Annals of Medicine

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Prognostic role of the controlling nutritional status

(CONUT) score in patients with biliary tract cancer:
a meta-analysis

Huijun Jiang & Zhibing Wang

To cite this article: Huijun Jiang & Zhibing Wang (2023) Prognostic role of the controlling
nutritional status (CONUT) score in patients with biliary tract cancer: a meta-analysis, Annals of
Medicine, 55:2, 2261461, DOI: 10.1080/07853890.2023.2261461

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Annals of Medicine
2023, VOL. 55, NO. 2, 2261461
https://doi.org/10.1080/07853890.2023.2261461

Research Article

Prognostic role of the controlling nutritional status (CONUT) score in

patients with biliary tract cancer: a meta-analysis
Huijun Jianga and Zhibing Wangb
a
Clinical Laboratory, Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, Huzhou, Zhejiang, China; bDepartment of
General Surgery, Traditional Chinese Medical Hospital of Huzhou Affiliated to Zhejiang Chinese Medical University, Huzhou, Zhejiang,
China

ABSTRACT ARTICLE HISTORY

Background: Previous reports have not reached consistent results regarding the prognostic Received 4 July 2023
significance of the controlling nutritional status (CONUT) score in biliary tract cancer (BTC). Revised 23 August 2023
Therefore, the present meta-analysis was conducted to investigate the precise role of the CONUT Accepted 15 September
2023
score in predicting the prognosis of BTC.
Methods: Electronic platforms including Web of Science, PubMed, Cochrane Library, and Embase KEYWORDS
were comprehensively searched up to May 2, 2023. We also determined combined hazard ratios CONUT; biliary tract
(HRs) and 95% confidence intervals (CIs) to estimate the role of the CONUT score in predicting cancer; meta-analysis;
the prognosis of patients with BTC. evidence-based medicine;
Results: Ten studies involving 1,441 patients were included in the present study. Nine studies prognosis
treated patients with surgical resection, and one study used percutaneous transhepatic biliary
stenting (PTBS) plus 125I seed intracavitary irradiation. Based on the combined data, a higher
CONUT score significantly predicted dismal overall survival (OS) (HR = 1.94, 95%CI = 1.41–2.66,
p < 0.001), inferior recurrence-free survival (RFS) (HR = 1.79, 95%CI = 1.48–2.17, p < 0.001) in BTC,
and low differentiation (OR = 1.57, 95%CI = 1.15–2.14, p = 0.004). Nonetheless, the CONUT score
was not related to sex, lymph node metastasis, microvascular invasion, perineural invasion, distant
metastasis, TNM stage, or tumor number in patients with BTC.
Conclusion: Higher CONUT scores significantly predicted worse OS and RFS in patients with BTC.
Moreover, BTC patients with high CONUT scores tended to have poor tumor differentiation. The
CONUT score could help clinicians stratify high-risk patients with BTC and devise individualized
treatment plans.

KEY MESSAGES
• As far as we know, this study is the first to analyze whether pretreatment CONUT is significant
for predicting the prognosis of BTC.
• A high CONUT significantly predicted worse OS and RFS in BTC patients.
• CONUT could help clinicians stratify high-risk BTC patients and devise individualized treatment
plans.
Abbreviations: CONUT: controlling nutritional status; BTC: biliary tract cancer; HR: hazard ratio;
CI: confidence interval; OS: overall survival; RFS: recurrence-free survival; GBC: gallbladder cancer;
ECC: extrahepatic cholangiocarcinoma; ICC: intrahepatic cholangiocarcinoma; HCC: hepatocellular
carcinoma; PNI: prognostic nutritional index; AGR: albumin to globulin ratio; GNRI: geriatric
nutritional risk index; CAR: C-reactive protein to albumin ratio; TC: total cholesterol; BC: breast
cancer; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; MeSH:
Medical Subject Headings; NOS: Newcastle-Ottawa Scale; OR: odds ratio; PTBS: percutaneous
transhepatic biliary stenting; OS: overall survival; RFS: recurrence-free survival; LNM: lymph node
metastasis; DFS: disease-free survival; CSS: cancer-specific survival; PFS: progression-free survival.

CONTACT Zhibing Wang wzb992077@163.com Department of General Surgery, Traditional Chinese Medical Hospital of Huzhou Affiliated to
Zhejiang Chinese Medical University, Huzhou, Zhejiang, China
Supplemental data for this article can be accessed online at https://doi.org/10.1080/07853890.2023.2261461.
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which
permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been
published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
2 H. JIANG AND Z. WANG
Introduction
Biliary tract cancer (BTC) refers to invasive carcinomas
such as gallbladder cancer (GBC), extrahepatic cholan-
giocarcinoma (ECC), and intrahepatic cholangiocarci-
noma (ICC) [1]. BTC accounts for approximately 3% of
all gastrointestinal cancers and ranks second among
hepatobiliary cancers in terms of morbidity, followed
by hepatocellular carcinoma [2,3]. According to the
disease stage, BTC has a dismal prognostic outcome,
with 5-year survival rates of 2%-15%, 2%-30% and
2%-70% for ICC, ECC, and GBC, respectively [4]. Surgery
is a potential radical therapy for BTC. Nonetheless, as
many patients with BTC do not have early symptoms,
they still have a poor prognosis. Over 65% of patients
with BTC are not candidates for surgery at the time of
diagnosis, and their 5-year survival and 1-year relapse
rates are 5–15% and 67%, respectively [5,6]. Therefore,
the identification of new and reliable biomarkers for
predicting BTC prognosis is urgently needed.
Increasing evidence has shown that nutritional sta-
tus is an important factor in cancer patients because it
can predict treatment tolerance and tumor develop-
ment [7]. Many blood test-derived biomarkers, includ-
ing the prognostic nutritional index (PNI) [8],
albumin-to-globulin ratio (AGR) [9], geriatric nutritional
risk index (GNRI) [10], and C-reactive protein-to-albu-
min ratio (CAR) [11] have been identified as effective
prognostic markers in various cancers. Notably, the
controlling nutritional status (CONUT) score represents
a verified nutritional evaluation system, which contrib-
utes to the comprehensive evaluation of host immu-
nocompetence and anabolism [12]. The CONUT score
is based on serum albumin levels, total cholesterol
(TC) content, and lymphocyte count [12] (Table 1). The
CONUT has attracted wide interest as a biomarker for
predicting cancer prognosis in breast cancer (BC) [13],
peripheral T-cell lymphoma [14], esophageal cancer
[15], and thyroid cancer [16]. Previous studies have
analyzed whether the CONUT score could be adopted
to predict the prognosis of patients with BTC, but their
findings have been inconsistent [17–26]. For instance,
Table 1. The scoring criteria for the CONUT.
Degree
Parameters Normal Light Moderate
Serum albumin (g/dL) 3.5–4.5 3.0–3.49 2.5–2.99
Score 1 2 4 6
Total lymphocyte (count/ ≥1600 1200–1599 800–1199
mm3)
Score 0 1 2 3
Total cholesterol (mg/dL) >180 140–180 100–139
Score 0 1 2 3
CONUT score (total) 0–1 2–4 5–8
CONUT: controlling nutritional status.
some studies have shown that the CONUT score is
important for predicting BTC prognosis [19,20,23,26],
whereas others have suggested that CONUT score is
not related to BTC prognosis [21,24]. Therefore, the
present meta-analysis reviewed the most recent data
to identify the significance of the CONUT score in pre-
dicting the prognosis of patients with BTC.
Materials and methods
Study guideline
The present study was conducted in accordance with
the guidelines of the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) 2020
statement (Supplementary File 1) [27].
Ethnics statement
As our analysis did not directly involve participants,
and we extracted the necessary data from previous
publications, institutional review board and ethics
committee approval was not required for this
meta-analysis.
Literature search
We comprehensively searched electronic platforms,
including Web of Science, PubMed, Cochrane Library,
and Embase, using Medical Subject Heading (MeSH)
terms combined with text words: (controlling nutri-
tional status or CONUT) and (biliary tract tumor, biliary
tract cancer, biliary tract neoplasm, cholangiocarci-
noma, bile duct cancer, gallbladder tumor, gallbladder
neoplasm, gallbladder cancer, and gallbladder carci-
noma). The literature search was conducted from the
inception of each database until May 2, 2023. We man-
ually reviewed the reference lists of the included stud-
ies to avoid omitting relevant articles.
Study eligibility criteria
Eligible studies were included based on the following
criteria: (1) BTC diagnosed through histology, (2)
Severe COUNT before treatment was measured, (3) studies
<2.5 that investigated the association between CONUT
score and survival outcomes in BTC, (4) hazard ratios
<800
(HRs) and associated 95% confidence intervals (CIs)
of survival analysis were obtained or calculated based
<100
on available data, (5) the threshold CONUT score
9–12 was determined, and (6) English-language articles.
Studies that met the following criteria were excluded:

(1) reviews, case reports, meeting abstracts, letters,
and comments; (2) studies that did not provide sur-
vival data; and (3) animal studies.
Data collection and quality evaluation
Two reviewers (HJ and ZW) reviewed eligible studies
and independently collected the required data. Any
disagreements were resolved through negotiations
until a consensus was reached. The following data
were collected from the included articles: first author,
country, publication year, sample size, sex, age, study
duration, histology, treatment, study design, threshold
CONUT score, study center, follow-up, neoadjuvant or
adjuvant treatments, survival endpoints, survival analy-
sis type, HRs with corresponding 95%CIs, and clinico-
pathological characteristics. The Newcastle–Ottawa
Scale (NOS) was used to assess the quality of the
included studies [28]. The NOS consists of three
domains–selection, comparability, and outcome–with a
score of 0–9 stars. An article with an NOS score ≥6
was considered high-quality.
Statistical analysis
The pooled HRs and corresponding 95%CIs were cal-
culated to estimate the significance of the CONUT
score in predicting the prognosis of patients with BTC.
Heterogeneity among studies was assessed using I2
statistics [29] and the chi-square Q test [30]. We
selected the random-effects model [31] for the calcu-
lation in the case of distinct heterogeneity (I2>50% or
p < 0.10); otherwise, we selected the fixed-effects
model [32]. An appropriate calculation model was
selected based on heterogeneity levels. We also per-
formed subgroup analysis to detect potential sources
of heterogeneity. Correlations between the CONUT
scores and clinicopathological features were assessed
by combining odds ratios (ORs) and 95%CIs. Moreover,
a sensitivity analysis was carried out to assess whether
individual studies affected the overall outcomes.
Funnel plots and Begg’s test were used to assess pub-
lication bias. Stata software version 12.0 (Stata Corp.,
College Station, TX, USA) was used for the statistical
analysis. Statistical significance was set at p < 0.05
(two-sided).
Results
Literature search process
As shown in Figure 1, 79 articles were initially obtained,
and 55 remained after the removal of duplicates.
Annals of Medicine 3
Through title and abstract screening, 44 irrelevant
studies or fundamental research in cell biology were
removed. Subsequently, we read the full text of 11
articles and discarded one because it did not provide
survival information. Finally, the present meta-analysis
included ten studies with 1,441 patients [17–26] (Figure
1; Table 2).
Features of included articles
Table 2 displays fundamental features of the included
articles [17–26]. Six studies were performed in Japan
[18,19,23–26] and four in China [17,20–22]. The sample
size of these studies ranged from 45 to 371, with the
median value of 121.5. All studies used a retrospective
design. Four articles included ECC cases [17,20,23,25];
three, ICC cases [18,21,24]; two, BTC cases [22,26]; and
one, GBC cases [19]. Nine studies treated patients with
surgical resection [18–26], and one study adopted per-
cutaneous transhepatic biliary stenting (PTBS) plus
125I seed intracavitary irradiation [17]. Five studies
used ≥3 as the cut-off value for CONUT [19–21,23,25],
four studies selected ≥2 [17,18,22,24], and one study
adopted ≥4 [26]. All 10 studies mentioned the role of
CONUT in predicting overall survival (OS) in BTC [17–
26]. Six studies provided data on the association
between CONUT and recurrence-free survival (RFS) in
patients with BTC [18,20,21,23,24,26]. Eight studies cal-
culated HRs together with 95%CIs by multivariable
regression [17–23,26], and two studies used univariate
analysis [24,25]. For the included articles, NOS scores
were 6–9 (median, 7), suggesting the articles were
high quality (Table 2). The details of NOS scores are
shown in Supplementary File 2.
CONUT and OS in BTC
Ten articles, including 1,441 patients, mentioned the
relationship between the CONUT score and OS in
BTC [17–26]. According to the pooled data (Figure 2
and Table 3), a higher CONUT score significantly pre-
dicted a dismal OS in BTC (HR = 1.94, 95%CI = 1.41–
2.66, p < 0.001). Owing to obvious heterogeneity, we
selected the random-effects model (I2=79.8%,
p < 0.001). Subgroup analysis revealed that a higher
CONUT score was still a prognostic factor for OS
regardless of country, sample size, treatment, thresh-
old, neoadjuvant/adjuvant treatments, treatment
intent, and type of survival analysis (all p < 0.05; Table
3). Moreover, the CONUT score significantly predicted
worse OS in patients with ECC, BTC, and GBC
(Table 3).
4 H. JIANG AND Z. WANG

Figure 1. Flow chart demonstrating the study selection process.

CONUT and RFS in BTC = 1.57, 95%CI = 1.15–2.14, p = 0.004; Table 5). However,
as shown in Table 5, there was a non-significant rela-
Six studies, including 783 patients [18,20,21,23,24,26]
tionship between CONUT score and sex (OR = 0.94,
investigated whether the CONUT score was significant in
95%CI = 0.72–1.21, p = 0.617), lymph node metastasis
predicting RFS in patients with BTC. According to the
(OR = 1.64, 95%CI = 0.95–2.82, p = 0.074), microvascu-
combined results (Figure 3 and Table 4), a higher CONUT
lar invasion (OR = 1.22, 95%CI = 0.92–1.62, p = 0.158),
score was significantly associated with shortened RFS in
perineural invasion (OR = 1.15, 95%CI = 0.74–1.80,
patients with BTC (HR = 1.79, 95%CI = 1.48–2.17,
p = 0.530), distant metastasis (OR = 1.15, 95%CI = 0.76–
p < 0.001). In the subgroup analysis, a higher CONUT
1.76, p = 0.505), TNM stage (OR = 1.23, 95%CI = 0.86–
score still significantly predicted RFS, regardless of coun-
1.76, p = 0.251), and tumor number (OR = 1.02, 95%CI
try, sample size, histology, or cutoff value (all p < 0.05;
= 0.34–3.03, p = 0.977) of BTC cases.
Table 4).

CONUT and clinicopathological factors
Six studies with 1,076 patients [18,20–23,26] provided
information on the relationship between the CONUT
score and the clinicopathological characteristics of
BTC. Based on the pooled results, a higher CONUT
score significantly predicted dismal differentiation (OR
Sensitivity analysis
A sensitivity analysis was performed to examine
whether each study affected the pooled outcomes. As
shown in Figure 4, after removing the included stud-
ies individually, the pooled HRs and 95%CIs for OS
and RFS remained almost unchanged, indicating the
reliability of our results.
Table 2. Baseline characteristics of included studies.
Follow-up
Sample Gender Age (years) Study Neoadjuvant / Treatment Cut-off (months) Survival Survival NOS
Study Year Country size (M/F) Median(range) period Histology Treatment adjuvant treatments intent value Median(range) endpoints analysis score
Cui, P. 2018 China 73 44/29 64.7 2012– ECC PTBS+125I No Palliative ≥2 1–30 OS Multivariate 7
2017
Miyata, T. 2018 Japan 71 45/26 64.8 2002– ICC Surgical Neoadjuvant Curative ≥2 36.9 OS, RFS Multivariate 8
2016 resection chemotherapy:
n=2
Utsumi, M. 2019 Japan 45 25/20 75(38–95) 2008– GBC Surgical No Curative ≥3 35(3–102) OS Multivariate 7
2017 resection
Wang, A. 2020 China 94 49/45 54.5(31–73) 2010– ECC Surgical No Curative ≥3 1–60 OS, RFS Multivariate 7
2019 resection
Zheng, Y. 2020 China 167 95/72 57.2 2012– ICC Surgical Adjuvant Curative ≥3 14(4–58) OS, RFS Multivariate 7
2018 resection chemotherapy:
n = 64
Sun, L. J. 2021 China 371 199/172 61.5(23–88) 2002– BTC Surgical No Curative ≥2 16 OS Multivariate 6
2017 resection
Terasaki, F. 2021 Japan 149 115/34 71(39–85) 2002– ECC Surgical Adjuvant therapy: Curative ≥3 53.5 OS, RFS Multivariate 8
2016 resection n = 15
Yugawa, K. 2021 Japan 78 55/23 66(39–87) 1998– ICC Surgical No Curative ≥2 1–60 OS, RFS Univariate 7
2018 resection
Asakura, R. 2022 Japan 169 112/57 70(63–75) 2000– ECC Surgical Adjuvant Curative ≥3 1–60 OS Univariate 9
2019 resection chemotherapy:
n = 82
Mito, M. 2022 Japan 224 152/72 72(31–90) 2006– BTC Surgical Adjuvant Curative ≥4 83.0(6.6–187.6) OS, RFS Multivariate 7
2020 resection chemotherapy:
n = 76
ICC: intrahepatic cholangiocarcinoma; ECC: extrahepatic cholangiocarcinoma; BTC: biliary tract cancer; GBC: gallbladder cancer; OS: overall survival; RFS: recurrence-free survival; PTBS: percutaneous transhepatic biliary
stenting; NOS: Newcastle-Ottawa Scale; M: male; F: female.
Annals of Medicine
5
6 H. JIANG AND Z. WANG

Figure 2. Forest plot verify the association between the CONUT and overall survival (OS) in patients with BTC.

Table 3. Subgroup analysis of association between CONUT and OS in patients with BTC.
No. of No. of
Variables studies patients Effects model HR (95%CI) p Heterogeneity I2(%) Ph
Total 10 1,441 Random 1.94(1.41–2.66) <0.001 79.8 <0.001
Country
 China 4 705 Random 1.82(1.06–3.14) 0.030 88.1 <0.001
Japan 6 736 Fixed 1.94(1.55–2.43) <0.001 1.5 0.407
Sample size
<100 5 361 Random 2.75(1.64–4.59) <0.001 55.0 0.064
≥100 5 1,080 Random 1.52(1.11–2.09) 0.009 78.4 0.001
Histology
 ICC 3 316 Random 1.46(0.79–2.70) 0.224 73.3 0.024
 ECC 4 485 Random 2.35(1.50–3.67) <0.001 59.1 0.062
BTC 2 595 Fixed 1.64(1.29–2.09) <0.001 4.3 0.307
GBC 1 45 – 4.69(1.48–14.88) 0.009 – –
Treatment
PTBS+125I 1 73 – 2.02(1.08–3.80) 0.028 – –
 Surgical resection 9 1,368 Random 1.93(1.37–2.72) <0.001 81.4 <0.001
Cut-off value
≥2 4 593 Fixed 1.65(1.28–2.11) <0.001 13.1 0.327
≥3 5 624 Random 2.21(1.20–4.07) 0.011 87.8 <0.001
≥4 1 224 – 1.91(1.31–2.76) 0.001 – –
Survival analysis
Multivariate 8 1,194 Random 2.09(1.42–3.09) <0.001 84.0 <0.001
Univariate 2 247 Fixed 1.57(1.08–2.28) 0.018 0 0.608
Neoadjuvant /adjuvant
treatments
Yes 5 780 Random 2.29(1.35–3.87) 0.011 82.0 <0.001
 No 5 661 Random 1.71(1.13–2.59) 0.002 70.4 0.009
Treatment
Palliative 1 73 – 2.02(1.08–3.80) 0.028 – –
 Curative 9 1,368 Random 1.93(1.37–2.72) <0.001 81.4 <0.001
ICC: intrahepatic cholangiocarcinoma; ECC: extrahepatic cholangiocarcinoma; BTC: biliary tract cancer; GBC: gallbladder cancer; OS: overall survival; PTBS:
percutaneous transhepatic biliary stenting; CONUT: controlling nutritional status.
 Annals of Medicine 7

Figure 3. Forest plot verify the association between the CONUT and recurrence-free survival (RFS) in patients with BTC.

Table 4. Subgroup analysis of association between CONUT and RFS in patients with BTC.
No. of No. of Heterogeneity
Variables studies patients Effects model HR (95%CI) p I2(%) Ph
Total 6 783 Fixed 1.79(1.48–2.17) <0.001 49.2 0.080
Country
 China 2 261 Random 2.46(1.04–5.81) 0.041 77.0 0.037
Japan 4 522 Fixed 1.69(1.36–2.12) <0.001 34.1 0.208
Sample size
<100 3 243 Random 1.89(1.03–3.48) 0.041 75.0 0.018
≥100 3 540 Fixed 1.95(1.51–2.52) <0.001 0 0.620
Histology
 ICC 3 316 Fixed 1.46(1.14–1.88) 0.003 0 0.569
 ECC 2 243 Random 2.70(1.41–5.18) 0.003 59.5 0.116
BTC 1 224 – 2.25(1.42–3.55) 0.001 – –
Cut-off value
≥2 2 149 Fixed 1.37(1.00–1.86) 0.048 0 0.435
≥3 3 410 Random 2.20(1.42–3.41) <0.001 54.2 0.113
≥4 1 224 – 2.25(1.42–3.55) 0.001 – –
Survival analysis
Multivariate 5 705 Fixed 2.02(1.62–2.52) <0.001 24.0 0.262
Univariate 1 78 – 1.25(0.85–1.83) 0.252 – –
Neoadjuvant /adjuvant
treatments
Yes 4 611 Fixed 1.88(1.49–2.37) <0.001 0 0.721
 No 2 172 Random 2.15(0.69–2.72) 0.188 87.5 0.005
ICC: intrahepatic cholangiocarcinoma; ECC: extrahepatic cholangiocarcinoma; BTC: biliary tract cancer; GBC: gallbladder cancer; RFS: recurrence-free survival;
PTBS: percutaneous transhepatic biliary stenting; CONUT: controlling nutritional status.

Table 5. The Correlation between CONUT score and clinicopathological features in patients with BTC.
No. of No. of
Factors studies patients Effects model OR (95%CI) p Heterogeneity I2(%) Ph
Gender (male vs female) 6 1,076 Fixed 0.94(0.72–1.21) 0.617 28.3 0.223
LN metastasis (yes vs no) 6 1,076 Random 1.64(0.95–2.82) 0.074 65.7 0.012
Microvascular invasion (yes vs no) 5 982 Fixed 1.22(0.92–1.62) 0.158 45.7 0.118
Perineural invasion (yes vs no) 5 1,005 Random 1.15(0.74–1.80) 0.530 52.9 0.075
Differentiation (poor vs well/moderate) 4 781 Fixed 1.57(1.15–2.14) 0.004 31.1 0.226
Distant metastasis (yes vs no) 3 744 Fixed 1.15(0.76–1.76) 0.505 0 0.789
TNM stage (III–IV vs I–II) 3 536 Fixed 1.23(0.86–1.76) 0.251 12.9 0.317
Tumor number (multiple vs single) 2 238 Random 1.02(0.34–3.03) 0.977 54.6 0.138
LN: lymph node; BTC: biliary tract cancer; CONUT: controlling nutritional status.
8 H. JIANG AND Z. WANG
Figure 4. Sensitivity analysis. (A) OS; (B) RFS.
Publication bias
Publication bias in the included studies was assessed
using Begg’s test and funnel plots. Symmetric plots
were observed in the funnel plots for OS and RFS
(Figure 5). Begg’s test results (p = 0.097 and 0.080 for
OS and RFS, respectively) indicated an absence of pub-
lication bias in the present study.
Discussion
The prognostic effect of the CONUT score in patients
with BTC has not been consistent in prior studies. This
study extracted information from ten articles involving
1,441 patients [17–26] and found that a higher CONUT
score predicted inferior OS and RFS in BTC patients.
Moreover, the CONUT score had a stable prognostic

Figure 5. Publication bias test. (A) Begg’s test for OS, p = 0.097; (B) Begg’s test for RFS, p = 0.080.
effect among diverse subgroups. We also identified a
significant connection between the CONUT score and
poor differentiation in BTC, indicating that BTC patients
with higher CONUT scores had more aggressive and
malignant tumors. Therefore, an elevated CONUT score
could be a strong predictor of tumor recurrence and
poor long-term prognosis of BTC. To the best of our
knowledge, this study is the first to analyze whether
the pretreatment CONUT score is significant in predict-
ing the prognosis of patients with BTC.
The CONUT score involves the serum albumin level,
TC concentration, and lymphocyte count; therefore,
the potential mechanisms of the prognostic effect of
the CONUT score for BTC are interpreted from several
Annals of Medicine 9
aspects. First, serum albumin level is a critical predictor
of nutritional status as a lower serum albumin level
indicates protein loss due to systemic responses [33].
In cancer patients, hypoalbuminemia indicates malnu-
trition and cachexia. Hypoalbuminemia has been
found to impair immune responses because nutrition
is a crucial determinant [34]. Lymphocytes play major
roles in cell-mediated immunity, cancer immune sur-
veillance, and immune editing. As tumor suppressors,
lymphocytes produce cytokines that inhibit the prolif-
eration and metastatic activity of cancer cells and
induce cell death [35]. Cholesterol is a major compo-
nent of mammalian cell membranes [36]. Circulating
blood is a source of cholesterol, which is composed of
10 H. JIANG AND Z. WANG
endocytosed low-density lipoprotein receptors. In
patients with cancer, low cholesterol levels are associ-
ated with poor prognoses [37]. Thus, as a combined
index of albumin level, TC content, and lymphocyte
count, the CONUT score can be a valuable prognostic
marker for BTC.
Significant heterogeneity was observed among the
studies in the OS analysis (Table 3). Heterogeneity is
derived from many variables, such as study type, sam-
ple size, study subjects, selection bias, and cutoff
value. We selected a random-effects model based on
the significant heterogeneity. The studies included in
this meta-analysis remained comparable because they
were selected based on uniform inclusion and exclu-
sion criteria. The CONUT cutoff values were not uni-
form in the included studies because they used
different methods to determine the cutoff values. This
is a limitation of this meta-analysis, as shown below.
Moreover, a subgroup analysis was conducted to eval-
uate the impact of the cutoff values on our results.
The results showed that various cutoff values did not
affect the prognostic value of CONUT for OS and RFS
in patients with BTC (Tables 3 and 4).
It should also be noted that BTC is a heterogeneous
disease that primarily comprises CCA and GBC. GBC is
the most common BTC, comprising 80–90% of cases
according to autopsy studies [38]. Previous studies
have indicated that patients with eCCA, iCCA, and GBC
have different prognoses [39]. The histological types
used in the meta-analysis are listed in Table 2. We also
conducted a subgroup analysis according to the histo-
logical subtype. As shown in Tables 3 and 4, CONUT
score significantly predicted worse OS in patients with
ECC, BTC, and GBC, but not in those with ICC. Moreover,
a higher CONUT score significantly predicted RFS
regardless of histology. This finding indicates that ICC
patients with a high CONUT score may experience
tumor recurrence, but the OS duration is not signifi-
cantly different from those with a low CONUT score.
Notably, this meta-analysis focused on CONUT [12],
a nutritional assessment tool based on serum albumin
level, TC content, and lymphocyte count (Table 1). The
total CONUT score is the sum of the three compo-
nents. CONUT was established in 2005 [12] and the
scoring system has been used until now. Table 1 is
consistent with the original CONUT scoring system in
the literature [40]. Compared to other nutritional tools
and parameters, such as the Glasgow prognostic score
(GPS), modified GPS [41,42], PNI [43,44], AGR [45,46],
systemic immune inflammation index [47–50], GNRI
[51–53], and CAR [40,54,55], CONUT has the following
advantages. First, CONUT is a standardized scoring sys-
tem with clear scoring criteria (Table 1). Therefore,
promoting and disseminating CONUT scores is easier.
Second, the CONUT score consists of three elements:
serum albumin level, TC content, and lymphocyte
count. These indicators comprehensively reflect nutri-
tional status. Therefore, CONUT is more reliable and
comprehensive. Third, CONUT scores ranged from 0 to
12. The CONUT score is a more refined and easily
quantifiable indicator than other nutritional evalua-
tion tools.
CONUT is a promising tool for guiding the manage-
ment of patients with BTC. When a low pretreatment
CONUT score is detected in an individual BTC patient,
nutritional support should be provided. Moreover, the
risk of tumor recurrence and poor survival and more
aggressive therapeutic strategies should be consid-
ered. During follow-up, the CONUT score should also
be monitored to facilitate the early detection of tumor
progression.
Recently, many meta-analyses have reported that the
CONUT score is significant for predicting the prognosis
of solid tumors [56–61]. According to Peng et al. in a
meta-analysis of 5,410 cases, a higher CONUT score
indicated worse OS, RFS, disease-free survival (DFS), and
cancer-specific survival (CSS) in upper urinary tract
urothelial carcinoma and renal cell carcinoma [62].
Zhang et al. demonstrated that a high CONUT score
had an unfavorable impact on OS, DFS, CSS, and
progression-free survival (PFS) compared to low CONUT
scores [57]. According to a recent meta-analysis involv-
ing 2,294 patients, a higher CONUT score predicted dis-
mal OS in pancreatic cancer [59]. Takagi et al. conducted
a meta-analysis of 2,601 cases and found that a higher
CONUT score predicted dismal OS, CSS, and RFS in col-
orectal cancer patients undergoing surgery [61]. In a
meta-analysis by Lu et al. that included 1,811 patients,
a high CONUT score predicted worse OS and PFS in
patients with hematological cancer [63].
This study had some limitations. First, all included
studies were conducted in Asia, which may make them
less applicable to other populations when applied on
a large scale. Second, all the studies had a retrospec-
tive design, which may have reduced the power of our
analysis. Third, the threshold for defining the high
CONUT score group was not uniform among the stud-
ies, which could have introduced a selection bias.
Fourth, most included studies (9 out of 10) enrolled
patients with BTC who underwent surgical resection.
Therefore, our results may be more applicable to BTC
patients undergoing surgery. Therefore, prospective
studies with larger sample sizes are needed to validate
our results.
In summary, a high CONUT score significantly pre-
dicted worse OS and RFS in patients with BTC.

Additionally, BTC patients with higher CONUT scores
tended to have poor tumor differentiation. The CONUT
score could help clinicians stratify high-risk BTC
patients and devise individualized treatment plans.
Acknowledgments
We would like to thank Editage (www.editage.com) for
English language editing.
Authors’ contributions
HJ and ZW design the project; HZ and ZW searched data-
bases and performed literature screen; HZ and ZW extracted
and analyzed the data, analysis; HZ and ZW evaluated the
quality of included literature; HZ contributed to writing the
manuscript. Final draft was approved by all the authors. All
authors contributed to the article and approved the submit-
ted version.
Disclosure statement
The authors declare that there is no conflict of interest.
Funding
The author(s) reported there is no funding associated with
the work featured in this article.
Data availability statement
The data that support the findings of this study are available
from the corresponding author upon reasonable request.
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