Oral Oncology 103 (2020) 104587

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

Association between dietary inflammatory index and upper aerodigestive T

tract cancer risk: A systematic review and dose-response meta-analysis
Jiahao Zhua, Yuxiao Linga, Shuai Mia, Hanzhu Chena, Jiayao Fana, Shaofang Caib,
⁎
Chunhong Fana, Qing Shena, Yingjun Lia,
a
School of Public Health, Hangzhou Medical College, Hangzhou, Zhejiang, China
b
Department of Science and Education, The Second Affiliated Hospital of Xiamen Medical College, Xiamen, China

A R T I C LE I N FO A B S T R A C T

Keywords: Objectives: The relationship between dietary inflammatory index (DII) and upper aerodigestive tract (UADT)
Upper aerodigestive tract cancers cancer risk have been investigated in a growing number of epidemiological studies. However, their findings were
Dietary inflammatory index inconsistent, and no systematic review or meta-analysis has been conducted up to now. This meta-analysis was
Diet carried out to examine potential dose-response relationship between DII score and UADT cancer risk.
Inflammation
Material and methods: A systematic search was conducted for relevant studies in PubMed and Web of Science up
Meta-analysis
to March 28, 2019. Categorical meta-analysis as well as linear and non-linear dose-response meta-analysis were
Dose-response
performed to evaluate association between DII and UADT cancer risk.
Results: Nine case-control studies with a total of 4138 cases and 15,326 healthy controls were eligible in the
present meta-analysis. The pooled odds ratios (ORs) of UADT cancer risk were 2.07 [95% confidence interval
(CI): 1.82, 2.35] for the highest DII score compared with the lowest and 1.53 (95% CI: 1.39, 1.69) for higher DII
score compared with lower score, respectively. Furthermore, a one-unit increment in DII score was associated
with an increased risk of 18% for UADT cancers (OR: 1.18; 95% CI: 1.15, 1.21). An upward trend towards a
positive association between elevated DII score and UADT cancer risk was also observed in non-linear dose-
response meta-analysis.
Conclusions: The present meta-analysis provides evidence of highly pro-inflammatory diets that might increase
risk of UADT cancers. Therefore, reducing pro-inflammatory components in diets should be considered to pre-
vent and control UADT cancers.

Introduction
According to different anatomic locations, cancers that affect lips,
oral cavity, pharynx, larynx, salivary glands and esophagus are com-
monly studied as a group called “upper aerodigestive tract (UADT)
cancers”, which is also described as “head and neck cancer” in some
literature [1,2]. As one of the most serious public health problems in
the world, UADT cancers are the sixth most prevalent malignancies
with 1.4 million new cases (8.1% of all sites) diagnosed in 2018 [3].
Existing researches have shown that smoking, alcohol drinking, genetic
predisposition and socioeconomic status are closely related to UADT
cancers [4–7]. Besides, diets have been reported as a critical risk factor
in recent studies [8]. It is now recognized that dietary components have
close interaction with chronic inflammation [9]. For instance, con-
sumption of phytochemicals and edible mushrooms may have anti-in-
flammatory properties [10,11], while diet consisting of saturated fatty
acids and red meat may result in pro-inflammation [12,13]. Increasing
evidences also suggest that diet-induced inflammation can mediate
occurrences and developments of cancers [14]. Hence, it is essential to
assess association between diet-related inflammation and UADT cancer
risk.
To compare inflammatory potentials of different diets, a literature-
derived and population-based dietary inflammatory index (DII) was
developed by Shipappa et al. in 2014 [15]. It is a novel scoring system
based on positive or negative effects of six inflammatory biomarkers in
45 dietary components. Higher DII scores represent a higher potential
of pro-inflammatory diets and are associated with inflammatory mar-
kers of higher levels, including C-reactive protein (CRP) and tumor
necrosis factor-alpha (TNF-α) [16,17]. Therefore, DII has a great epi-
demiological significance in predicting chronic diseases and may pro-
vide a valid method to investigate the relationship between diet-related
inflammation and UADT cancer risk.

⁎
Corresponding author at: School of Public Health, Hangzhou Medical College, 481 Binwen Road, Binjiang District, Hangzhou 310053, Zhejiang, China.
E-mail address: 2016034036@hmc.edu.cn (Y. Li).

https://doi.org/10.1016/j.oraloncology.2020.104587
Received 17 September 2019; Received in revised form 17 January 2020; Accepted 4 February 2020
1368-8375/ © 2020 Elsevier Ltd. All rights reserved.
J. Zhu, et al.
In the past few years, DII has been found related to several types of
cancers, including colorectal cancer [18], prostate cancer [19] and
gynecological cancers [20] in systematic reviews and meta-analyses.
For UADT cancers, previous studies have confirmed that higher DII
score was associated with increased risk of esophageal cancer [21].
However, Abe et al. showed that DII score was not associated with
laryngeal cancer risk [2]. Furthermore, as far as we know, there is no
systematic review or meta-analysis to explain the inconsistent findings
and report dose-response relationships between DII score and UADT
cancer risk.
Hence, our study is aimed to comprehensively analyze results from
published studies and investigate both linear and non-linear dose-re-
sponse relationships between DII score and UADT cancer risk through
systematic review and meta-analysis method.
Materials and methods
Search strategy
This systematic review and meta-analysis was conducted in ac-
cordance with guidelines in checklist of Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) [22]. PubMed and Web
of Science were systematically searched to identify all relevant epide-
miological literature published up until March 28, 2019. Electronic
search keywords were as follows: (“inflammatory” OR “inflammation”
OR “anti-inflammatory” OR “pro-inflammatory”) AND (“diet-related”
OR “diet” OR “dietary”) AND (“cancer” OR “carcinoma” OR “neo-
plasm” OR “adenoma”) AND (“prospective” OR “cohort” OR “case-
control” OR “case-cohort”). This search was restricted to articles pub-
lished in English. Reference cites of all retrieved reviews and articles
were also manually checked to identify relevant additional publica-
tions.
Inclusion criteria
Articles that could meet the following explicit criteria were con-
sidered eligible: (1) all cohort, case-cohort or case-control studies re-
ported on association between the DII score and UADT cancer risk; (2)
DII score was computed at baseline with continuous or categorical DII
(the highest category of DII versus the lowest category of DII); (3)
studies that provided original risk ratio (RR), hazard ratio (HR), or odds
ratio (OR) with corresponding 95% confidence interval (CI), or suffi-
cient information was reported to calculate them; and (4) reported DII
ranges as well as numbers of cases and participants or person-years in
each category of DII.
Assessment of study quality
After reviewing all original articles independently, two of the au-
thors (Zhu and Ling) used the Newcastle-Ottawa Quality Assessment
Scale (NOS) to assess methodological qualities of each selected study
[23]. This scale consists of three aspects of selection, comparability and
exposure with a scoring range from zero (the lowest) to nine (the
highest). The article was defined to be of a relatively high quality if its
NOS score was higher than median score (> 7). Any discrepancy was
discussed and resolved by consensus.
Data extraction
A standard data extraction checklist was used to extract effective
data from all eligible studies. Information contained name of the first
author, publication year, duration of follow-up, country or race of the
participants, cancer site, DII assessment tool, number of DII compo-
nents, number of cancer cases and healthy controls, age, gender and
risk estimates with corresponding 95% CIs for each category of the DII,
and multivariate adjustments from each included study were extracted.
2
Oral Oncology 103 (2020) 104587
This process was independently completed by two of the authors (Zhu
and Fan). Any discrepancy was discussed and resolved by consensus. If
a study provides more than one multivariate risk estimates, a model
with the most comprehensive adjustment will be adopted. We also
extracted DII components from each study and listed detailed in-
formation in supplementary materials. If insufficient data is provided
by eligible studies, the corresponding authors will be contacted for
more information.
Statistical analysis
To obtain the association between DII score and UADT cancer risk, a
meta-analysis method was used to pool extracted ORs with 95% CIs
from studies included. For categorical meta-analysis, forest plots were
generated for DII of the highest category compared with that of the
lowest category as well as that of higher category compared with DII of
lower category. In analysis of higher DII compared with lower DII,
different categorical DII in a single study were synthesized into a single
estimate as higher DII score, while DII in reference group was defined as
lower DII score [24]. For linear dose-response meta-analysis, ORs with
95% CIs from continuous DII were applied to generate the forest plots.
When continuous DII from the original articles were not available, we
calculated estimates of UADT cancer risk of each one-unit increment in
DII score [25]. The between-study heterogeneity of effect size among
the studies was assessed through inconsistency index (I2) and Cochran
Q test [26]. I2 value > 50% or P value < 0.05 was considered sta-
tistically significant. A fixed-effects model was applied to calculate
pooled results when no statistically significant heterogeneity was pre-
sented; otherwise, a random-effects model was performed to provide
more conservative estimates.
Meanwhile, subgroup and meta-regression analyses were conducted
using cancer site, ethnicity, length of follow-up, age, study quality,
number of DII components and energy-adjusted DII (Yes or No) to in-
vestigate sources of heterogeneity. Due to the insufficient number of
studies on other UADT cancers, only esophageal cancer was separately
analyzed.
We also conducted non-linear dose-response meta-analysis using the
methods of Greenland and Longnecker [25]. Studies with ≥3 quanti-
tative categories of exposures were adopted. For qualified articles,
distributions of case, sample size, dose values of DII, OR and 95% CI in
each category were extracted for trend estimations. If dose value of any
category was not directly provided, midpoints of upper and lower
boundaries in each category were assigned to each corresponding OR
[27]. If upper limit of the highest category or lower limit of the lowest
category was open-ended, dose values of DII were considered as end
value of the category after adding or reducing dose interval values of
adjacent categories [28]. Restricted cubic splines with 4 knots at fixed
percentiles (5%, 35%, 65% and 95%) of the distribution were adopted
to assess potential curvilinear relationships [29]. We calculated P value
for non-linear relationship by setting coefficients of the second and
third splines, which equaled to zero. Dose-response meta-analyses were
performed through GLST commands.
To explore potential impacts of each article on summary risk esti-
mations, sensitivity analysis was performed by exclusion of each study
in turn. The risk of publication bias was assessed by Egger’s linear re-
gression test and Begg’s rank correlation test with funnel plots [30,31].
All statistical analyses on this meta-analysis were performed by STATA
software, version 15.1 (Stata Corp, College Station, Texas USA).
P < 0.05 was considered statistically significant.
Results
Study search and characteristics
Figure 1 provides the flow diagram of process of detailed literature
screening. Through initial searches, a total of 2281 potential-related
J. Zhu, et al.
Fig. 1. Flow chart of literature search and study selection for systematic review and meta-analysis.
studies were found. After evaluating the abstracts and titles of the ar-
ticles, 2262 of them were excluded because of irrelevances or dupli-
cations. Next, 19 articles were obtained for full-text assessment. 10
articles were excluded for the following reasons: 4 articles were meta-
analyses or reviews, and 6 of them did not study on UADT cancer risk.
Finally, 9 case-control studies with a total of 4138 cases and 15,326
healthy controls met the inclusion criteria [2,32–39].
Baseline characteristics of included studies are given in Table 1.
Those articles were published between 2015 and 2018. Several coun-
tries were involved in the analysis, of which 3 studies were from Asia, 4
were from Italy, 1 was from Ireland and 1 was from Sweden. Various
types of cancers were represented: 6 articles reported on esophageal
cancer, 2 reported on oral cavity cancer, 3 reported on pharyngeal
cancer, and 2 reported on laryngeal cancer. Food intake information in
all articles was obtained through food-frequency questionnaires (FFQ).
The method of Shivappa et al. was used for DII calculation. All articles
reported OR from categorical DII, and only five studies reported con-
tinuous DII. Four studies reported the energy-adjusted DII (E-DII) as the
exposure. Supplemental Table 1 shows the dietary components used to
calculate DII score in each study. 45 food variables contained in the DII
with inflammatory potentials are presented in Supplemental Table 2. In
addition, further information on data extraction, including categorical
cut-points, lists of covariates and boundaries of DII in each category
were recorded in Supplemental Table 3. Concrete NOS scoring in-
formation was provided in Supplemental Table 4 (see Appendix A).
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Oral Oncology 103 (2020) 104587
DII and risk of UADT cancers
As is shown in Figure 2, a significantly positive association was
found between DII of the highest category and increasing risk of UADT
cancers (pooled OR: 2.07; 95% CI: 1.82, 2.35), when comparing with
DII of the lowest category. The pooled OR of UADT cancer risk was 1.53
(95% CI: 1.39, 1.69) for higher DII scores compared with lower DII
scores. No evident heterogeneity was observed among studies included
(I2 = 34.4%, P-heterogeneity = 0.123 for the highest vs. the lowest;
I2 = 24.5%, P-heterogeneity = 0.203 for higher vs. lower).
Subgroup analysis and meta-regression
Subgroup analysis was conducted to seek for more information.
Results stratified by potential modifying factors are shown in Table 2.
For higher DII vs. lower DII, no statistically significant heterogeneity
existed across strata of all the analyzed factors. However, in the analysis
of the highest DII vs. the lowest DII, association between DII and UADT
cancer risk appeared to be more pronounced among population with
age > 60 years old (pooled OR: 2.72; 95% CI: 2.17, 3.41) than in those
with age ≤ 60 years old (pooled OR: 1.81; 95% CI: 1.55, 2.11; P-re-
gression = 0.017), and among studies with higher quality (pooled OR:
2.82; 95% CI: 2.25, 3.53) than those with lower quality (pooled OR:
1.78; 95% CI: 1.52, 2.08; P-regression = 0.032).
 Table 1
J. Zhu, et al.

General characteristics of included studies in the meta-analysis of DII and UADT cancer risk.
Study first author, Duration Races/nati- Cancer site DII measurement (no. Of Study design Sample size Mean/ Female/male OR (continuous/highest vs. lowest, 95% CI) Study quality
year [ref] onalities DII components) (n1/n2)a median age (n1/n2)a (NOS score)
(n1/n2)a

Abe, 2018 [2] January 2001- Japanese Upper aerodigestive tract item Matched case- 1028/3081 60/60 202/826 Highest vs. lowest (oral cavity): 2.38 (1.52, 6
November cancer FFQ (19) control 615/2466 3.72)
2005 Highest vs. lowest (nasopharynx): 4.99
(1.14, 21.79)
Highest vs. lowest (oropharynx): 1.71 (0.65,
4.50)
Highest vs. lowest (hypopharynx): 4.05
(1.24, 13.25)
Highest vs. lowest (larynx): 0.59 (0.25,
1.38)
Highest vs. lowest (salivary gland): 2.91
(0.40, 21.19)
Highest vs. lowest (esophagus): 1.71 (1.54,
1.90)
Highest vs. lowest (upper aerodigestive
tract): 1.73 (1.37, 2,20)
Tang, 2018 [40] January 2008- Chinese Oesophageal cancer 137-item FFQ (22) Matched case- 359/380 61.4/60.6 99/260 Highest vs. lowest: 2.55 (1.61, 4.06) 8
December control 111/269
2009
Shivappa, 2017 2002–2005 Irish Oesophageal 101-item FFQ (25) Matched case- 224/256 64.3/63.0 35/189 Highest vs. lowest: 1.96 (1.11, 3.47) 7
[41] adenocarcinoma control 40/216

4
Shivappa, 2017 1992–2009 Italian Oral and pharyngeal item Matched case- 946/2492 58/58 190/756 Highest vs. lowest (oral): 2.08 (1.47, 2.93) 7
[47] cancer FFQ (15) control 995/1497 Continuous (oral): 1.20 (1.11, 1.30)
Highest vs. lowest (hypopharynx): 1.64
(0.93, 2.89)
Continuous (hypopharynx): 1.15 (1.01,
1.32)
Highest vs. lowest (oropharynx): 1.60 (0.97,
2.63)
Continuous (oropharynx): 1.10 (0.98, 1.23)
Shivappa, 2016 January 1992- Italian- Nasopharyngeal cancer item Matched case- 198/594 52/52 41/157 Highest vs. lowest: 1.64 (1.06, 2.55) 7
[42] December Caucasian FFQ (31) control 123/471 Continuous: 1.19 (1.05, 1.36)
2008
Shivappa, 2016 1992–2000 Italian Laryngeal cancer item Matched case- 460/1088 61/61 45/415 Highest vs. lowest: 3.30 (2.06, 5.28) 8
[43] FFQ (31) control 225/863 Continuous: 1.27 (1.15, 1.40)
Shivappa, 2015 NR Iran Esophageal squamous cell 125-item FFQ (27) Matched case- 47/96 58/58 29/18 Highest vs. lowest: 8.24 (2.03, 33.47) 7
[44] carcinoma control 58/38 Continuous: 3.58 (1.76, 7.62)
Shivappa, 2015 1992–2010 Italian Esophageal squamous cell item Matched case- 304/743 60/60 29/275 Highest vs. lowest: 2.47 (1.40, 4.36) 8
[45] carcinoma FFQ (31) control 150/593 Continuous: 1.23 (1.10, 1.38)
Lu, December Swedish Oesophageal cancer 120-item FFQ (36) Matched case- 594/806 65/65 106/488 Highest vs. lowest (oesophageal squamous 9
2015 [46] 1994- control 139/667 cell cancer): 4.35 (2.24, 8.43)
December Highest vs. lowest (oesophageal or
1997 gastroesophageal junction
adenocarcinoma): 2.42 (1.57, 3.73)

Abbreviations: DII, dietary inflammatory index; UADT, upper aerodigestive tract; ref, reference; OR, odds ratio; CI, confidence interval; NOS, Newcastle-Ottawa Quality Assessment Scale; FFQ, food-frequency ques-
tionnaire; NR, not reported.
a
n1 was number of cases and n2 was number of controls for case-control study.
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J. Zhu, et al. Oral Oncology 103 (2020) 104587

Table 2
Subgroup analysis results for DII and UADT cancer risk.
The highest DII vs. the lowest DII Higher DII vs. lower DII

a 2 b c
Variable N Pooled OR (95% CI) I (%) P value P value Na Pooled OR (95% CI) I2 (%) P valueb P valuec

All studies 8 2.07 (1.82, 2.35) 34.4 0.123 – 9 1.53 (1.39, 1.69) 24.5 0.203 –
Cancer site
Oral cavity 2 2.19 (1.66, 2.87) 0.0 0.640 0.732 2 1.57 (1.17, 2.10) 0.0 0.915 0.872
Pharynx 3 1.77 (1.36, 2.30) 0.0 0.532 3 1.96 (1.23, 3.13) 77.0 0.001
Larynx 2 1.45 (0.27, 7.82) 91.6 0.001 2 1.07 (0.37, 3.10) 87.3 0.005
Salivary glands 1 0.59 (0.25, 1.39) – – 1 1.61 (0.61, 4.24) – –
Esophagus 5 2.29 (1.75, 3.00) 61.1 0.025 6 1.61 (1.40, 1.87) 45.7 0.087
Ethnicity
Asian 2 1.99 (1.38, 2.87) 53.3 0.143 0.276 3 1.80 (1.18, 2.76) 67.6 0.046 0.493
Italian 4 2.05 (1.70, 2.47) 27.4 0.229 4 1.40 (1.18, 1.67) 0.0 0.739
Other European countries 2 2.58 (1.90, 3.50) 40.6 0.186 2 1.83 (1.44, 2.33) 21.5 0.280
Length of follow-up
>7 4 2.05 (1.70, 2.47) 27.4 0.229 0.605 4 1.40 (1.18, 1.67) 0.0 0.739 0.297
≤7 4 2.29 (1.73, 3.05) 52.1 0.080 4 1.57 (1.40, 1.76) 22.0 0.274
Age
> 60 4 2.72 (2.17, 3.41) 4.8 0.379 0.017 4 1.81 (1.49, 2.19) 0.0 0.623 0.089
≤60 4 1.81 (1.55, 2.11) 0.0 0.782 5 1.45 (1.30, 1.62) 26.1 0.229
Study quality
NOS score, > 7 4 2.82 (2.25, 3.53) 0.0 0.567 0.032 4 1.75 (1.44, 2.13) 0.0 0.424 0.329
NOS score, ≤7 4 1.78 (1.52, 2.08) 0.0 0.931 5 1.47 (1.32, 1.64) 29.1 0.206
DII components
≥27 4 2.51 (2.02, 3.14) 47.3 0.108 0.088 5 1.74 (1.41, 2.15) 49.8 0.076 0.276
< 27 4 1.87 (1.60, 2.19) 0.0 0.682 4 1.49 (1.34, 1.65) 0.0 0.715
E-DII
Yes 4 1.88 (1.55, 2.28) 0.0 0.816 0.163 4 1.41 (1.19, 1.67) 0.0 0.772 0.219
No 4 2.56 (1.85, 3.53) 65.0 0.022 5 1.82 (1.43, 2.31) 53.2 0.058

Abbreviations: DII, dietary inflammatory index; UADT, upper aerodigestive tract; OR, odds ratio; CI, confidence interval; NOS, Newcastle-Ottawa Quality Assessment
Scale; E-DII, energy adjusted DII.
a
The number of studies included.
b
P value for heterogeneity within each subgroup.
c
P value for heterogeneity between subgroups with meta-regression analysis.

Fig. 2. Forest plots of pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) of UADT cancer risk for (A) the highest DII versus the lowest DII
and (B) higher DII versus lower DII.

Dose-response analysis Sensitivity analysis and publication bias

Figs. 3 and 4 describe the dose-response relationship between DII
and UADT as well as esophageal cancer risk. As is shown in Fig. 3, an
increment of 1 unit in DII score was associated with increasing UADT
(pooled OR: 1.18; 95% CI: 1.15, 1.21) and esophageal cancer risk
(pooled OR: 1.18; 95% CI: 1.13, 1.24). Fig. 4 describes the linear and
non-linear dose-response relationship of increased DII with UADT and
esophageal cancer risk. This indicated that risk of UADT cancer in-
creased significantly along with increments in DII score. The relation-
ship between esophageal cancer and elevated DII in dose-response
analysis showed similar rising trend.
Sensitivity analysis indicated that none of studies had a substantial
change on the pooled results. Begg’s funnel plot appeared to be sym-
metrical, and no significant asymmetry was assessed by Egger’s and
Begg’s tests (P > 0.05) in categorical meta-analysis (see Appendix A).
Discussion
The present meta-analysis collected currently published studies and
examined association between DII score and UADT cancer risk. The
findings revealed that high pro-inflammatory features in diets

5
J. Zhu, et al.
Fig. 3. Forest plots of pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) for a one-unit increment in DII score with risk of (A) UADT cancers
and (B) esophageal cancer.
calculated by a higher DII score were associated with increasing risk of
UADT cancers regardless of cancer site, ethnicity of participants,
follow-up duration, age, study quality, number of DII components, and
DII with energy-adjusted at baseline. For categorical meta-analysis,
UADT cancers whose risks were doubled were observed when in-
dividuals with highest DII scores when compared with those with
lowest ones, and 53% of increased risk of UADT cancers were dis-
covered for higher DII compared with lower DII. For linear dose-re-
sponse meta-analysis, a one-unit increment in DII score was associated
with an increase of 18% in risks of UADT and esophageal cancer. For
nonlinear dose-response meta-analysis, risks of UADT and esophageal
cancer increased continuously along with increments in the DII score.
Therefore, assessments of DII in diets for UADT cancer prevention is of
great significance for public health.
As a major source of various nutrients, diets play an essential role in
daily life. Interactions of several components in dietary factors have
been explored in recent nutritional epidemiology rather than individual
components. Hence, various dietary patterns and indices were used to
investigate the relationship between chronic diseases and diets. For
example, reduction of UADT cancer risk was closely related and ad-
hered to traditional Mediterranean diet [8], and high scores of Healthy
Eating Index-2005 (HEI-2005) were associated with lower risk of eso-
phageal cancer [40]. Unlike those dietary indices, DII score was
Fig. 4. Linear and non-linear dose-response relationship between DII and risk of (A) UADT cancers and (B) esophageal cancer. X Coordinate: “DII” is the value of DII
subtracted from the baseline value of DII. The P values for the nonlinearity test were all < 0.001. Data fitting was based on fixed-effects restricted cubic splines
models using fixed percentiles 5%, 35%, 65%, and 95% as knot locations.
6
Oral Oncology 103 (2020) 104587
designed and developed based on intakes of foods that regulated in-
flammation [15]. As a hot spot of researches all along, the role of in-
volvements and occurrences of diets in developments of chronic in-
flammation has also been gradually recognized [41]. Latest studies
have shown that inflammatory components were closely related to tu-
morigeneses of all stages by participating in formation of inflammatory
tumor microenvironment (TME) [42]. It has confirmed that high intake
of red and processed meat [43], fat [44] and preserved food [45] in-
creased the incidence of UADT cancer; while diets that contained ve-
getables, fruits [46], fish [47], vitamins [48], and folates [49] were
considered as protective factors of UADT cancers. Consumption of those
food components can be calculated as a specific DII score to reflect
inflammation potentials. Results of our analysis suggested that a pro-
inflammatory diet (with a high DII score) was positively associated with
UADT cancer risk.
According to our results, association between DII and UADT cancer
risk was influenced by age. Association between DII and UADT cancer
risk appeared to be more significant within individuals older than 60. It
was found by a study in Italy that DII increasing with age might be
owing to modifications of dietary habits [50]. Similar results were
observed in American and Pakistani populations [51,52]. However, as
the range of age was only from 52 to 65 in the present study, effects of
age should be interpreted with caution. Influences of confounding
J. Zhu, et al.
factors other than age should be considered. After being stratified based
on quality score, an apparently stronger relationship between DII and
UADT cancer risk was revealed among studies with higher quality score
compared to those with lower one. We found that blinding of cases and
control groups were mentioned in studies with higher quality score.
Interviewers may be more inclined to give higher DII scores to case
groups without implementing the blind method. Association between
DII and UADT cancer risk would be more significant in lower-quality
studies. This is inconsistent with our results. It is worth noting that the
average age of participants was higher in studies with higher quality
score. Thus, age might be a major confounding factor in different as-
sociation between DII and cancer risk in strata of quality score.
A meta-analysis published in 2018 indicated that DII with more
dietary components increased site-specific cancer risk [53]. However,
no significant difference among subgroups stratified based on numbers
of DII components was found in this analysis. One possible explanation
was that some food parameters like isoflavones and pepper were con-
sumed at a low level among population included, thus contributions of
those dietary ingredients to DII scores were limited. Another possible
cause was that a limited number of articles involving different numbers
of DII components had been published. Also, we were not able to ex-
plore association among different combinations of DII and UADT cancer
risk. Contributions of each component of DII to this association were
also worth exploring. For example, alcohol has been proved to be a
major risk factor of UADT cancers. However, in DII scoring systems,
alcohol was attributed to components that inhibited inflammation.
Several potential mechanisms have been proposed to explain the
relationship between DII score and UADT cancer risk. In epidemiolo-
gical studies, body mass index (BMI) is an important indicator of phy-
sical health. It was well acknowledged that excess fat and carbohy-
drates in diets contributed to weight gain, obesity or higher BMI, which
increased possibilities of UADT cancer formation by affecting epige-
netic modifications (e.g., DNA methylation) [54]. Moreover, DII score
was based on effects of dietary parameters on the follow six in-
flammatory biomarkers: IL-1β, IL-4, IL-6, IL-10, TNF-α and CRP. Mann
et al. proposed that IL-1 participated in invasions and metastases of
UADT cancers by inducing gelatinases (GLs) [55]. Other studies have
reported that IL-6 was involved in development of microenvironment of
UADT cancers [56]. Cytokines such as IL-4 and IL-10 had marked ef-
fects on immune suppression [57]. Compared with other types of
cancer, diets were more closely related to gastrointestinal cancer due to
direct contacts among food, nutrients and digestive tracts [58]. Re-
cently, potential carcinogenic effects of gastrointestinal microbiota
have been found. A decrease in microbial diversities or an increase in
gram-negative anaerobes in esophagus may lead to development of
cancer by altering human-host immune system [59]. Besides, DNA
damages mediated by oxidative stress markers might contribute to
UADT cancers [60]. Although diets are associated with tumorigenesis
through a variety of biological pathways, DII score provides an effective
way to measure inflammatory potentials of multiple dietary compo-
nents.
There are some limitations in present meta-analysis which should
not be neglected. Firstly, results of this research were based on case-
control studies. Selection and recall biases were unavoidable in selec-
tion of subjects and acquisition of previous information. Secondly, al-
though food intake information in all articles was obtained through
FFQ, dietary components involved in each FFQ were different (17–36
variables). Errors of measurements and differences in food nutrient
compositions of different regions were also unavoidable. Thirdly, all
studies included came from Europe and Asia. Therefore, results of this
article were more applicable to those countries. Finally, although the
overall relationship between multiple food ingredients and inflamma-
tions could be assessed through DII, people did not consume nutrients
in isolation. Design of DII was based upon literatures about effects of
each individual food ingredient on inflammatory biomarkers, which
might lead to weaker links compared to diet patterns. Despite the above
7
Oral Oncology 103 (2020) 104587
limitations, strengths of this meta-analysis were still worth mentioning.
Firstly, the relationship between DII and UADT cancer risk was com-
prehensively assessed in the article for the first time, and linear as well
as non-linear dose-response diagrams were used to clarify changes in
UADT cancer risk with increased DII. Moreover, the method of
Shivappa et al. was applied to calculate DII score in each study, which
improved the comparability. Besides, no significant heterogeneity ex-
isted in studies included. Sensitivity analysis and tests for publication
bias also proved the robustness of the results.
In conclusion, the present systematic review and dose-response
meta-analysis confirmed the positive and significant association be-
tween DII and risk of UADT cancers. Thus, reducing pro-inflammatory
components in diets should be considered to prevent and control UADT
cancers. However, due to limited researches included in this analysis,
further prospective studies with larger sample sizes and higher quality
are needed to confirm the results.
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.
Acknowledgements
This work was supported by National Natural Science Foundation of
China (grant number 81703289).
Role of the Funding Source
The funding source had no involvement.
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.oraloncology.2020.104587.
References
[1] Santos FBG, Leonhardt FD, Abrahao M. Prevention of upper aerodigestive tract
cancer through active search strategies and use of equipped propaedeutics. Braz J
Otorhinolaryngol 2019.
[2] Abe M, Shivappa N, Ito H, Oze I, Abe T, Shimizu Y, et al. Dietary inflammatory
index and risk of upper aerodigestive tract cancer in Japanese adults. Oncotarget
2018;9:24028–40.
[3] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer
statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36
cancers in 185 countries. CA Cancer J Clin 2018;68:394–424.
[4] Al-Dakkak I, Khadra M. Socio-economic status and upper aerodigestive tract cancer.
Evid Based Dent 2011;12:87–8.
[5] Matsuo K, Gallus S, Negri E, Kawakita D, Oze I, Hosono S, et al. Time to first ci-
garette and upper aerodigestive tract cancer risk in Japan. Cancer Epidemiol
Biomarkers Prev 2012;21:1986–92.
[6] Li Y, Mao Y, Zhang Y, Cai S, Chen G, Ding Y, et al. Alcohol drinking and upper
aerodigestive tract cancer mortality: a systematic review and meta-analysis. Oral
Oncol 2014;50:269–75.
[7] Marques CR, Da Silva TM, De Albuquerque DM, Chaves MS, Marques Filho MF,
Oliveira JS, et al. NAT2, XRCC1 and hOGG1 polymorphisms, cigarette smoking,
alcohol consumption and risk of upper aerodigestive tract cancer. Anticancer Res
2014;34:3217–24.
[8] Samoli E, Lagiou A, Nikolopoulos E, Lagogiannis G, Barbouni A, Lefantzis D, et al.
Mediterranean diet and upper aerodigestive tract cancer: the Greek segment of the
Alcohol-Related Cancers and Genetic Susceptibility in Europe study. Br J Nutr
2010;104:1369–74.
[9] Ahluwalia N, Andreeva VA, Kesse-Guyot E, Hercberg S. Dietary patterns, in-
flammation and the metabolic syndrome. Diabetes Metab 2013;39:99–110.
[10] Muszynska B, Grzywacz-Kisielewska A, Kala K, Gdula-Argasinska J. Anti-in-
flammatory properties of edible mushrooms: a review. Food Chem
2018;243:373–81.
[11] Islam MA, Alam F, Solayman M, Khalil MI, Kamal MA, Gan SH. Dietary phyto-
chemicals: natural swords combating inflammation and oxidation-mediated de-
generative diseases. Oxid Med Cell Longev 2016;2016:5137431.
[12] Dumas JA, Bunn JY, Nickerson J, Crain KI, Ebenstein DB, Tarleton EK, et al. Dietary
saturated fat and monounsaturated fat have reversible effects on brain function and
J. Zhu, et al.
the secretion of pro-inflammatory cytokines in young women. Metabolism
2016;65:1582–8.
[13] Samraj AN, Pearce OM, Laubli H, Crittenden AN, Bergfeld AK, Banda K, et al. A red
meat-derived glycan promotes inflammation and cancer progression. Proc Natl
Acad Sci USA 2015;112:542–7.
[14] Baniyash M, Sade-Feldman M, Kanterman J. Chronic inflammation and cancer:
suppressing the suppressors. Cancer Immunol Immunother 2014;63:11–20.
[15] Shivappa N, Steck SE, Hurley TG, Hussey JR, Hebert JR. Designing and developing
a literature-derived, population-based dietary inflammatory index. Public Health
Nutr 2014;17:1689–96.
[16] Shivappa N, Hebert JR, Rietzschel ER, De Buyzere ML, Langlois M, Debruyne E,
et al. Associations between dietary inflammatory index and inflammatory markers
in the Asklepios Study. Br J Nutr 2015;113:665–71.
[17] Shivappa N, Steck SE, Hurley TG, Hussey JR, Ma Y, Ockene IS, et al. A population-
based dietary inflammatory index predicts levels of C-reactive protein in the
Seasonal Variation of Blood Cholesterol Study (SEASONS). Public Health Nutr
2014;17:1825–33.
[18] Shivappa N, Godos J, Hebert JR, Wirth MD, Piuri G, Speciani AF, et al. Dietary
inflammatory index and colorectal cancer risk-a meta-analysis. Nutrients 2017:9.
[19] Mohseni R, Abbasi S, Mohseni F, Rahimi F, Alizadeh S. Association between dietary
inflammatory index and the risk of prostate cancer: a meta-analysis. Nutr Cancer
2019;71:359–66.
[20] Liu ZY, Gao XP, Zhu S, Liu YH, Wang LJ, Jing CX, et al. Dietary inflammatory index
and risk of gynecological cancers: a systematic review and meta-analysis of ob-
servational studies. J Gynecol Oncol 2019;30:e23.
[21] Li D, Hao X, Li J, Wu Z, Chen S, Lin J, et al. Dose-response relation between dietary
inflammatory index and human cancer risk: evidence from 44 epidemiologic studies
involving 1,082,092 participants. Am J Clin Nutr 2018;107:371–88.
[22] Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for
systematic reviews and meta-analyses: the PRISMA statement. PLoS Med
2009;6:e1000097.
[23] Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the
quality of nonrandomized studies in meta-analyses. Eur J Epidemiol
2010;25:603–5.
[24] Li Y, Gu M, Jing F, Cai S, Bao C, Wang J, et al. Association between physical activity
and all cancer mortality: dose-response meta-analysis of cohort studies. Int J Cancer
2016;138:818–32.
[25] Greenland S, Longnecker MP. Methods for trend estimation from summarized dose-
response data, with applications to meta-analysis. Am J Epidemiol
1992;135:1301–9.
[26] Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-
analyses. BMJ 2003;327:557–60.
[27] Lee YC, Cohet C, Yang YC, Stayner L, Hashibe M, Straif K. Meta-analysis of epi-
demiologic studies on cigarette smoking and liver cancer. Int J Epidemiol
2009;38:1497–511.
[28] Bagnardi V, Zambon A, Quatto P, Corrao G. Flexible meta-regression functions for
modeling aggregate dose-response data, with an application to alcohol and mor-
tality. Am J Epidemiol 2004;159:1077–86.
[29] Orsini N, Li R, Wolk A, Khudyakov P, Spiegelman D. Meta-analysis for linear and
nonlinear dose-response relations: examples, an evaluation of approximations, and
software. Am J Epidemiol 2012;175:66–73.
[30] Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by
a simple, graphical test. BMJ 1997;315:629–34.
[31] Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for
publication bias. Biometrics 1994;50:1088–101.
[32] Tang L, Shivappa N, Hebert JR, Lee AH, Xu F, Binns CW. Dietary inflammatory
index and risk of oesophageal cancer in Xinjiang Uyghur Autonomous Region.
China Br J Nutr 2018;119:1068–75.
[33] Shivappa N, Hebert JR, Anderson LA, Shrubsole MJ, Murray LJ, Getty LB, et al.
Dietary inflammatory index and risk of reflux oesophagitis, Barrett's oesophagus
and oesophageal adenocarcinoma: a population-based case-control study. Br J Nutr
2017;117:1323–31.
[34] Shivappa N, Hebert JR, Rosato V, Garavello W, Serraino D, La Vecchia C.
Inflammatory potential of diet and risk of oral and pharyngeal cancer in a large
case-control study from Italy. Int J Cancer 2017;141:471–9.
[35] Shivappa N, Hebert JR, Zucchetto A, Montella M, Libra M, Garavello W, et al.
Increased Risk of Nasopharyngeal Carcinoma with Increasing Levels of Diet-
Associated Inflammation in an Italian Case-Control Study. Nutr Cancer
2016;68:1123–30.
[36] Shivappa N, Hebert JR, Rosato V, Serraino D, La Vecchia C. Inflammatory potential
of diet and risk of laryngeal cancer in a case-control study from Italy. Cancer Causes
Control 2016;27:1027–34.
Oral Oncology 103 (2020) 104587
[37] Shivappa N, Hebert JR, Rashidkhani B. Dietary inflammatory index and risk of
esophageal squamous cell cancer in a case-control study from Iran. Nutr Cancer
2015;67:1253–9.
[38] Shivappa N, Zucchetto A, Serraino D, Rossi M, La Vecchia C, Hebert JR. Dietary
inflammatory index and risk of esophageal squamous cell cancer in a case-control
study from Italy. Cancer Causes Control 2015;26:1439–47.
[39] Lu Y, Shivappa N, Lin Y, Lagergren J, Hebert JR. Diet-related inflammation and
oesophageal cancer by histological type: a nationwide case-control study in
Sweden. Eur J Nutr 2016;55:1683–94.
[40] Li WQ, Park Y, Wu JW, Ren JS, Goldstein AM, Taylor PR, et al. Index-based dietary
patterns and risk of esophageal and gastric cancer in a large cohort study. Clin
Gastroenterol Hepatol 2013;11(1130–6):e2.
[41] Emerson SR, Kurti SP, Harms CA, Haub MD, Melgarejo T, Logan C, et al. Magnitude
and timing of the postprandial inflammatory response to a high-fat meal in healthy
adults: a systematic review. Adv Nutr 2017;8:213–25.
[42] Singh N, Baby D, Rajguru JP, Patil PB, Thakkannavar SS, Pujari VB. Inflammation
and cancer. Ann Afr Med 2019;18:121–6.
[43] Zhu HC, Yang X, Xu LP, Zhao LJ, Tao GZ, Zhang C, et al. Meat consumption is
associated with esophageal cancer risk in a meat- and cancer-histological-type de-
pendent manner. Dig Dis Sci 2014;59:664–73.
[44] O'Doherty MG, Cantwell MM, Murray LJ, Anderson LA, Abnet CC, Group FS.
Dietary fat and meat intakes and risk of reflux esophagitis, Barrett's esophagus and
esophageal adenocarcinoma. Int J Cancer 2011;129:1493–502.
[45] Hung HC, Huang MC, Lee JM, Wu DC, Hsu HK, Wu MT. Association between diet
and esophageal cancer in Taiwan. J Gastroenterol Hepatol 2004;19:632–7.
[46] Bravi F, Bosetti C, Filomeno M, Levi F, Garavello W, Galimberti S, et al. Foods,
nutrients and the risk of oral and pharyngeal cancer. Br J Cancer
2013;109:2904–10.
[47] Salehi M, Moradi-Lakeh M, Salehi MH, Nojomi M, Kolahdooz F. Meat, fish, and
esophageal cancer risk: a systematic review and dose-response meta-analysis. Nutr
Rev 2013;71:257–67.
[48] Edefonti V, Hashibe M, Parpinel M, Ferraroni M, Turati F, Serraino D, et al. Vitamin
E intake from natural sources and head and neck cancer risk: a pooled analysis in
the International Head and Neck Cancer Epidemiology consortium. Br J Cancer
2015;113:182–92.
[49] Galeone C, Edefonti V, Parpinel M, Leoncini E, Matsuo K, Talamini R, et al. Folate
intake and the risk of oral cavity and pharyngeal cancer: a pooled analysis within
the International Head and Neck Cancer Epidemiology Consortium. Int J Cancer
2015;136:904–14.
[50] Accardi G, Shivappa N, Di Maso M, Hebert JR, Fratino L, Montella M, et al. Dietary
inflammatory index and cancer risk in the elderly: a pooled-analysis of Italian case-
control studies. Nutrition 2019;63–64:205–10.
[51] Bergmans RS, Palta M, Robert SA, Berger LM, Ehrenthal DB, Malecki KM.
Associations between food security status and dietary inflammatory potential
within lower-income adults from the United States National Health and Nutrition
Examination Survey, Cycles 2007 to 2014. J Acad Nutr Diet 2018;118:994–1005.
[52] Alam I, Shivappa N, Hebert JR, Pawelec G, Larbi A. Relationships between the
inflammatory potential of the diet, aging and anthropometric measurements in a
cross-sectional study in Pakistan. Nutr Healthy Aging 2018;4:335–43.
[53] Jayedi A, Emadi A, Shab-Bidar S. Dietary inflammatory index and site-specific
cancer risk: a systematic review and dose-response meta-analysis. Adv Nutr
2018;9:388–403.
[54] Kaz AM, Wong CJ, Varadan V, Willis JE, Chak A, Grady WM. Global DNA methy-
lation patterns in Barrett's esophagus, dysplastic Barrett's, and esophageal adeno-
carcinoma are associated with BMI, gender, and tobacco use. Clin Epigenetics
2016;8:111.
[55] Mann EA, Hibbs MS, Spiro JD, Bowik C, Wang XZ, Clawson M, et al. Cytokine
regulation of gelatinase production by head and neck squamous cell carcinoma: the
role of tumor necrosis factor-alpha. Ann Otol Rhinol Laryngol 1995;104:203–9.
[56] Nitsch SM, Pries R, Wollenberg B. Head and neck cancer triggers increased IL-6
production of CD34+ stem cells from human cord blood. Vivo 2007;21:493–8.
[57] Pries R, Wollenberg B. Cytokines in head and neck cancer. Cytokine Growth Factor
Rev 2006;17:141–6.
[58] Muscaritoli M, Amabile MI, Molfino A. Foods and their components promoting
gastrointestinal cancer. Curr Opin Clin Nutr Metab Care 2016;19:377–81.
[59] Lv J, Guo L, Liu JJ, Zhao HP, Zhang J, Wang JH. Alteration of the esophageal
microbiota in Barrett's esophagus and esophageal adenocarcinoma. World J
Gastroenterol 2019;25:2149–61.
[60] Hardikar S, Onstad L, Song X, Wilson AM, Montine TJ, Kratz M, et al. Inflammation
and oxidative stress markers and esophageal adenocarcinoma incidence in a
Barrett's esophagus cohort. Cancer Epidemiol Biomarkers Prev 2014;23:2393–403.