Oral Oncology 111 (2020) 105025

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Oral Oncology
journal homepage: www.elsevier.com/locate/oraloncology

A prospective randomized controlled trial on the value of prophylactic oral T

nutritional supplementation in locally advanced nasopharyngeal carcinoma
patients receiving chemo-radiotherapy
Shuang Huanga, Yongfeng Piaoa, Caineng Caoa, Jia Chenb, Wei Shengb, Zekai Shuc,
Yonghong Huaa, Feng Jianga, Qiaoying Hua, Xiaozhong Chena, Yuanyuan Chena,
⁎

a
Department of Head and Neck Radiotherapy, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Cancer and Basic
Medicine (ICBM) Chinese Academy of Sciences, Zhejiang Province Key Laboratory of Radiation Oncology, 1st Banshan Road, Gongshu District, Hangzhou 310000, China
b
Hangzhou YITU Healthcare Technology Co., Ltd, Xihu District, Hangzhou 310012, China
c
The 2nd Clinical Medical College of Zhejiang, Chinese Medical University, No. 534, Binwen Road, Hangzhou 310053, China

ARTICLE INFO ABSTRACT

Keywords: Objectives: We investigated the effect of prophylactic oral nutrition supplements (ONS) in locally advanced
Nasopharyngeal carcinoma nasopharyngeal carcinoma patients receiving neoadjuvant chemotherapy and concurrent chemoradiotherapy
Chemoradiotherapy (CCRT).
Nutrition intervention Methods: Eligible patients were randomly assigned to an intervention or control group. Patients in the inter-
Treatment tolerance
vention group were supported with prophylactic ONS from the beginning of CCRT. The control group received
nutritional support only when necessary. Bodyweight, hematological indexes, nutritional status, and quality of
life were measured at baseline and before, during, and after RT.
Results: We evaluated 114 patients from October 2016 to May 2018. More than half of patients experienced
significant weight loss during CCRT, which continued for three months after radiotherapy (RT). Compared to
baseline, the rate of weight loss ≥ 5% before, during, at the end of RT, and one and three months after RT were
3.5%, 28.9%, 51.8%, 61.4%, and 61.4%, respectively. Nutritional status and global health status scores pro-
gressively decreased during treatment. The rate of RT interruption was higher in the control group than in the
intervention group (7.14% vs. 0%, χ2 = 4.29, P = 0.04). More patients experienced concurrent chemotherapy
interruption in the control group than in the intervention group (28.57% vs 10.34%, χ2 = 6.08, P = 0.01).
There were no significant differences in weight loss, nutritional status, quality of life, and global health status
between two groups.
Conclusions: Malnutrition and weight loss progressively increased during treatment. Prophylactic ONS can im-
prove tolerance to CCRT, but it offers no advantage on short-term weight loss or nutritional assessment scores.

Introduction
Unintentional weight loss and malnutrition are common in patients
with nasopharyngeal carcinoma (NPC) [1,2]. Despite advances in
radiotherapy (RT), treatment-induced toxicity, which compromises
dietary intake and nutritional status of patients, remains a common
complication [3]. Martin et al. [4], who developed a weight-prognosis
model based on approximately 10,000 cancer patients, reported that
weight loss is an independent prognostic factor for survival. In locally
advanced NPC, concurrent chemoradiotherapy (CCRT) aggravates
several complications such as xerostomia, nausea and vomiting, taste
disturbances, and mucositis, which lead to decreased consumption,
weight loss, and poor treatment tolerance. A large retrospective re-
search [5] including more than 2000 NPC patients concluded that
weight loss (≥5%) was independently associated with low overall
survival rates among underweight and normal-weight patients. Some
researchers [6,7] have proposed that oral nutrition supplements (ONS)
may reduce weight loss and improve the nutritional status and prog-
nosis of head and neck cancer (HNC) patients. However, most of the
studies had a retrospective design. Therefore, there is a need for well-
designed prospective clinical trials on NPC. Additionally, the role and
timing of ONS remain unclear. Our previous retrospective study [8]
showed that current nutrition intervention during RT can’t signifcantly
reverse nutritional status of nasopharyngeal carcinoma patients.

⁎
Corresponding author.
E-mail addresses: huangshuang@zjcc.org.cn (S. Huang), chenyy@zjcc.org.cn (Y. Chen).

https://doi.org/10.1016/j.oraloncology.2020.105025
Received 22 March 2020; Received in revised form 31 August 2020; Accepted 20 September 2020
1368-8375/ © 2020 Elsevier Ltd. All rights reserved.
S. Huang, et al.
However, it was a retrospective study without consistent standard nu-
tritional screening and intervention. Therefore, we performed a pro-
spective trial to investigate the effect of prophylactic ONS on nutritional
status and treatment tolerance in locally advanced NPC patients.
Materials and methods
Study design and patients enrollment
This was a randomized, open-label, controlled trial performed at a
tertiary cancer hospital (registration: NCT 02948699). We tried to ex-
plore whether the phyprophylactic ONS from the beginning of radio-
therapy can decrease the weight loss, improve treatment tolerance and
the overall survival of NPC patients receiving CCRT. From October
2016 to May 2018, we recruited eligible patients diagnosed with locally
advanced NPC. Informed written consent was obtained from all pa-
tients. We randomly assigned the patients to either an intervention
group or a control group by a research nurse. Inclusion criteria were the
following, 18–65 y of age; presence of histologically-confirmed NCP;
stage III and IV NPC without metastasis or lesions according to the
AJCC 7th stage system; oral consumption; ECOG (Eastern Cooperative
Oncology Group) ranging from 0 to 2; and normal hemodynamic in-
dices suitable for RT.
Randomization and masking
Patients were randomized into intervention or controlled arm (1:1)
through a computer-generated random list consisting of randomly
permuted blocks of four patient numbers. The enrollment was done by
the investigator and assigned to either of treatment arms according to
the randomization number. Since the intervention was nutrition pro-
ducts, patients were aware of the arm they were assigned to. The pri-
mary end point was overall survival, which was defined as the time
from randomization to death from any cause; Secondary end points
included progress-free survival, weight loss, treatment adherence and
quality of life. The outcomes were assessed by a trained nurse, and the
result was kept concealed until the end of the trial. An independent
statistician did the statistical analysis and conveyed the results to in-
vestigators.
Ethical statement
The trial was conducted in accordance with the principles of the
Declaration of Helsinki and Good Clinical Practice guidelines as defined
by the International Conference on Harmonisation. Written informed
consent was obtained from all the patients before enrollment. Patients
could withdraw consent at any time after enrollment. The protocol was
approved by the institutional ethics review board of our hospital.
Radiotherapy and chemotherapy
The patients received neo-adjuvant chemotherapy including doc-
etaxel and platinum followed by CCRT. CCRT means two or three cycles
of concurrent chemotherapy based on cisplatin were administered
every 3 weeks during the radiotherapy. Radiation was delivered by
intensity-modulated radiotherapy (IMRT) or helical tomography
radiotherapy (TOMO). Dose fractionation and total dose followed the
guidelines of our institute [9], which are in accordance with the In-
ternational Commission on Radiation Units and Measurements (reports
50 and 62).
Intervention
Patients in the intervention group received prophylactic ONS from
the beginning to the end of RT. A specialized artificial nutritional for-
mula (Nutrison®, Nutricia Pharmaceutical Co., Ltd, Wuxi, China) was
2
Oral Oncology 111 (2020) 105025
administered according to the daily food intake of patients. Patients
would take 400 ml ONS per day from the beginning of RT. Once the
patients oral dietary declined, ONS will be added several times per day
and make sure the total energy reach to 30 kcal/kg per day as re-
commended by ESPEN [10,11]. A dietitian would help patients adjust
their energy intake every week. In order to improve the compliance,
one can of ONS will be free for every three cans. Nutricia Pharmaceu-
tical provided the free ONS and was not involved in the trial design,
data collection or analysis, or manuscript preparation or review. The
last author vouches for the completeness and accuracy of the data and
for the adherence of the trial to the protocol. When patients were un-
able to maintain adequate oral intakes (< 60% of estimated require-
ments despite the use of ONS) due to severe mucositis or sore throat,
nasogastric tubes were allowed. Patients in the control group were
given a regular diet with no prophylactic ONS. Due to ethical principles,
essential nutritional supplements were prescribed in the control group
when necessary, such when oral intake < 50%, weight loss > 5% per
month, or there were severe malnutrition-related symptoms.
Nutritional status and quality of life assessment
We collected data including height, body weight, complications,
hematological indexes, nutritional assessments, and quality of life be-
fore, during, and after RT. BMI was calculated as height (in meters)
divided by weight (in kilograms). The Nutritional Risk Screening 2002
Scale (NRS2002) [12] and Patient-Generated Subjective Global As-
sessment (PG-SGA) [13] were used as nutrition screening and assess-
ment tools. Quality of life was assessed using the European Organiza-
tion for the Research and Treatment of Cancer Quality of Life
Questionnaire (EORTC QLQ-C30) [14]. We collected data from six time
points to monitor nutritional status: baseline (T1), time before RT (T2),
half-time of RT (T3), end of RT (T4), one month after RT (T5), and three
months after RT (T6).
Statistical considerations
The study had a parallel group design with block randomization
(1:1). Baseline clinical characteristics were expressed as mean and
standard deviation (SD) for normally distributed variables, mean and
interquartile range for abnormally distributed variables, and frequency
and percentages for categorical variables. Differences in baseline clin-
ical characteristics were compared using t-test, Wilcoxon rank sum test
(or Mann-Whitney U test), or Chi-square test (or Fisher's exact prob-
ability). Repeated measures ANOVA was used in the analysis of primary
and secondary outcomes at different time points. In multivariate ana-
lysis, a mixed linear model was used for continuous variables and a
general linear mixed model was used for categorical variables. SAS 9.4
(SAS Institute, Cary, North Carolina, USA) was used for statistical
analysis. Statistical significance was set at P < 0.05.
Results
Patient characteristics
A total of 143 patients were recruited; however, 24 patients de-
clined to participate due to lack of awareness of nutrition and un-
acceptance of clinical trials. Five patients withdrew from the trial be-
fore the initiation of trial treatment (1 patient presented with a new
metastatic lesion in liver, 1 patient received induction chemotherapy
and radiotherapy without concurrent chemotherapy, and 3 refused to
be assigned to the experimental group or the control group). The re-
maining 114 patients were randomly assigned to an intervention group
(58 patients) or a control group (56 patients; Fig. 1). Approximately
10.5% patients experienced weight loss at the time of diagnosis. Base-
line characteristics were comparable between the two groups. Patient
and clinical characteristics and baseline nutritional status are
S. Huang, et al. Oral Oncology 111 (2020) 105025

Fig. 1. Recruitment and randomization design.

Table 1
Characteristics of patients at baseline.
Total (n = 114) Intervention group (n = 58) Control group (n = 56) P-value

Age 50.11 ± 8.59 49.07 ± 9.16 51.2 ± 7.89 0.19

Sex 0.46
Female 31 (27.19%) 14 17
Male 83 (72.81%) 44 39
Smoking 0.72
No 65 (57.02%) 34 31
Yes 49 (42.98%) 24 25
Alcohol consumption 0.59
No 70 (61.4%) 37 33
Yes 44 (38.6%) 21 23
Hypertension 0.89
No 91 (79.82%) 46 45
Yes 23 (20.18%) 12 11
Diabetes 0.43
No 108 (94.74%) 56 52
Yes 6 (5.26%) 2 4
T stage 0.64
1 9 (7.89%) 5 4
2 9 (7.89%) 4 5
3 69 (60.53%) 37 32
4 27 (23.68%) 12 15
N stage 0.79
0 5 (4.39%) 1 4
1 47 (41.23%) 24 23
2 40 (35.09%) 26 14
3 22 (19.3%) 7 15
BMI 0.30
< 18.5 3 (2.63%) 2 1
18.5–23 75 (65.79%) 40 35
≥23 36 (31.58%) 16 20
WL before treat 0.24(fisher exact)
No 102 52 50
Yes 12 6 6
PGSGA (Median, Range) 2 (1–13) 2 (1–9) 0.80
NRS 2002 (Median, Range) 1 (1–4) 1 (1–4) 0.22
Alb 43.99 ± 3.48 44.11 ± 3.09 43.86 ± 3.87 0.71
Pre-Alb 268.78 ± 60.05 273.34 ± 49.92 264.05 ± 69.15 0.41
Quality of life 66.67 (0–100) 66.67 (16.67–100) 66.67 (0–100) 0.97

BMI: body mass index; WL: weight loss; Alb: albumin; Pre-Alb: pre-albumin.

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S. Huang, et al.
summarized in Table 1.
Weight loss and nutritional status
After neoadjuvant chemotherapy, patients in both groups experi-
enced a slight weight gain (66.16 ± 10.87 kg vs. 66.65 ± 9.04 kg,
P = 0.828). Most of patients experienced noticeable weight loss during
and after CCRT. During the whole course of treatment, the mean weight
loss across all patients was 4.5% (3 ± 3.68 kg). Compared to baseline,
the rate of weight loss ≥ 5% was 3.5% (T2), 28.9% (T3), 51.8% (T4),
61.4% (T5), and 61.4% (T6), and the rate of weight loss > 10% was 0
(T2), 4.4% (T3), 18.4% (T4), 29.8% (T5), and 29.8% (T6), which
progressively increased during RT but slowly decreased after RT. The
incidences of PG-SGA ≥ 4 (moderate malnutrition) were 32.6% (T2),
39% (T3), 95.9% (T4), 100% (T5), and 78.7% (T6), and the incidences
of PG-SGA ≥ 9 (severe malnutrition) were 2.3% (T2), 10.5% (T3), 50%
(T4), 72.3% (T5), and 14.8% (T6). However, there was no statistical
difference in body weight, weight loss, or nutritional status including
NRS2002 and PG-SGA in repeated measures ANOVA between the in-
tervention and control groups.
Nasogastric tubes were used in eight patients (six in the intervention
group and two in the control group) due to severe mucositis and sore
throat. Patients who finished 75% or above of the planned nutrition
supplements were defined as compliance. The compliance rate of ONS
was 54% in the intervention group. Approximately, 20% patients in the
control group received ONS due to a marked decline in food intake. In
the intervention group, there were only mild to moderate nutrition-
associated adverse reactions such as abdominal distention and diarrhea.
Quality of life
Overall quality of life was assessed with questionnaires from base-
line to the end of RT. There were no significant effects of prophylactic
ONS on quality of life after adjusting for baseline differences. Quality of
life at T5 and T6 could not be assessed due to hospital discharge.
Treatment tolerance and toxicity
All participants completed RT. Four patients in the control group
delayed RT for > 5 d, including one patient with serious malnutrition
and fatigue, one patient with severe anemia, and two patients with
inadequate positioning during RT due to weight loss. No patients in the
intervention group delayed RT. There was a higher interruption rate of
RT in the control group than the intervention group (7.14% vs. 0%,
P = 0.04). More patients received two cycles of concurrent che-
motherapy in the intervention group than in the control group.
Therapeutic toxicity may affect nutritional status. Grade 3/4 mucositis
and grade 2/3 skin reactions were observed in 26.3% and 23.7% of the
patients, respectively. Even though more serious reactions were ob-
served in the control group, there were no statistical differences be-
tween the two groups. For example, the rates of grade 3/4 mucositis
were 22.4% and 30.4%, and the rates of grade 2/3 skin reactions were
21% and 27% in the intervention and control groups, respectively
(P > 0.05). Our primary, secondary, and tertiary outcomes are listed
in Table 2.
Univariate and multivariate analysis
Based on univariate analysis (supplement table1), time (which is
defined as a continuous variable including 4 moments: baseline, before
and after RT, 3 months after RT) (P < 0.001), sex (P < 0.001), and
hypertension (P < 0.001) were relevant factors of weight loss.
However, age, T or N stage, diabetes, chemoradiotherapy, and group
were not statistically associated with weight loss. For multivariate
analysis, the outcomes of nutritional status measured by weight, PG-
SGA, C30, ALB, and pre-ALB were analyzed using a generalized linear
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Oral Oncology 111 (2020) 105025
mixed model to take into account the repeated measurements on sub-
jects over time. The model included a random individual-level intercept
to account for repeated measures (Table 3). However, there were no
significant differences among the three models in weight loss and nu-
tritional assessments after adjusting for confounding variables.
Discussion
Studies [11,15] have focused on nutritional support; however, there
is little evidence on ONS in NPC patients. A prospective observational
study [16] revealed that the median weight loss was 6.9 kg after RT in
NPC. In this prospective study using nutrition intervention, the median
weight loss was only 4.5% (~3 kg), which is lower than the values
previously reported without nutrition support (7–18.1%) [17]. Though
most patients received prophylactic ONS or ONS when necessary,
51.8% among the patients experienced WL > 5% at the end of RT. It
suggests that there is still a cumulative calorie deficit in spite of nu-
tritional support. Della Valle et al. [18] also reported that the energy
requirement to maintain body weight was greater than expected (at
least 35 kcal/kg) both during and after chemoradiotherapy.
Our findings revealed that the rate of suspension or delay of RT was
significantly lower and the completion rate of concurrent che-
motherapy was much higher in the intervention group than in the
control group. Cereda [7] also reported that the use of ONS in HNC
patients reduced the need for changes in scheduled anti-cancer treat-
ments (HR = 0.40, P = 0.029). Meng LB et al. [6], who retrospectively
analyzed 78 NPC patients, reported fewer days of delayed RT due to
toxicity in patients from the intervention group who were initially ad-
ministered by oral nutrition (a commercial product). However, pro-
phylactic ONS had no significant effects on weight loss or nutritional
assessment scores. Even though a systematic review reported an overall
positive effect of nutritional interventions during chemoradiotherapy,
the effectiveness of early ONS in weight loss management within cancer
patients is still inconclusive [15,19,20]. Prophylactic nutritional inter-
ventions are reported to be ineffective in the control of body weight and
body composition in some studies [17]. Kiss et al. [21] concluded that,
while nutritional support improved overall patient satisfaction, it did
not affect body weight during RT in HNC patients. Brown et al. [22],
who prospectively studied 131 HNC patients, observed no effect of
prophylactic nutritional intervention on weight loss (10.9 ± 6.6%
standard care vs. 10.8 ± 5.6% intervention, P = 0.930), quality of life,
or clinical outcomes. These results are consistent with our study find-
ings; however, we provided new evidence in locally advanced NPC
patients. Some researchers have suggested that early ONS decreases
weight loss and improves nutritional status. To the best of our knowl-
edge, the only other prospective study [23] on nutritional intervention
for NPC patients concluded that ONS was beneficial in reducing weight
loss (59.11 kg, 95% CI = 58.48–59.74 vs. 58.14 kg, 95%
CI = 57.51–58.78, P = 0.036). The range of 95% CI in this study in-
dicated that the body weights of enrolled patients were relatively si-
milar. It demonstrated that the composition of patients in this study is
quite different from our study. Their participants had much more si-
milar weights. Three months after CRT, the advantage of ONS on body
weight disappeared (57.09. vs 57.40 kg, P = 0.711). Second, no ad-
ditional nutritional supplements were provided for patients in the
control group in Jiang’research. However, in our study, we provided
nutritional supplements in the control group when necessary. Those
factors may lead to a contradictory result with our study. Xu et al. [24],
who assessed prophylactic PEG feeding before the initiation of CCRT in
NPC patients, observed that prophylactic PEG could minimize the
percentage of body weight loss ≥ 5% but not < 10% and maintain
nutritional status. However, there were some selection bias in the ret-
rospective study. Highly compliant patients are more receptive to using
a PEG tube.
As a well-designed prospective study, there is no benefit of pro-
phylactic ONS according to our results. Initially, we suspected that
S. Huang, et al. Oral Oncology 111 (2020) 105025

Table 2
Intergroup differences before, during, and after treatment.
Intervention group Control group Statistics P

Primary outcomes
Weight (Kg) (mean ± SD) F = 0.05 0.83
T1 65.78 ± 10.92 65.7 ± 9.45
T2 66.16 ± 10.87 66.65 ± 9.04
T3 63.3 ± 10.12 64.64 ± 9.36
T4 61.78 ± 10.14 62.49 ± 9.1
T5 60.86 ± 10.04 61.67 ± 8.80
T6 60.54 ± 9.98 61.56 ± 8.89

Weight Loss (%) > 5%

T1 NA NA χ2 = 2.48 0.12
T2 1.72 5.36
T3 37.93 19.64
T4 53.45 48.21
T5 63.79 58.93
T6 67.24 55.36

Weight Loss (%) > 10% χ2 = 1.75 0.19

T1 NA NA
T2 0 0
T3 3.45 3.57
T4 22.41 12.5
T5 32.76 26.78
T6 32.76 26.78

Secondary outcomes
PGSGA Score (Median, Quantile) F = 2.01 0.16
T1 2 (1–3) 2 (1–3)
T2 2.5 (2–5) 3 (2–5)
T3 11.5 (8–15) 9 (6–12)
T4 12 (9–16) 11 (7–17)

NRS 2002 (median, quantile) F = 7.72 0.006

T1 1 (1–2) 1 (1–1)
T2 1 (1–2) 1 (1–1)
T3 3 (2–4) 2 (1–3)
T4 3 (2–4) 2 (1–3)

Quality of life (median, quantile) F = 0.01 0.91

T1 10 (8–12) 10 (8–12)
T2 10 (8–12) 11 (9–12)
T3 8 (7–10) 9 (7–10)
T4 7 (6–8.5) 6 (5–8)
TP (mean ± SD) F = 7.32 0.008
T1 73.41 ± 4.76 74.80 ± 5.91
T2 65.36 ± 4.39 66.24 ± 5.25
T3 66.96 ± 4.93 68.67 ± 4.73
T4 65.6 ± 5.24 68.88 ± 6.27

ALB (mean ± SD) F = 4.65 0.033

T1 44.11 ± 3.09 43.86 ± 3.87
T2 40.9 ± 3.39 41.51 ± 3.93
T3 41.22 ± 3.89 42.4 ± 2.93
T4 39.52 ± 3.93 42.01 ± 4.06

Pre_ALB (mean ± SD) F = 0.12 0.73

T1 273.34 ± 49.92 264.05 ± 69.15
T2 268.05 ± 55.35 266.54 ± 56.84
T3 248.13 ± 56.42 244.3 ± 56.66
T4 233.67 ± 61.29 237.71 ± 55.78

Tertiary outcomes
Radiotherapy/Chemotherapy tolerance
Cisplatin Dose in CCRT(mg Median/Range) 161.46 (94.03–197.60) 159.15 (0.00–195.81) Z = −1.31 0.19
Mean dose of cisplatin (mg) 254 221 – –
CCRT ≥ 2cycles 45/58 37/56 – –
Chemotherapy interruption 10.34% 28.57% χ2 = 6.08 0.01
RT interruption 0% 7.14% χ2 = 4.29 0.04
Grade 3/4Mucositis 22.4% 30.4% 0.338
Grade 2/3 Skin reaction 21% 27% 0.446

TP: total protein, ALB: albumin, Pre-ALB: pre-albumin, CC: concurrent chemotherapy

more cycles and higher cumulative doses of concurrent chemotherapy
in the intervention group may cause adverse reactions and compromise
oral intake, which may affect ONS administration and nutritional
status. Therefore, we used a generalized linear mixed model to identify
the effects of more cycles of concurrent chemotherapy. After controlling
for the effects of different chemotherapy cycles and doses, the differ-
ence between the two groups became smaller but still without statistical
significance.
It is undeniable that treatment group showed more weight loss than
control group at various time points. Though not significant in

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S. Huang, et al. Oral Oncology 111 (2020) 105025

Table 3
Generalized linear mixed models of main (primary and secondary) outcomes before and after treatment.
Outcomes Model 1 Model 2 Model 3

β s.e. P Β s.e. P β s.e. P

Weight 0.62 1.83 0.74 0.31 1.09 0.78 0.21 1.10 0.85
WL > 5% −0.48 0.43 0.27 −0.26 0.48 0.59 −0.30 0.49 0.54
WL > 10% −0.56 0.56 0.22 −0.59 0.53 0.27 −0.57 0.56 0.31
PGSGA −0.70 0.51 0.17 −0.50 0.51 0.33 −0.42 0.51 0.41
C30 −0.02 0.36 0.96 0.007 0.38 0.99 −0.03 0.38 0.93
TP 1.80 0.70 0.011 2.08 0.70 0.004 1.95 0.70 0.007
ALB 0.84 0.50 0.09 1.20 0.48 0.014 1.10 0.48 0.023
Pre_ALB −3.25 7.40 0.66 −1.91 7.31 0.79 −1.16 7.37 0.87

Model 1: only group and assessment moment were included. Model 2: model 1 + covariates (age, sex, T stage, N stage, hypertension, diabetes, BMI grade, smoking,
and alcohol consumption). Model 3: model 2 + concurrent chemotherapy dose.

aggregate overall all time points, the difference at multiple time points
is not trivial. We considered that this difference may be due to patients
in the intervention group receiving more cycles of concurrent che-
motherapy. Cisplatin has a longer period of delayed vomiting. More
cycles of concurrent chemotherapy with cisplatin means that patients
will experience longer periods of nausea and vomiting, which have a
greater impact on their appetites and food intakes, possibly offsetting
some positive effects of nutritional support. In addition, there may be
several potential explanations for the negative findings on bodyweight.
First, NPC patients may require more energy and longer nutritional
support to maintain body weight than our expectation. Two studies
[6,7] reported significant benefits on weight change when nutritional
interventions were applied from the beginning to three months after the
end of RT. Second, the characteristics of our patients were diverse as
the eligibility criteria focused on newly diagnosed patients without any
prior assessment of their nutritional status. A prospective study [25]
focused on esophageal cancer patients with malnutrition at diagnosis
concluded that enteral nutrition may reduce body weight loss during
RT and improve treatment outcomes after RT. A systematic review by
Schueren [15] recommended nutritional intervention for patients at
risk for malnutrition as these patients are more likely to benefit from
dietary supplements. Third, individual nutrition counseling throughout
treatment was not included due to lack of adequate financial resources
and manpower. A prospective randomized study [26] on 111 colorectal
patients reported that dietary counselling was more effective than
dietary supplementation alone. One study [7] demonstrated that HNC
patients who received ONS and nutrition counselling from the start to
three months after treatment experienced less weight loss and improved
quality of life.
Another possible factor that may impact the study outcomes was the
poor adherence to the prescribed nutritional intervention. One of the
greatest challenges in nutritional intervention studies is patients’ com-
pliance. A systematic review by Hubbard GP [27] revealed that overall
nutrition compliance was 78% (37% to 100%), with no significant
differences between randomized controlled studies and other research
studies (79% vs. 77%). Compliance in other two prospective interven-
tional studies were 51% [22] and 17% [28]. Pastore et al. [29] reported
that 36% of patients in the intervention group and 14% patients in the
control group stopped taking ONS. A systematic review [15] also
blamed the negative effect of high-energy ONS on limited patient
compliance. Key factors that affect compliance among Chinese NPC
patients include nausea, vomiting, reduced appetite, and poor nutrition
awareness. Patients would prefer to consume more Chinese herbal
products than formula nutrients. Therefore, multimodal and individual
nutritional strategies might be required as opposed to single ONS. There
should be more focus on patient education and conselling about nu-
trition and strategies that support patients’ feeding in future clinical
practice.
We thought that bodyweight measurement is convenient but is not
the most sensitive indicator in nutritional intervention studies. After
NACT (T2), body weight increased but nutritional status measured by
NRS2002 and PG-SGA decreased in this study. Because body weight
may be affected by several other factors in the treatment such as edema
caused by corticosteroids, which are essential for the NACT including
docetaxel. Lin et al. [30] concluded that body weight and BMI are not
adequate predictors of NPC. In contrast, body composition such as fat-
free mass index and body fat percentage may more adequately reflect
any changes in nutritional status. Ding HP et al. [31] showed that body
composition, especially the fat-free mass index, is valuable for diag-
nosing malnutrition in NPC patients receiving CCRT. Future interven-
tional studies are supposed to include these indexes.
In conclusion, our findings revealed that malnutrition and weight
loss in NPC patients progressively increased during chemoradiotherapy
in spite of prophylactic intervention. Prophylactic ONS improved the
tolerance of concurrent chemotherapy and decreased the interruption
of RT, but it did not improve weight loss or nutritional assessment
scores. But there still some limitations. Future studies should have
larger sample sizes, more complex strategies, and more accurate and
sensitive indicators to identify patients who would benefit from pro-
phylactic nutritional interventions.
Funding sources
This work was supported by the National Natural Science
Foundation of China (Surface; grant number 81672971) and Zhejiang
Medical and Health General Research Program (Surface; grant number
20182448552).
Statement of authorship
YY Chen designed, implemented the trial protocol and managed the
trial; J Chen and W Sheng contributed to data and statistical analysis;
Yongfeng Piao and Caineng Cao contributed to recruit of patients, data
acquisition. S Huang wrote the first draft of manuscript, which was
reviewed by all the authors. All the authors approved the final content
of the manuscript.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.oraloncology.2020.105025.

6
S. Huang, et al.
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