Keywords
vitamin D - prostatic neoplasms - PSA response - mortality - systematic review - meta-analysis
Introduction
Prostate cancer is the second most frequent cancer in men, worldwide [1]. In the United States of America and European countries, approximately 25% of new
cancer cases in men are due to prostate cancer [1]
[2] . The pathogenesis of this disease is complex. It is suggested that the growth of
prostate cancer is highly dependent on circulating androgens, especially testosterone.
In many cases, cancer has extended beyond the prostate gland at the time of diagnosis
and primary hormone therapy cannot stop or slow its progression [3]. Before 2004, chemotherapy was not considered a viable treatment for this cancer,
but after 2 trials, chemotherapy, especially using docetaxel, has been found to be
effective [4]
[5].
Several studies have investigated the therapeutic effect of nutritional supplements
like pomegranate juice or extract pills [6]
[7] and green tea [8]
[9] on prostate cancer. Beyond the classic role of vitamin D in regulating bone health
[10], cardiometabolic risk factors [11]
[12] and proper hormonal function [13]
[14], vitamin D supplementation has attracted attention for its possible therapeutic
effect on prostate cancer [15]
[16] because some trials have shown that vitamin D supplementation reduces circulating
androgens (including testosterone and dihydrotestosterone) [17], reduces PSA secretion and inhibits cell growth [18] of hormone-sensitive prostate cancer cell line (LNCaP cells) [19], and improves apoptosis[20]. Several clinical trials tried to investigate the effect of high dose vitamin D
administration on prostate cancer, in recent years [18]
[21]
[22], however, the results are inconsistent. For instance, Schwartz et al. [23] and Morris et al. [24] could not show a significant response to vitamin D in combination with chemotherapy
whereas Shamsedine et al. [21] and Beer et al. [25] observed a significant effect of vitamin D supplementation on Prostate-Specific
Antigen (PSA) levels when accompanied with chemotherapy. In contrast, a study done
by Srinivas et al. [26] was halted due to the results of a trial, using DN101 in combination of docetaxel
because of a higher death rate in vitamin D supplemented group compared to placebo
group.
According to our knowledge there has been no systematic review published of the effect
of vitamin D supplementation on prostate cancer progression. In the present study,
we review the published clinical evidence, and carry out a meta-analysis to quantify
the effect of vitamin D supplementation on: 1) serum PSA levels; and 2) prostate cancer
survival. In addition, we report on the toxicity and adverse events reported in these
trials as a result of vitamin D administration in patients with prostate cancer.
Materials and Methods
The present systematic review is conducted and reported based on PRISMA guidelines.
The study protocol was registered in the international prospective register of systematic
reviews (PROSPERO) database (http://www.crd.york.ac.uk/PROSPERO, registration no: CRD42015015770).
Data sources and search strategy
We used the following 2 groups of MeSH and non-MeSH keywords for searching PubMed,
Scopus, ISI web of science and Google scholar up to 10 September 2017: 1) “Vitamin
D”, “Ergocalciferols”, “Cholecalciferol”, “Calcitriol”, “Calcifediol”, “25-Hydroxyvitamin
D 2”, “25-hydroxyvitamin D” ,“1-25-dihydroxy-23,23-difluorovitamin D3, “25(OH)D, “25-OH
vitamin D”, “1,25(OH)(2)D, “1,25(OH)D, “1,25-(OH)(2) D(3)”, “25-hydroxyvitamin D”,
“Vitamin D”, “25-(OH)D(3)”, “25-(OH)D(2)”, “Vitamin D 3”, “Vitamin D3”, “Cholecalciferols,
“Ergocalciferol” , “Vitamin D 2”, “Vitamin D2”, “DN101” and 2) “Prostate“, “Prostatic
Neoplasms”, “Prostatic Neoplasm”, “Prostatic Cancer”, “Cancer of Prostate”, “Prostate
Neoplasm”, “prostate cancer”, “prostate carcinoma”, “gamma-Seminoprotein”, “gamma
Seminoprotein”, “hK3 Kallikrein”, “Semenogelase”, “Kallikrein hK3”, “Seminin”, “Prostate
Specific Antigen” and “PSA”. No language, date, or study design filters were applied
to our search. The reference list of retrieved primary and review articles were reviewed
to identify studies possibly missed by our search strategy. All titles and abstracts
were reviewed separately by 2 authors (SS and ASA) and any disagreement was resolved
through discussion.
Eligibility criteria
All clinical trials (single group, parallel or cross over RCTs), which examined the
effect of vitamin D supplementation on adult men with prostate cancer were included
in the present systematic review.
Data extraction
Data on surname of the first author, publication date, sample size, participants’
age, vitamin D dose used for supplementation, calcium restriction prescription, medications
used for chemotherapy and their dose, number of participants with PSA response proportion
(reduction of serum PSA level to lower than half of baseline level), mortality rate
in treatment and control group, PSA change, and data on toxicity were extracted separately
by 2 independent authors (SS and ASA).
Quality assessment
The Cochrane Collaboration’s tool for risk of Bias assessment was used by 2 authors
(SS and ASA) independently for assessment of the quality of the controlled clinical
trials [27]. We judged the quality of the studies on the basis of 5 domains (random sequence
generation, allocation concealment, blinding of outcome assessment, incomplete outcome
data, and selective reporting). Each study was rated by the reviewers as being at
low, high, or unclear risk of bias for each of the 5 domains. Studies, which were
low risk according to at least 3 domains were considered as low risk-of-bias and those
with 2 and lower than 2 low risk domains were regarded to be at some or and high risk-of-bias,
respectively, [27]. All of the single group studies were classified as high risk, because they do not
have a control group.
Statistical analysis
The sample size and number of patients with a PSA response proportion (defined as
a reduction of serum PSA level to lower than half of baseline level) in the intervention
group was used to calculate the PSA response proportion (as event rate). Event rates
were transformed, and the event rate and corresponding standard error (SE) was used
as the effect size in meta-analysis for single arm studies. For the controlled clinical
trials, the response rate in the intervention and control group was used to calculate
the risk ratio (response rate ratio), and the natural logarithm of the risk ratio
and its corresponding SE was used for meta-analysis. We also computed mortality rate
in each arm of randomized clinical trials to calculate the mortality rate ratio to
be used as the effect size for meta-analysis. A number of controlled clinical trials
also reported the effect of vitamin D on serum PSA levels for baseline and after intervention
period. We calculated the mean change in serum PSA levels. As none of included studies
reported standard deviation (SD) for baseline, after intervention and change in serum
PSA levels at the same time, the SD for PSA change was calculated, assuming a correlation
of 0.5 between baseline and post- intervention values.
The DerSimonian and Laird random-effects model was used to pool the effect estimates
in all meta-analyses [28]. Statistical heterogeneity between studies was evaluated using Cochran’s Q test
and the I-squared statistic (I2) [29]. Sensitivity analyses were performed by recalculating the pooled effects after:
1) removing the highest-weighted study from a given analysis (the “leave-one-out”
analysis) [30]; and 2) testing alternatives to the 0.5 correlation between baseline and post-treatment
values, which were set to 0.1 and 0.9.
The potential for publication bias was assessed by visual inspection of funnel plots
and using statistical tests of asymmetry, including Egger’s regression asymmetry test
and Begg’s adjusted rank correlation test [31]. Statistical analyses were conducted using STATA version 11.2 (Stata Corp, College
Station, TX, USA). p-Values less than 0.05 were considered as statistically significant
for treatment differences; and less than 0.10 for assessments of publication bias
and statistical heterogeneity.
Results
The literature search retrieved 1290 potentially-relevant citations. After screening
titles/abstracts and removal of irrelevant records, 40 potentially related articles
were selected and their full-text was assessed for eligibility. Eighteen reports were
excluded because they were conducted on the same study populations as other included
studies (n=6) [19]
[25]
[32]
[33]
[34]
[35], did not provide relevant outcome (n=9) [36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44], were review article (n=1) [45], authors’ reply (n=1) [46] and study protocol (n=1) [47]. Consequently, twenty-two studies [3]
[15]
[16]
[18]
[21]
[22]
[23]
[24]
[26]
[32]
[35]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58] were included in the systematic review ([Fig. 1]). Sixteen studies were single arm trial in design [3]
[18]
[21]
[22]
[23]
[24]
[26]
[32]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[56] and 6 were randomized controlled trials [15]
[16]
[35]
[55]
[57]
[58]. The study characteristics for single group and randomized clinical trials are included
in [Tables 1] and [2] respectively. These papers have been published between 1995 and 2013; one of them was conducted
in Middle East [21] and 3 studies in the European continent [18]
[22]
[55] and the rest were conducted in North America [3]
[15]
[16]
[23]
[24]
[25]
[26]
[32]
[35]
[48]
[49]
[51]
[52]
[53]
[54]
[56]
[57]
[58]. The sample size ranged from 14 to 953 patients with prostate cancer. Some studies
examined the effect of vitamin D alone and the others administered chemotherapy drugs
including docetaxel, naproxen, zoledronic acid, dexamethasone, carboplatin, and mitoxantrone
along with vitamin D supplementation ([Table 1], [2]).
Fig. 1 Flow diagram for study selection process. .
Table 1 Main characteristics of single arm studies included in the systematic review.
|
Authors (year) [Ref]
|
Location
|
No. Participants
|
Age (median)
|
Vitamin D prescription
|
Calcium restriction diet
|
Chemotherapy or usage of other drugs
|
Results
|
|
Osborn et al. (1995) [48]
|
USA
|
14
|
77
|
1.5 μg of calcitriol daily, after 15 days 1 μg of calcitriol daily, after 28 days
1.5 μg of calcitriol daily
|
No
|
Type of chemotherapy not mentioned
|
No objective responses were observed
|
|
Liu et al. (2003) [49]
|
USA
|
26
|
70
|
12.5 μg 1a-OH-D2 (5 each of 2.5 μg capsules) continuous once a day before their AM
meals
|
No
|
No chemotherapy regimens
|
No objective responses were observed
|
|
Beer et al. (2003) [50]
|
USA
|
39
|
73
|
Calcitriol 0.5 μg/kg was given orally in 4 divided doses over 4 h on day 1
|
Yes
|
Docetaxel+Dexamethasone
|
Thirty of 37 patients (81%; 95% CI=68–94%) achieved a PSA response
|
|
Beer et al. (2003) [51]
|
USA
|
22
|
69
|
Calcitriol 0.5 μg/kg was given orally once a week orally once a week. Each weekly
dose was divided into 4 doses and taken orally during each hour of a 4-h
|
Yes
|
Type of chemotherapy not mentioned
|
No objective responses were observed
|
|
Beer et al. (2004) [52]
|
USA
|
18
|
76
|
Calcitriol 0.5 μg/kg was given orally over a 4-h period.
|
Yes
|
Dexamethasone+Carboplatin
|
One of 17 patients (6%, 95% CI=0–28%) achieved a confirmed PSA response
|
|
Morris et al. (2004) [24]
|
USA
|
32
|
70
|
Calcitriol dose administered: 4, 6, 8, 10, 14, 20, 24, or 30 μg taken orally before
bedtime on days 1, 2, and 3 of each week
|
No
|
Dexamethasone+ Zoledronate
|
No objective responses were observed
|
|
Tiffany et al. (2005) [53]
|
USA
|
24
|
67
|
Calcitriol (60 μg as 0.5 g tablets) was given orally in 4 divided doses for 4 h on
day 1
|
No
|
Dexamethasone+Estramustine +Docetaxel+Aspirin+warfarin
|
Seven of the 22 patients (32%, 95% CI=12–51%) achieved a confirmed PSA response
|
|
Schwartz et al. (2006) [23]
|
USA
|
18
|
74
|
Paricalcitol i. v. 3 times per week on an escalating dose of 5 to 25 μg
|
No
|
Type of chemotherapy not mentioned
|
No objective responses were observed
|
|
Trump et al. (2006) [32]
|
USA
|
43
|
69
|
Calcitriol was administered weekly at a dose of 8 μg for 1 month, and at a dose of
12 μg, for 1 month, at a dose of 10 μg every 3 days of a week
|
No
|
Dexamethasone
|
Eight of 43 patients (18.6%) (median decrease 64%; range, 55–92%) achieved a confirmed
PSA response
|
|
Flaig et al. (2006) [54]
|
USA
|
40
|
72
|
0.5 μg of daily calcitriol added at the start of week 5
|
Yes
|
Dexamethasone + Carboplatin
|
13 of 34 treated patients (38.2%; 95% CI=22.2–56.4%) achieved a confirmed PSA response
|
|
Petrioli et al. (2007) [22]
|
Italy
|
26
|
68
|
Calcitriol (32 μg as 0.5 μg tablets) given orally in 3 divided doses on day 1
|
No
|
Docetaxel+Dexamethasone
|
Eight patients (31%, 95% CI=16.5–50.1%) achieved a confirmed PSA response
|
|
Chan et al. (2008) [56]
|
USA
|
19
|
70
|
180 μg of DN-101 on day 1
|
No
|
Mitoxantrone
|
Five of 19 patients (26%, 95% CI=9–51%) achieved a confirmed PSA response
|
|
Newsom et al. (2009) [18]
|
UK
|
26
|
68
|
Most patients received vitamin D 25 μg once daily, 7 treated earlier in the study
were given 10 μg once daily
|
No
|
Dexamethasone
|
Two patients (8%) (95% CI=25–50%) achieved a confirmed PSA response
|
|
Srinivas et al. (2009)[26]
|
USA
|
21
|
64
|
high dose calcitriol (DN101) (45 μg once per week)
|
Yes
|
Naproxen
|
No objective responses were observed
|
|
Chadha et al. (2010) [3]
|
USA
|
18
|
68
|
Intravenous calcitriol on Day 2 of each week (74 μg) over 1 h, 4 to 8 h
|
No
|
Dexamethasone
|
No objective responses were observed
|
|
Shamseddine et al. (2013) [21]
|
Lebanon
|
30
|
75
|
Calcitriol 0.5 μg/kg orally in 4 divided doses over 4 h on day 1 of each treatment
week
|
No
|
Docetaxel+ Zoledronate
|
Eleven of 30 patients achieved a confirmed PSA response
|
Table 2 Main characteristics of randomized controlled rials (RCTs) included in the meta-analysis.
|
Authors (year) [Ref]
|
Location
|
No. Participants
|
Age
|
Vitamin D (intervention group)
|
Control group
|
Duration
|
Chemotherapy or usage of other drugs
|
Results
|
|
Colli et al. (2006) [55]
|
Italy
|
116
|
≥50
|
150 μg a vitamin D3 analogue (BXL628)
|
Placebo capsules, daily
|
12 weeks
|
Not mentioned
|
PSA change were not significant between intervention and control groups.
|
|
Beer et al. (2007) [15]
|
USA
|
250
|
≥18
|
45 μg vitamin D3 (DN-101) orally on day 1
|
45 μg placebo, orally on day 1
|
3 weeks of a 4-week cycle
|
Dexamethasone+Docetaxel
|
Vitamin D treatment was associated with improved survival and PSA response
|
|
Attia et al. (2008) [16]
|
USA
|
70
|
≥18
|
10 μg doxercalciferol, day 1–28
|
10 μg placebo, day 1–28
|
A 4-week cycle
|
Docetaxel
|
Daily doxercalciferol with weekly docetaxel did not enhance PSA response rate or survival
|
|
Scher et al. (2011) [35]
|
USA
|
953
|
≥50
|
45 μg a high-dose vitamin D3 (DN-101) orally on day 1, 8, and 15
|
5 mg prednisone twice daily with 75 mg/m2 docetaxel and 24 mg dexamethasone every 3 weeks
|
3 of every 4 weeks
|
Dexamethasone+Docetaxel
|
Vitamin D treatment was associated with shorter survival than the control
|
|
Wagner et al. (2013) [57]
|
USA
|
66
|
≥50
|
Eligible patients were randomly allocated vitamin D3 doses: 1) 400 IU , 2) 10 000
IU and 3) 40 000 IU
|
Patients in the control (nonrandomized) arm did not receive any supplemental vitamin
D
|
4 weeks
|
Not mentioned
|
PSA change were observed in 61%, 70%, and 81% of patients treated with 400, 10 000,
and 40 000 IU/d of vitamin D3, respectively
|
|
Gee et al. (2013) [58]
|
Canada
|
31
|
≥50
|
10 μg 1α-hydroxyvitamin D2, daily
|
Just observation
|
A 3- to 8-week cycle
|
Not mentioned
|
PSA change was not significant between intervention and control groups
|
Risk of bias across included studies
[Table 3] provides information on the risk of bias for each of the randomized controlled trials
included in the present study. Only 6 studies were placebo controlled trial; therefore,
we assessed for methodological quality using Cochrane collaboration’s tool for assessing
risk of bias [15]
[16]
[35]
[55]
[57]
[58]. All eligible studies were low risk regarding 4 or more domains and were ranked
as good quality.
Table 3 Study quality and risk of bias assessment.a
|
First author (year ) [Ref]
|
Sequence generation
|
Allocation concealment
|
Blinding of outcome assessment
|
Incomplete outcome data
|
Selective reporting
|
Score
|
Overall quality
|
|
Colli (2006) [55]
|
+
|
+
|
?
|
+
|
+
|
4
|
Good
|
|
Beer (2007) [15]
|
+
|
+
|
+
|
+
|
+
|
5
|
Good
|
|
Attia (2008)[ 16]
|
+
|
+
|
?
|
+
|
+
|
4
|
Good
|
|
Scher (2011) [35]
|
+
|
+
|
+
|
+
|
+
|
5
|
Good
|
|
Wagner (2013) [57]
|
–
|
+
|
?
|
+
|
+
|
3
|
Good
|
|
Gee (2013) [58]
|
+
|
+
|
?
|
+
|
+
|
4
|
Good
|
a+: Low risk; –: High risk; ?: Unclear.
Meta-analysis
Meta-analysis of controlled clinical trials
Prostate cancer progression
Out of 6 placebo controlled trials [15]
[16]
[35]
[55]
[57]
[58], 3 studies with 1486 participants, examined the effect of vitamin D supplementation
on serum PSA levels. Our analysis showed that the mean PSA change from baseline was
not significantly different between vitamin D supplementation and placebo groups [weighted
mean difference (WMD)=–1.66 ng/ml, 95% CI: –0.69, 0.36, p=0.543) [55]
[57]
[58], with no evidence of heterogeneity between studies (Cochrane Q test, Q statistic=1.97,
p=0.373, I2=0.0%, τ2=0.0). This result was not sensitive to the correlation coefficient selected to calculate
the SD for change values.
Two trials investigated the effect of vitamin D supplementation on PSA response proportion
[57]
[58]. In these trials, vitamin D supplementation does not significantly affect PSA response
proportion (RP=1.18, 95% CI: 0.97, 1.45, p=0.104) and the heterogeneity was not significant
(Cochrane Q test, Q statistic=0.55, p=0.46, I2=0.0%, τ2=0.0).
Mortality
The effect of vitamin D supplementation on mortality rate in patients with prostate
cancer was assessed in 3 trials [15]
[16]
[35] with 1273 participants and 477 events including 224 deaths in the control groups
and 253 deaths in the vitamin D supplemented group occurred for any cause during the
follow-up. There were no significant differences in total mortality between participants
receiving vitamin D supplementation and those receiving placebo [risk ratio (RR)=1.05,
95% CI: 0.81–1.36; p=0.713; [Fig. 2], however, the heterogeneity between studies was high (Cochrane Q test, Q statistic=7.34,
p=0.025, I2=72.8%%, τ2=0.037). When a study done by Beer et al. [15] was excluded in the sensitive analysis, the overall result was changes and the analysis
on the two remaining clinical trials [16]
[35] showed that vitamin D supplementation increases the risk of mortality by 19% (RR=1.19,
95% CI: 1.03–1.38; p=0.014) with no evidence of heterogeneity (Cochrane Q test, Q
statistic=0.70, p=0.402, I2=0.0%, τ2=0.0).
Fig. 2 Meta-analyses of randomized controlled clinical trials investigating the effect of
vitamin D supplementation on mortality rate. Analysis was conducted using random effects
model.
Toxicity
The possible side-effects related to vitamin D supplementation was reported in a number
of included studies were also investigated [15]
[16]
[35]. Results of the meta-analyses on the risk ratio of side-effects are reported in
[Table 4]
. In total, side-effects were generally similar in vitamin D supplemented and control
group; however, our analysis revealed that nausea and loss of taste were experienced
more in in the vitamin D supplemented group compared to placebo group.
Table 4 The meta-analysis of the specific side-effects of vitamin D versus placebo extracted
from randomized controlled clinical trials.
|
Adverse event
|
Number of studies
|
Number of participants
|
Risk ratio (95% CI)
|
p
|
Heterogeneity
|
|
p
|
Q statistic
|
Degrees of freedom
|
Tau-squared
|
I2 (%)
|
|
Anemia
|
2
|
1203
|
0.920 (0.527–1.606)
|
0.769
|
0.569
|
0.32
|
1
|
0.0000
|
0.0
|
|
Diarrhea
|
3
|
1273
|
1.220 (0.689–2.159)
|
0.495
|
0.271
|
2.61
|
2
|
0.1009
|
23.4
|
|
Dyspnea
|
3
|
1203
|
1.247 (0.530–2.932)
|
0.613
|
0.192
|
3.30
|
2
|
0.2670
|
39.3
|
|
Fatigue
|
3
|
1273
|
0.852 (0.308–2.359)
|
0.758
|
0.033
|
6.82
|
2
|
0.4891
|
70.7
|
|
Leukopenia
|
3
|
1273
|
0.905 (0.677–1.210)
|
0.500
|
0.417
|
1.75
|
2
|
0.0000
|
0.0
|
|
Hyperglycemia
|
3
|
1273
|
0.904 (0.685–1.193)
|
0.475
|
0.409
|
1.79
|
2
|
0.0000
|
0.0
|
|
Hypercalcemia
|
2
|
1023
|
3.511 (0.580–21.242)
|
0.171
|
0.840
|
0.04
|
1
|
0.0000
|
0.0
|
|
Loss of taste
|
2
|
1203
|
1.365 (1.088–1.712)
|
0.007
|
0.385
|
0.75
|
1
|
0.0000
|
0.0
|
|
Nausea
|
3
|
1273
|
1.180 (1.021–1.364)
|
0.025
|
0.866
|
0.29
|
2
|
0.0000
|
0.0
|
|
Neutropenia
|
3
|
1273
|
0.615 (0.267–1.418)
|
0.254
|
0.075
|
5.19
|
2
|
0.3175
|
61.4
|
Publication bias
The funnel plot depicting the effect sizes against their corresponding error were
symmetrical and the statistical asymmetry tests including Egger's and Begg’s tests
showed no evidence of publication bias for studies investigating the effect of vitamin
D supplementation on serum PSA change from baseline (p-value for Egger’s test=0.441;
p-value for Begg’s test=0.296) and mortality rate (p-value for Egger’s test=0.201;
p-value for Begg’s test=0.296).
Meta-analysis of single arm clinical trials
The meta-analysis of 16 relevant trials with no control group [3]
[18]
[21]
[22]
[23]
[24]
[26]
[32]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[56] revealed a statically significant effect of vitamin D supplementation with or without
chemotherapy medication on the improvement of prostate cancer in terms of PSA response
proportion (the reduction in serum PSA levels) by 19% (Event rate=0.19, 95% CI: 0.07–0.30,
p=0.002) ([Fig. 3]). Heterogeneity was high across the selected studies (Cochrane Q test, Q statistic=153.51,
degrees of freedom=15, p<0.001, I2=90.2%%, τ2=0.0517). The subgroup analysis by co-therapies calcium restriction in the treatment
period and the type of vitamin D supplemented for study attendants is illustrated
in [Table 5]. dexamethasone (response proportion=0.48, 95% CI: 0.12–0.84, p=0.008) Moreover,
vitamin D supplements increased the PSA response proportion on a calcium-unrestricted
diet (response proportion=0.15, 95% CI: 0.0.64–0.285, p=0.001) [25]
[26]
[51]
[52]
[54]. In the subgroup meta-analysis categorized based on type of vitamin D, only calcitriol
treatment significantly affected PSA response (response proportion=0.23, 95% CI: 0.07–0.40,
p=0.004) [3]
[21]
[22]
[24]
[25]
[32]
[48]
[51]
[52]
[53]
[54].
Fig. 3 Forest plot describing the effect of vitamin D supplementation on PSA response proportion
in single arm trials. Analysis was conducted using random effects model.
Table 5 Subgroup analysis as well as overall analysis of the effects of vitamin D supplementation
on PSA response in single arm trials included in the meta–analysis.
|
Subgroup (Ref)
|
Number of studies
|
Number of participants
|
Meta-analysis
Event rate (95% CI)
|
Heterogeneity
|
p between group
|
|
p Effect
|
Q statistic
|
Degree of freedom
|
p within group
|
I2 (%)
|
Tau-squared
|
|
Chemotherapy drugs
|
|
None
|
5
|
123
|
0.040 (0.017–0.105)
|
0.223
|
0.55
|
4
|
0.969
|
0.00
|
0.000
|
<0.001
|
|
Docetaxel and Dexamethasone
|
3
|
72
|
0.484 (0.126–0.841)
|
0.008
|
29.71
|
2
|
0.00
|
93.3
|
0.092
|
|
|
Zoledronate
|
1
|
32
|
0.016 (0.001–0.118)
|
0.765
|
0.00
|
0
|
–
|
–
|
0.000
|
|
|
Dexamethasone and Carboplatin
|
2
|
58
|
0.220 (0.001–0.537)
|
0.173
|
8.15
|
1
|
0.004
|
87.7
|
0.045
|
|
|
Dexamethasone
|
2
|
61
|
0.114 0.001–0.270)
|
0.150
|
2.62
|
1
|
0.106
|
61.8
|
0.007
|
|
|
Mitoxantrone
|
1
|
19
|
0.263 (0.071–0.455)
|
0.007
|
0.00
|
0
|
–
|
–
|
0.000
|
|
|
Naproxen
|
1
|
21
|
0.026 (0.001–0.180)
|
0.738
|
0.00
|
0
|
–
|
–
|
0.000
|
|
|
Docetaxel and Zoledronate
|
1
|
30
|
0.478 (0.285–0.672)
|
0.000
|
0.00
|
0
|
–
|
–
|
0.000
|
|
|
Calcium restriction diet
|
|
Yes
|
5
|
140
|
0.172 (0.1–0.281)
|
0.116
|
101.17
|
4
|
0.00
|
96.0
|
0.1321
|
0.001
|
|
No
|
11
|
276
|
0.150 (0.064–0.235)
|
0.001
|
35.08
|
10
|
0.00
|
71.5
|
0.0144
|
|
|
Type of vitamin D treatment
|
|
Calcitriol
|
11
|
306
|
0.239 (0.078–0.401)
|
0.004
|
133.90
|
10
|
0.000
|
92.5
|
0.068
|
0.004
|
|
Alfacalcidol
|
1
|
26
|
0.024 (0.001–0.167)
|
0.744
|
0.00
|
0
|
–
|
–
|
0.000
|
|
|
Paricalcitol
|
1
|
18
|
0.026 (0.001–0.180)
|
0.738
|
0.00
|
0
|
–
|
–
|
0.000
|
|
|
DN-101 (high-dose calcitriol)
|
2
|
40
|
0.138 (0.094–0.369)
|
0.245
|
3.56
|
1
|
0.059
|
71.9
|
0.020
|
|
|
Ergocalciferol
|
1
|
26
|
0.080 (0.045–0.205)
|
0.209
|
0.00
|
0
|
–
|
–
|
0.000
|
|
|
Overall
|
16
|
416
|
0.190 (0.072–0.308)
|
0.002
|
153.51
|
15
|
0.000
|
90.2
|
0.0517
|
|
Discussion
In this study, we found no convincing evidence of benefit of vitamin D supplements
on serum PSA levels, PSA response proportion, or mortality. No effect on mortality
was seen in studies of either design. We found that vitamin D modestly improves the
PSA response proportion in single arm before-after studies, but not in randomized
controlled trials. Further, the effect in the single arm studies was lower when limited
to those trials, which administered vitamin D with calcium restriction prescription.
The protective effect vitamin D against developing prostate cancer was proposed by
Schwartz and Hulka for the first time when they found that the risk of prostate cancer
was elevated in the elderly with lower serum vitamin D levels [59]. Moreover, the inverse association between sun exposure as a main source of vitamin
D synthesis and risk of prostate cancer supported the hypothesis of protective effect
of vitamin D against the development of prostate cancer [60]
[61]
[62]. In contrast, A meta-analysis of 21 observational studies found an elevated risk
of prostate cancer in subjects with increased 25-hydroxyvitamin D levels and announced
that vitamin D supplementation should be administered with caution [63]. Furthermore, a recent meta-analysis of 19 prospective cohort or nested case–control
studies suggested per 10 ng/ml increment in circulating 25[OH]D concentration, the
risk of prostate cancer was approximately 4% elevated [64]. Moreover, recent meta-analyses found the association between some race-related
vitamin D receptors (VDR) polymorphisms (TaqI, FokI, Cdx2, ApaI, BsmI) and an increased
risk of prostate cancer [65]
[66]
[67]. It should be noted that the seasonal variation might also affect the association
found between the vitamin D and prostate cancer [68], since the sun exposure is the most important source regulator of serum vitamin
D [69].
Posadzki et al. [70] reviewed double-blind, placebo-controlled randomized clinical trials of non-herbal
dietary supplements and vitamins for evidence of reducing PSA levels in prostate cancer
patients. Only one double-blind, placebo-controlled trial [52] was identified, which concluded that dietary supplements including vitamin D are
not effective treatments for patients with prostate cancer. A narrative review by
Giammanco et al. [71] of vitamin D and cancer concluded that vitamin D and its analogues might be effective
in preventing the progression of some type of cancer including breast cancer and prostate
cancer but they also concluded that vitamin D therapy in patients with prostate cancer
had no beneficial effect. In the present systematic review, we have included before-after
studies and demonstrated that these studies might be misleading and their result are
different from parallel double blind studies. Furthermore, we included 6 randomized
clinical trials.
The present meta-analysis revealed that vitamin D supplementation not only is not
beneficial for patients with prostate cancer but although it was not statistically
significant, might increase the risk of overall mortality. A justifiable mechanism
is that vitamin D supplementation increase IGF-1 concentrations, consistent with the
hypothesis that IGF-1 may increase the risk of prostate cancer.
In a large clinical trial it was assumed that adding calcitriol to docetaxel might
improve antitumor activity [15]. Vitamin D might be beneficial by offsetting the gastrointestinal toxicity of docetaxel,
but this hypothesis needs conclusive evidence. Additional proposed mechanisms by which
vitamin D may reduce toxicity include: effects on cell proliferation, gene expression,
singling pathways, cell differentiation, apoptosis, autophagy, antioxidant defense
and DNA repair, prostaglandin synthesis and metabolism, angiogenesis and an improved
immune response [71]. The finding from microarray data analysis recently suggested that calcitriol via
upregulation expression of prostaglandin catabolizing enzyme 15-prostaglandin dehydrogenase
(PGDH) and down-regulation expression of the prostaglandin synthesizing enzyme cyclooxygenase-2
(COX-2) inhibits prostaglandin actions in prostate cancer cells growth [72]
[73]
[74]. But our results cannot prove these effects in prostatic cancer patients.
Our finding suggests that vitamin D supplements has beneficial effect on PSA response
proportion following diets without calcium restriction. Gao et al. by meta-analysis
of twelve 12 prospective studies concluded that dairy product and calcium intakes
were directly associated with the risk of prostate cancer [75]. A high calcium consumption lead to increased risk of prostate cancer by inhibiting
the bioactive metabolite of vitamin D [76]
[77].
There are a number of limitations that should be considered while interpreting the
results. One of the limitations is that the included studies did not report the baseline
and the after intervention vitamin D status of the participants. The effect of vitamin
D supplementation might be different in patients deficient in vitamin D. The other
noticeable issue in the present meta-analysis is that before-after studies are highly
misleading compared to randomized controlled clinical trials. For example, vitamin
D modestly increases the PSA response proportion in single arm studies, however, the
similar effect was not observed in randomized controlled trials. Also we should consider
that most of studies were single arm and the only 6 double blind randomized clinical
trials were included in our meta-analysis however these studies were powerful ones.
Conclusion
In this systematic review and meta-analysis, we found that vitamin D supplementation
does not benefit patients with prostate cancer. High dose vitamin D supplementation
for improving the disease state should not be recommended based on our results. The
possible beneficial effects of vitamin D supplementation in deficient subjects with
prostate cancer should be examined in the future investigations.
Authors’ Contribution
SSh, SSo, and ASA contributed in conception, search, screening, and data extraction
and revised the manuscript; ASA, SSh and SSo provided the first draft of the manuscript.
ASA also contributed in statistical analysis. RJD and MA contributed in the data interpretation
and critically revised the manuscript. All authors contributed to the study design
and drafting of the manuscript.
Funding
The study was funded by Nutrition and Food Security Research Center, Shahid Sadoughi
University of Medical Sciences, Yazd, Iran. There was no external funding support.
