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Effects of vitamin D supplementation on inammatory response in patients
with cancer and precancerous lesions: systematic review and meta-analysis
of randomized trials.
Tarenyika Gwenzi
German Cancer Research Center https://orcid.org/0000-0001-5683-6315
Anna Zhu
German Cancer Research Center
Petra Schrotz-King
German Cancer Research Center
Ben Schöttker
German Cancer Research Center
Michael Hoffmeister
German Cancer Research Center
Hermann Brenner ( h.brenner@Dkfz-Heidelberg.de )
German Cancer Research Center https://orcid.org/0000-0002-6129-1572
Systematic Review
Keywords: Cancer, precancer, Vitamin D3 supplement, inammation, biomarker
Posted Date: March 24th, 2023
DOI: https://doi.org/10.21203/rs.3.rs-2722981/v1
License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License
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Abstract
Purpose
Inammation plays a key role in tumor development and progression. Vitamin D has potential tumor suppressing effects through modulation of inammatory
processes. The aim of this systematic review and meta-analysis of randomized controlled trials (RCTs) was to summarize and evaluate the effects of vitamin
D3 supplementation (VID3S) on serum inammatory biomarkers among patients with cancer or pre-cancerous lesions (PROSPERO Reg #: CRD42022295694).
Methods
We searched PubMed, Web of Science and Cochrane databases until November 2022. The effects of VID3S were estimated from pooled standardized mean
differences (SMDs) with their 95% condence intervals (CIs) for inammatory biomarker follow-up levels between intervention and control groups. The study
was conducted according to the PRISMA guidelines and quality assessment of included studies was conducted using the Cochrane Risk of Bias tool.
Results
Eight RCTs with a total of 592 patients who had cancer or pre-cancerous conditions were included in the meta-analyses. VID3S signicantly lowered serum
levels of tumor necrosis factor (TNF)-α [SMD (95%CI): -1.65 (-3.07; -0.24)]. VID3S also reduced serum levels of interleukin (IL)-6 and C-reactive protein (CRP)
but the effects did not reach statistical signicance [SMD (95%CI): -0.83 (-1.78; 0.13) and − 0.09 (-0.35; 0.16), respectively]. VID3S did not have any effect on
IL-10 serum levels [SMD (95%CI): 0.00 (-0.50; 0.49)].
Conclusions
Our study shows evidence of a signicant reduction of TNF-α levels by VID3S for patients with cancer or precancerous lesions. Patients with cancer or
precancerous lesions may benet from personalized VID3S in suppressing tumour-promoting inammatory response.
Introduction
Low levels of serum 25-hydroxyvitamin D [25(OH)D], the most commonly used marker of vitamin D status, have been found to be associated with poor
survival outcomes in patients with various forms of cancers including colorectal cancer (CRC) [1], breast [2], prostate [3], lung [4], pancreatic [5] and liver
cancer [6]. As a result, it has been suggested that vitamin D3 supplementation (VID3S) of cancer patients may be helpful to improve their prognosis even
though evidence from randomized controlled trial (RCTs) remains sparse [7, 8]. However, several meta-analyses of (RCTs) have consistently reported a
signicant 13% reduction of cancer mortality by VID3S in older adults [9–11]. Moreover, a recent meta-analysis of RCTs reported a signicant 35% reduction of
CRC mortality by VID3S among patients with prior CRC diagnosis [12]. VID3S has also shown benets on recurrence and metabolic proles in patients with
adenomas [13].
While the exact mechanism by which vitamin D may inuence cancer outcomes is still elusive, recent evidence suggests various pathways including
modulation of inammatory processes [14, 15]. Inammatory markers are associated with neoplastic growth, higher tumor grade, and increased mortality in
cancer patients [16, 17]. Consequently, it seems plausible that VID3S could be a potential supportive therapy to improve cancer outcomes via modulation of
inammatory processes.
The aim of this study is to summarize and evaluate the effects of VID3S on serum inammatory biomarkers among patients with cancer or pre-cancerous
lesions through a systematic review and meta-analysis of published RCTs.
Materials And Methods
The protocol of this systematic review was registered in the international prospective register of systematic reviews before data extraction (PROSPERO,
registration no. CRD42022295694). The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines [18] were followed for
systematic review and meta-analysis.
Search Strategy and Data Extraction
The target of this review were original RCTs including patients with cancer or precancerous lesions where the intervention was VID3S, with or without co-
interventions. Observational studies, unpublished studies, abstracts, reviews, dissertations, theses, editorials, study protocols, clinical guidelines,
commentaries, and letters were excluded. Studies were included in meta-analyses if they had reported follow-up mean values and their respective standard
deviations of inammatory serum biomarkers for both the intervention and control groups.
Systematic searches were conducted using Medline (PubMed interface), the Cochrane Central Register of Controlled Trials (CENTRAL), and ISI Web of Science
databases from inception until November 2022. One researcher (T.G) with the help of a librarian conducted the searches and screened studies for review
inclusion. The PRISMA ow diagram of the study identication and selection is provided in Fig.1 and the search strings are given in Supplementary Table1.
For database searches, we used medical subject headings (MeSH), free-text words, synonyms, and related terms for the concepts: “vitamin D
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supplementation”, “cancer”, “adenoma”, “inammatory biomarker”, and “randomized controlled trial”. No time restrictions for the searches were applied but
non-English publications were excluded.
The EndNote software version 9 was used for reference management. For included studies, two researchers (T.G, A.Z) independently extracted the following
data using a standardized data extraction form: rst author, publication year, country, number of participants, cancer site and stage, sex, VID3S dosage, mean
baseline serum concentration of 25(OH)D, compliance rate, outcome biomarker under investigation, mean/standard deviation of serum biomarker levels at
follow-up for intervention and control groups, and maximum follow-up time. Initial discrepancies in extracted data were resolved by further review and
discussion. For studies that did not report any of the predened data domains, contacts were made to the authors requesting for the details.
Assessment of study quality
The Cochrane risk-of-bias (CRoB 2) tool [19] for randomized trials was used in the quality assessment of included studies for various domains including
completeness of outcome data, blinding, sequence generation, allocation concealment, and selective outcome reporting. Risk of bias judgement was
independently performed by two researchers (T.G, A.Z) and summarized as low, high, or uncertain based on the extracted data items. In cases of critical point
disagreements between the two researchers, consensus was reached by further discussion among all authors.
Statistical Analyses
Serum inammatory biomarker levels were assessed in various units of measurement in different RCTs. Therefore, standardized mean differences (SMDs)
between intervention and control groups of biomarker levels at follow-up were used in the meta-analyses. Effect sizes were considered large, moderate, or
small if SMD was > 0.7, 0.4–0.7 or < 0.4, respectively [20]. SMDs were summarized together with their respective 95% CIs and presented in forest plots. Meta-
analyses were not conducted if there were insucient numbers of studies (< 2) for a given outcome biomarker. To investigate the sources of heterogeneity and
variation of intervention effects, subgroup analyses were conducted for subgroups dened by intervention duration, baseline 25(OH)D status, VID3S dosage
regimen, cancer/precancerous condition, and study country of origin. Visualisation of heterogeneity was done using forest plots while statistical assessment
was done by Cochran’s Q test and I² index (< 25% low, 25% – 50% moderate, > 50% high heterogeneity). Where possible, sensitivity analyses were conducted to
address high heterogeneity. Analyses for publication bias were not conducted for meta-analyses with fewer than 10 studies. All statistical analyses were
conducted using random effects models with open access Review Manager (RevMan) computer program, version 5.4. The level of signicance was set at p =
0.05 in two-sided testing for all statistical tests.
Results
Search strategy and study selection
The process of the study selection is depicted in Fig.1. Out of 4,788 individual studies, 26 were considered in the full-text screening. One [21] more study was
included via cross-referencing. Nine studies [13, 21–28] were nally included in this systematic review and eight studies were included in the meta-analyses
with a total of 592 patients. Other studies were excluded based on predened criteria as depicted in Supplementary Table2.
Description of studies included in the meta-analyses
General information about the included studies can be found in Table1. The eight studies included in the meta-analyses had sample sizes ranging from 30 to
100. Six of the eight studies were conducted in Iran. Four studies [24, 25, 27, 28] investigated the effects of VID3S on inammatory markers among breast
cancer patients, while two studies [13, 23] focused on patients with cervical intraepithelial neoplasia (CIN). The other two studies investigated the effects of
VID3S on inammatory biomarkers among patients with CRC [26] and colorectal cancer adenoma [22]. Five trials provided VID3S as weekly [24–26] or bi-
weekly [13, 23] oral bolus doses of 50 000 international units (IU), and the remaining three trials [22, 27, 28] gave daily doses ranging from 20 IU to 4000 IU.
Intervention follow-up times ranged from 8 to 24 weeks, and intervention compliance rates were reported to be over 80% for ve studies [13, 22–24, 26] while
the other three studies [25, 27, 28] did not report on compliance rates. Baseline mean 25(OH)D serum levels were reported in seven studies. Four studies [22,
24, 27, 28] had patients in the intervention arm with mean 25(OH)D levels in the sucient range [i.e. 25(OH)D > 20 ng/mL] while three studies [13, 23, 26] had
mean 25(OH)D levels in the decient range [i.e. 25(OH)D < 12 ng/mL]. Five studies [13, 22, 23, 25, 26] reported on the effects of VID3S on serum C-reactive
protein (CRP) concentrations while serum concentrations of tumor necrosis factor-alpha (TNF-α) [22, 24, 26, 28] and interleukin (IL)-6 [22, 26–28] were each
reported on in four studies. Two studies [22, 28] reported on serum levels of IL-10. Four biomarkers could not be included in the meta-analyses because of
insucient studies (see Supplementary Table3). In addition, two studies [22, 26] reported on the effects of VID3S with calcium/omega-3 fatty acid co-
supplements (see study details in Supplementary Table4 and meta-analyses results in Supplementary Fig.1). Serum inammatory biomarkers were assayed
using enzyme linked immunosorbent assay (ELISA) technique in all studies except in one [21] that did not report on the details of biomarker assay technique
used.
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Table 1
General information of studies included in the meta-analyses.
First author,
year, reference Country Mean
Age
(SD)
Cancer
site&stage F
(%) Baseline mean
25(OH)D ng/mL
(intervention/placebo)
Intervention
(Vitamin
D3
Dosage)
Number of
participants
(intervention/placebo)
Biomarker
investigated Biomarker Se
at Follow-Up:
(SD)
Intervention
Hopkins et al,
2011 [22] USA 60.2
(8.1) Colorectal
Adenoma 30 21.0 /20.4 400 IU
twice daily 22/21 CRP
(µg/ml) 0.99
(1.97)
400 IU
twice daily 22/21 TNF-α
(pg/ml) 2.73
(2.52)
400 IU
twice daily 22/21 IL-6 (pg/ml) 0.67
(3.76)
400 IU
twice daily 22/21 IL-10
(pg/ml) 0.43
(1.38)
Vahedpoor, et
al 2017 [23] Iran 36.9
(7.4) CIN, I 100 10.8/11.2 50 000 IU
every 2
weeks
29/29 CRP
(µg/ml) 1.96
(3.72)
Vahedpoor et
al, 2018 [13] Iran 41.9
(7.2) CIN, II-III 100 11.5/12.4 50 000 IU
every 2
weeks
29/29 CRP
(µg/ml) 3.80
(1.57)
Shahvegharasl
et al, 2019 [25] Iran 41.1
(5.6) BC, I-III 100 NR 50 000 IU
every week 22/22 CRP
(µg/ml) 4.19
(3.89)
Mohseni et al,
2019 [24] Iran 47.7
(8.0) BC 100 28.0/15.3 50 000 IU
every week 26/26 TNF-α
(pg/ml) 14.5
(1.60)
Haidari et al,
2020 [26] Iran 57.1
(11.4) CRC, II/III 23.8 11.6/11.2 50 000 IU
every week 21/20 CRP
(µg/ml) 1.44
(0.8)
23.8 11.6/11.2 50 000 IU
every week 21/20 TNF-α
(pg/ml) 4.93
(2.34)
23.8 11.6/11.2 50 000 IU
every week 21/20 IL-6 (pg/ml) 33.54
(28.8)
El-Bassiouny
et al, 2022 [27] Egypt 49.6
(5.8) BC, II 100 21.4/20.7 20 IU daily 50/50 IL-6 (pg/ml) 39.68
(10.47)
1Naderi et al,
2022 [28]
Iran 48.0
(8.0) BC, 0-II 100 41.2/43.4 4000 IU
daily 10/10 TNF-α
(pg/ml) 17.96
(4.37)
IL-6 (pg/ml) 0.3
(0.19)
IL-10
(pg/ml) 83.04
(67.31)
Notes:
F female; USA United States of America; BC Breast Cancer; CIN Cervical Intraepithelial Neoplasia; NR Not Reported; IU International Units; i.v intravenous; SD S
CRP C-reactive protein; TNF-α tumor necrosis factor alpha; IL interleukin; µg microgram; ng nanogram; pg picogram; ml millilitre.
1Study compared vitamin D supplementation group and those on yoga intervention.
Only two studies reported mean time of blood sample collection after surgery: Li et al (day 1–6 after surgery for the follow-up) and Naderi et al (> 3 years pos
baseline and follow-up)
Risk of bias assessment
The results of the risk of bias assessment are shown in Supplementary Table5. Five studies [13, 21–23, 25] had a good overall quality, two [24, 26] had fair
quality and the remaining two [27, 28] had poor quality. Three studies [26–28] had a high attrition rate (> 15%). In terms of randomization, one study employed
triple blinding, six employed double blinding and one employed single blinding (results not shown).
Effect of VID3S on CRP
The meta-analysis on CRP serum levels was conducted with ve studies [13, 22, 23, 25, 26] comprising a total of 244 patients who had cancer or precancerous
lesions. VID3S did not show a signicant effect on CRP serum levels after 8–24 weeks of supplementation (SMD, 95%CI: -0.09, -0.35; 0.16) (Fig.2, panel A).
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The quality of four [13, 22, 23, 25] of the included studies was good while one study [26] had a fair quality. Furthermore, a sensitivity analysis of three studies
[13, 23, 26] with 157 patients with a mean 25(OH)D at baseline in the deciency range suggested a possible modest effect of VID3S in reducing serum CRP
levels, but the effect did not reach statistical signicance (SMD, 95%CI: -0.14, -0.46; 0.17) (Fig.2, panel B). In both meta-analyses, no heterogeneity was
observed.
Effect of VID3S on TNF-α
The pooled result of four studies [22, 24, 26, 28] with 156 patients who had cancer or precancerous lesions showed that 8–24 weeks of VID3S had a large
effect in reducing TNF-α serum levels (SMD, 95%CI: -1.65, -3.07; -0.24) (Fig.3, panel A). For this meta-analysis, the quality of included studies was fair for two
studies [24, 26] while one [22] had good quality and one [28] had poor quality. Because considerable heterogeneity was observed for this analysis (I2 = 93%, p <
0.01), a sensitivity analysis was conducted including only studies with daily dosage regimens of VID3S (total participants = 63). The results indicated a large
effect in reducing serum TNF-α without heterogeneity in the meta-analysis (SMD, 95%CI: -0.85, -1.37; -0.33) (Fig.3, panel B).
Effect of VID3S on IL-6
The meta-analysis of four studies [22, 26–28] investigating the effect of VID3S on IL-6 serum levels for a total of 204 patients with cancer or precancerous
lesions suggested a large decrease in IL-6 levels, which though did not reach statistical signicance (SMD, 95%CI: -0.83, -1.78; 0.13) (Fig.4, panel A). VID3S
duration was between 8 and 24 weeks. Two studies [27, 28] included in the meta-analysis were of poor quality, and considerable heterogeneity was observed
(I2 = 89%, p < 0.01), with apparently much lower effects in the better quality studies. A follow-up sensitivity analysis of two studies [22, 26] with good and fair
quality (total participants = 84) showed a small (though statistically non-signicant) effect in reducing IL-6 levels (SMD, 95%CI: -0.21, -0.64; 0.22) with no
heterogeneity (I2 = 0%, p = 0.95) (Fig.4, panel B). It is important to note that baseline mean 25(OH)D serum levels were in the normal range in each of these two
studies.
Effect of VID3S on IL-10
The pooled result of two studies [22, 28] for 63 patients who had cancer/precancerous lesions and mean 25(OH)D levels in the normal range at baseline did
not show any effect of daily dosage regimens of VID3S for 12–24 weeks on serum IL-10 levels (SMD, 95%CI: 0.00, -0.50; 0.49) (Fig.5). In this meta-analysis,
one study [22] had good quality while one study [28] had poor quality and no heterogeneity was observed (I2 = 0%, p = 0.74).
Discussion
To the best of our knowledge, this is the rst systematic review and meta-analyses with the objective of evaluating potential anti-inammatory effects of
VID3S in adults with cancer or precancerous lesions based on RCT evidence. Our study showed evidence of signicant reduction of serum TNF-alpha levels. In
addition, meta-analyses suggested a potentially large effect on IL-6 levels and a potentially small effect on CRP levels by VID3S, but the effect estimates were
not statistically signicant. No differences in IL-10 follow-up serum levels were observed after VID3S.
The role of vitamin D in modulation of inammatory processes is mediated via the regulation of vitamin D responsive gene expression in several human cells
[29]. Mechanistic studies suggest that vitamin D may downregulate the expression of nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NF-κB)
and also inhibit immune-cell-mediated inammatory responses via vitamin D receptors (VDRs) that are expressed in human cells [30]. Thus, it is plausible that
VID3S may be of clinical value in reducing tumor-promoting inammatory cytokines such as CRP, TNF-α and IL-6 in colorectal, prostate, breast, pancreatic and
liver cancers, in which these markers are highly expressed [29].
In our meta-analysis, a small non-signicant effect of VID3S was observed in reducing CRP serum levels in patients who had mean 25(OH)D levels in the
vitamin D deciency range. Similarly small but signicant CRP changes after VID3S have previously been reported for patients with rheumatoid arthritis and
vitamin D deciency [31]. Higher but still safe doses of VID3S and long-term treatment might be needed to achieve larger effects [32]. On the other hand, a
recent meta-analysis of RCTs showed a signicant effect of daily VID3S in reducing serum levels of high-sensitivity CRP (but no effect on TNF-α and IL-6)
among patients with type 2 diabetes mellitus [33].
There was a large and signicant effect of VID3S in reducing serum TNF-α levels for patients with cancer/precancerous lesions. A sensitivity analysis for
studies that had a daily oral dosage regimen of VID3S showed a more precise effect estimation of reduction in TNF-α serum levels. Daily dosage regimens
may offer a number of benets over bolus doses [34]. In agreement with our ndings, treatment of prostate cancer (PCa) cell lines with calcitriol has
demonstrated downstream inhibition of TNF-α production [35]. However, large and sustained effects in the suppression of TNF-α may require higher vitamin D
doses as reported in a study showing a dose-dependent suppression of TNF-α by vitamin D in
Mycobacterium tuberculosis
infected mononuclear cells [36].
Our meta-analysis has shown a large but statistically non-signicant effect by VID3S in reducing IL-6 serum levels for patients with cancer/precancerous
lesions. Calcitriol downregulates IL-6 expression in both normal colon and colorectal cancer cells [29, 37]. In addition, an in vitro study by Nonn and colleagues
showed that normal and PCa cells treated with vitamin D exhibited inhibition of TNF-α-stimulated IL-6 production [35]. However, VID3S had no effect on serum
IL-6 in a meta-analysis of RCT studies with healthy, obese and overweight adults [38], suggesting that healthy individuals may not benet from the anti-
inammatory effects of VID3S.
Our results showed no effect of VID3S on serum IL-10, an anti-inammatory cytokine. Similar to our ndings, treatment of human colon cancer cell lines with
vitamin D has previously shown strong effects on TNF-α and IL-6 levels, but only a weak effect in increasing IL-10 levels [39]. In an RCT by Naderi and
colleagues, IL-10 gene expression was increased much more by high dose (4,000 IU/day) VID3S and yoga co-intervention than by low-dose (2,000 IU/day)
VIDS3 and yoga among breast cancer patients [28]. These ndings support the hypothesis that high VID3S may have clinically signicant IL-10 mediated anti-
inammatory effects in cancer patients. However, more evidence is required to establish VID3S dosages necessary to attain IL-10 level changes.
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Potential sources of heterogeneity
Variations in intervention such as dosage, duration and compliance rates are possible sources of heterogeneity. Our study included individual trials that had
patients with different mean vitamin D status at baseline. Some studies have shown benets in attaining sucient serum 25(OH)D states among decient
populations with large single bolus doses, while others have shown benets with daily low doses of VID3S [24, 26, 40, 41]. However, higher doses are more
prone to high calcaemic toxicity [42]. Recommendations by the European expert panel have suggested large loading doses of 6000 IU/day for 4–12 weeks for
patients at high risk of 25(OH)D deciency, followed by 800–2000 IU/day as maintenance doses with the aim of reaching serum therapeutic levels of 12–20
ng/mL [43]. Heterogeneity may also arise from variations in geography, study design or quality, sample sizes, age, sex, race or ethnicity, VDR gene
polymorphisms, obesity states, site and stage of cancer [22, 24, 44–48].
Limitations
Most of the trials included in our study recruited patients with a sucient mean baseline vitamin D status and who may not benet much from VID3S. In
addition, considerable heterogeneity observed in most of our meta-analyses makes it dicult to infer the ndings to a specic patient group. Unfortunately,
our study could not investigate all the potential sources of heterogeneity because of the limited number of included studies. Likewise, publication bias could
not be systematically examined given the low numbers of RCTs. Overall, both the limited number of studies and the limited number of participants within
studies limited the possibility to draw strong conclusions on the effects of VID3S on inammatory response among our target population.
Conclusions
Although evidence is still very limited, with a low number of mostly small and partly poor-quality studies, we found evidence of a signicant reduction of
serum TNF-α levels by VID3S for patients with cancer and precancerous lesions. This main result supports hypotheses that patients with carcinomas or
precancerous lesions may benet from anti-inammatory effects of personalized VID3S. However, existing evidence is still sparse. Further high-quality RCTs
are needed, which ideally should include much larger numbers of patients and treat them for at least 12 weeks with suciently high daily vitamin D3 doses.
Future studies should also pay particular attention to the role of the baseline vitamin D status and potential interactions of VID3S with genetic and clinical
factors, such as specic types of cancer therapy or treatment with various types of anti-inammatory drugs.
Declarations
Acknowledgements:TG and HB designed research and BS contributed to the design of the study; TG and AZ collected the data; TG analyzed data; TG and HB
wrote the paper. PS-K and MH contributed in providing critical feedback on the manuscript. All authors read and approved the nal manuscript.
Funding information: There was no extramural funding for this systematic review and meta-analysis.
Data availability: Original data generated and analyzed during this study are included in this published article or in the data repositories listed in References.
Disclosure statement: The authors have nothing to disclose.
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Abbreviations
Abbreviation Full name
CIN Cervical Intraepithelial Neoplasia
CRC Colorectal cancer
CRP C-reactive protein
IL Interleukin
NF-kB Nuclear factor-kappa light chain B
PCa Prostate cancer
RCT Randomised Controlled Trial
SMD Standardised Mean Difference
TNF-αTumor necrosis factor-alpha
VDR Vitamin D receptor
VID3S Vitamin D3 supplementation
25(OH)D 25-hydroxyvitamin D
95% CI 95% condence interval
Figures
Page 9/12
Figure 1
PRISMA study selection ow diagram.
Page 10/12
Figure 2
Effect of vitamin D3 supplementation on C-reactive protein serum levels for patients with cancer/precancer conditions after 8 - 24 weeks intervention.
Page 11/12
Figure 3
Effect of vitamin D3 supplementation on tumor necrosis factor-α serum levels for patients with cancer/precancer conditions after 8 - 24 weeks intervention.
Page 12/12
Figure 4
Meta-analyses of studies on the effect of vitamin D3 supplementation over 8 - 24 weeks on interleukin-6 serum levels in studies among patients with
cancer/precancerous conditions.
Figure 5
Effect of vitamin D3 supplementation on interleukin-10 serum levels for patients with cancer/precancer conditions after 12 - 24 weeks intervention (n = 63).
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SupplementallesforpeerreviewTG.docx
