HNC and appropriate measures should be
further investigated.
Second, we studied to what extent changes over time of dietary
intake relate to parallel changes in skeletal muscle mass in a gender-
specific subgroup. Interestingly, change of dietary energy intake was
associated with more skeletal muscle mass loss in women (P = 0.013,
95% CI = 0.003–0.027). In men, the association of stDEI (P = 0.788,
Y. Cao et al. European Journal of Oncology Nursing 53 (2021) 101943

Table 3
Comparison of dietary intake among three time-points.
Intensity-modulated radiotherapy time point P-value

T1 (n = 287) T2 (n = 287) T3 (n = 287)

Dietary intake- Median (IQR)

DEI kcal/d 1456.53 (1175.08–1841.00) bc 1100.30 (813.45–1451.57) ac
945.06 (600.83–1335.28) ab <0.001
Carbohydrate g/d 184.96 (139.06–253.82) bc 133.91 (88.58–200.07) ac 108.36 (65.56–154.84) ab <0.001
DPI g/d 56.13 (44.59–70.37) bc 47.30 (32.13–59.94) ac 39.59 (25.31–58.19) ab <0.001
Fat g/d 53.61 (44.32–68.00) bc 42.51 (28.62–53.18) ac 34.84 (21.33–48.79) ab <0.001
stDEI kcal/kg/day 24.01 (19.41–30.04) bc 18.03 (13.12–23.77) ac 14.95 (9.83–21.09) ab <0.001
stDPI g/kg/day 0.92 (0.72–1.13) bc 0.75 (0.54–0.99) ac 0.63 (0.42–0.94) ab <0.001
DPEI/DEI 0.15 (0.13, 0.17) bc 0.16 (0.14, 0.19) ac 0.17 (0.14, 0.22) ab <0.001
Dietary standards- n (%)
stDEI-b - n (%) 155 (54.01%) 229 (79.79%) 245 (85.37%) <0.001
stDPI-b - n (%) 169 (58.89%) 216 (75.26%) 219 (76.31%) <0.001

DEI, daily energy intake; DPI, daily protein intake; stDEI, standardized daily energy intake; stDPI, standardized daily energy intake; DPEI/DEI, daily energy provided
by protein/daily energy intake; stDEI-b, DEI below standard; stDPI, DPI below standard; T1, baseline; T2, mid-treatment; T3, end-treatment.
P values are a comparison among groups using analysis of GEE or trend chi-square.
a
P < 0.05 vs. baseline by ANOVA-GEE; bP < 0.05 vs. medium-treatment by ANOVA-GEE; cP < 0.05 vs. post-treatment by ANOVA-GEE.

Table 4
Univariate analysis of variables on dietary intake and ASMI.
Univariate analysis Dietary intake (stDEI) n = 287 ASMI n = 287

β 95%CI P-value β 95%CI P-value

Time-points
T1 = 1 0a – – 0a – –
T2 = 2 − 6.224 − 7.530, − 4.919 <0.001 − 0.178 − 0.220, − 0.135 <0.001
T3 = 3 − 9.197 − 10.590, − 7.804 <0.001 − 0.441 − 0.454, − 0.399 <0.001
Gender -men 0.761 − 0.768, 2.289 0.329 1.367 1.172, 1.562 <0.001
Age ≥60 1.143 − 0.264, 2.550 0.111 − 0.329 − 0.578, − 0.080 0.010
Diabetes 0.708 − 1.796, 3.211 0.580 0.344 − 0.010, 0.698 0.056
RT type
RT = 1 0a – – 0a – –
Postoperative RT = 2 3.686 1.944, 5.428 <0.001 − 0.154 − 0.520, 0.213 0.411
CT + RT = 3 0.028 − 1.763, 1.819 0.975 0.088 − 0.288, 0.463 0.648
Postoperative CT + RT = 4 3.894 1.776, 6.011 <0.001 0.102 − 0.301, 0.505 0.621
stDEI – – – 0.009 0.001, 0.017 0.029
stDPI – – – 0.079 − 0.133, 0.292 0.465

CI, confidence interval; Bold = statistical significance.

Table 5
Univariate and multivariate analysis of variables on ASMI in men and women.
Men n = 187 Women n = 100

Univariate analysis Multivariate analysis Univariate analysis Multivariate analysis

β 95%CI P value β 95%CI P value β 95%CI P value β 95%CI P value

Time-points
T1 = 1 0a – – 0a – – 0a – – 0a – –
T2 = 2 − 0.227 − 0.274, <0.001 − 0.218 − 0.285, <0.001 − 0.085 − 0.167, 0.045 − 0.012 − 0.111, 0.088 0.817
− 0.181 − 0.151 − 0.002
T3 = 3 − 0.463 − 0.517, <0.001 − 0.452 − 0.533, <0.001 − 0.400 − 0.468, <0.001 − 0.243 − 0.388, 0.001
− 0.409 − 0.370 − 0.332 − 0.097
Age ≥60 − 0.237 − 0.463, 0.040 − 0.242 − 0.468, 0.037 − 0.282 − 0.627, 0.062 0.108 − 0.326 − 0.678, 0.027 0.070
− 0.011 − 0.015
Diabetes 0.187 − 0.135, 0.510 0.255 0.195 − 0.119, 0.509 0.223 0.258 − 0.304, 0.820 0.368 0.296 − 0.148, 0.741 0.191
stDEI 0.001 − 0.007, 0.009 0.788 0.001 − 0.006, 0.009 0.710 0.014 0.000, 0.027 0.046 0.015 0.003, 0.027 0.013
stDPI − 0.160 − 0.354, 0.033 0.104 – – – 0.166 − 0.213, 0.546 0.390 – – –

CI, confidence interval; Bold = statistical significance.

95% CI = − 0.007–0.009) with the ASMI lost its significance. In general,
our findings appear to contradict current understandings. One expla­
nation is that this may relate to the fact that women are more susceptible
to an impairment of adequate food intake during treatment (Sebastian
et al., 2015). In women, a steeper decline in ASM and ASMI was
observed in participants whose energy intake fell below standard. Ful­
filled energy requirement in whom protein intake fell below standard
conferred a benefit in preserving ASM and ASMI in women (Fig. 2 E & F),
while a similar trend didn’t appear in men. This is further strengthened
by Christensen et al. who reported that men and women respond
differently to a low-energy diet, in which fat mass had a larger reduction
in women (Christensen et al., 2018). Another reason could lie in the
treatment process, which contributes more to ASMI declines in men. One
assumption is that men undergoing radiotherapy had more severe
inflammation profiles upon treatment. C-reactive protein (CRP), a
plasma marker of inflammation, rose indicating an acute phase response
which contributes to activating the inflammatory cascade, which in turn
stimulates the release of cytokines interleukin 6 (IL-6). This

6
Y. Cao et al.
subsequently leads to a reduction in skeletal muscle protein synthesis
and muscle wasting (White, 2017; Zimmers et al., 2016). Elevated CRP
and IL-6 are more severe in diseased men, though in women they
naturally occur at higher levels (Gaines et al., 2015; Niles et al., 2018).
Furthermore, circulating IL-6 levels were only associated with muscle
loss in male Apc Min/+ mice (cachexia model) but not female ones
(Hetzler et al., 2015). Strikingly, a stronger association between changes
in BMI and CRP in men was discovered previously (Yatsuya et al., 2011).
This is in line with the observation in our study assumption that men
undergoing radiotherapy incurred skeletal muscle loss responses earlier
starting from T1 to T2, which was earlier than that of women, who only
actually showed significant skeletal muscle at T3 of radiotherapy
(Table 5). Therefore, larger randomized controlled trials should be
conducted to understand this and enable further interpretations.
Protein intake during energy deprivation also generated energy
which did not represent total protein uptake for muscle synthesis. This in
turn could lead to the result that protein supplements don’t preserve
lean body mass which has been observed by other RCT studies during
pronounced energy restriction (Oikawa et al., 2018). This could mean
that not only diet but age plays a role in skeletal muscle mass reduction
especially in men (Table 5). In a 3 year follow-up study, evidence of total
and leg muscle mass loss was detected in a community-dwelling elderly
population of men, suggesting that muscle decline might also be related
to men aged over 60 years(Goodpaster et al., 2006), that men lose more
skeletal muscle mass than women do (Janssen et al., 2000). This evi­
dence suggests that males over 60 years have lower muscle mass,
possibly through pathophysiology which is associated with an
age-related decline of androgens (Peng et al., 2018).
The strength of our study is that it showed that when muscle mass
was measured during radiotherapy to identify muscle mass in patients,
they experienced changes and had greater losses than general hospi­
talized patients. However, there are limitations to this study. First, given
its observational and exploratory nature, we identified the association in
our cohort by GEE and didn’t compare covariates of men and women at
baseline. Nevertheless, all vital covariates in our study have been
included in the multivariate GEE analysis. Secondly, we assessed skel­
etal muscle mass using BIA in contrast to many previous studies which
used cross-sectional CT images to assess skeletal mass. Although BIA
cannot directly measure muscle, it can estimate skeletal muscle mass by
equations and is a rapid, non-invasive method that can be performed
repeatedly as we did in our longitudinal study. It is also accepted by
AWGS as an option for identifying sarcopenia. However, we do not have
data of muscle function in this population which would define sarco­
penia according to the AWGS criterion. Therefore, when we perform
correlation analysis, ASMI was applied rather than sarcopenia for these
circumstances. Thirdly, the 24-h dietary recall employed for this study
might not be representative of the average daily intake due to patient
self-reporting, and all types of protein were not recorded. Further
analysis as to whether the intake of whey protein is a more accurate
indicator of muscle mass is warranted.
5. Conclusion
In conclusion, significant muscle loss occurred in patients with HNC
during radiotherapy (T1, T2 and T3), which was independently associ­
ated with treatment time-point and age (>60) of patients in men and
decreased dietary energy intake in women. As pathophysiological
mechanisms between men and women differ, upcoming intervention
studies are needed to test the hypothesis that more energy supplemen­
tation in women would predicts greater improvements, and multimodal
implementations can be more precise when modulated by gender.
Funding
This study was funded by the National Key Research and Develop­
ment Project under grant number 2017YFC1309204 and Chinese
7
European Journal of Oncology Nursing 53 (2021) 101943
Medical Association Project under grant number CMAPH-NRP2019002.
CRediT authorship contribution statement
Yiwei Cao: Conceptualization, Formal analysis, Data curation,
Writing – original draft, Writing – review & editing. Qian Lu: Concep­
tualization, Supervision, Funding acquisition. Bing Zhuang: Data
curation, Formal analysis, Writing – review & editing. Lichuan Zhang:
Investigation, Writing – review & editing. Yujie Wang: Investigation.
Shuai Jin: Investigation. Shaowen Xiao: Methodology. Sanli Jin:
Methodology. Baomin Zheng: Methodology. Yan Sun: Supervision,
Resources.
Declaration of competing interest
The authors declare no potential conflict of interest.
Acknowledgments
We thank the generosity of KanCare Nutrition into donating the
Kang’ai nutritional system as a gift for dietary analysis. We also would
like to acknowledge the support from Hongmei, Li and the dietician at
Peking University Cancer Hospital.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.ejon.2021.101943.
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