131 


The North African Journal of Food and Nutrition Research: (2019) 03; (05): 131-139 
https://doi.org/10.5281/zenodo.2575438 

Review Article 


OPEN 



ACCESS 


PM? 

THE NORTH AFRICAN JOURNAL OF 
FOOD AND NUTRITION RESEARCH 


elSSN: 2588-1582 


Contents lists available at 
Journal homepage: https://www.najfnr.org 


Association between carotenoids and prostate cancer risk: A 

Meta-Analysis 

Hadjer BENKHADDA \ Manel BOUCHENTOUF \ Salah Eddine EL HERRAG 1 * 

1 Department of Biology, Faculty of Natural and Life Sciences, Djillali Liabes University, PO Box 89, Sidi-Bel-Abbes (22000), Algeria 


ARTICLE INFO 


ABSTRACT 


Article history: 

Received 11 November 2018 
Accepted 20 January 2019 
Available online 17 February 2019 

Keywords: 

Prostate cancer 
Carotenoids 
Lycopene, (3-Carotene 
a-Carotene, p-cryptoxanthin 
Lutein/zeaxanthin, 

Meta-analysis. 


Access this 

article online 

Quick Response Code: 

Website: 

www.naifnr.ora 


L@JL£J 



httos://doi.ora/10.5281/zenodo.2575438 


* Corresponding author Tel: +213 697813902 


Background: Carotenoids have been hypothesized to promote the prevention and 
treatment of prostate cancer (PC). Aims: Conducting a meta-analysis to assess whether 
the association differs by the type of carotenoids and to compare the relationships of 
each type of carotenoid with PC risk. Methods and Material: A literature search was 
conducted using the PubMed database. Pertinent studies were included in the meta¬ 
analysis of higher versus lower categories of dietary intakes or serum concentrations of 
carotenoids in relation to PC. A random-effects model was used to obtain the pooled 
odds ratios (ORs) and their confidence intervals (95%) of the case-control and cohort 
studies, for generic inverse variance data. Results: 13 identified studies involved 44,861 
participants. The meta-analysis determined, for total carotenoids and lycopene, a 
statistically significant relationship with PC risk; OR: 0.88; 95% Cl 0.81-0.96 and 0.87; 95% 
Cl 0.77-0.99 respectively. However, no other carotenoid was noticed to have a 
statistically significant association with PC risk. Comparison of the effect of each type of 
carotenoid on PC risk showed that lycopene, lutein-zeaxanthin, and p-cryptoxanthin had 
a moderate inverse but not statistically significant relationship with PC risk. Compared 
to p-carotene, and a-carotene results, their effect estimates were higher than the 
previous carotenoids. Conclusions: Our findings indicate that PC was inversely 
associated with total carotenoids and lycopene dietary intake and serum concentrations. 
These data provide support for the utilization of carotenoids for the treatment and 
prevention of PC. 

Article edited by Pr. Meghit Boumediene KHALED and Dr. Mickael RIALLAND 
^ salaheddine.elherraq@univ-sba.dz 


1. INTRODUCTION 


Prostate cancer (PC) or carcinoma of the prostate is 
ranked as the second most common cancer within men 
worldwide [1]. An estimated number of 1.3 million cases 
were diagnosed worldwide with PC in 2018, accounting for 
13.5 % of the cancers diagnosed in men, with almost 63 % 
of them (802.294) occurring in more developed regions [2]. 
The development of PC is complex and influenced by a 
combination of genetic, hormonal, and social factors. 
Carotenoids represent biologically active phytochemicals 
which are present as micro-components in fruits and 


vegetables and are responsible for their yellow, orange and 
red colors [3]. These micronutrients are thought to be 
responsible for the beneficial properties of fruits and 
vegetables in preventing human diseases including 
cardiovascular diseases [4], cancer [ 5-71 , and other chronic 
diseases, and have distinct anti-oxidative properties, 
including protecting DNA and other important 
biomolecules from free radicals [8]. In recent years the 
antioxidant properties of carotenoids have been the major 
focus of research. More than 600 carotenoids have so far 


This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work 
is properly cited. © 2017 The Authors. The North African Journal of Food and Nutrition Research. 


Nor. Afr. J. Food Nutr. Res. I January - June 2019 Volume 03 Issue 05 


























Benkhadda et al.: Carotenoids and prostate cancer 


132 


been identified in nature. However, only about 40 are 
present in a typical human diet. Among these 40, about 20 
carotenoids have been identified in human blood and 
tissues. Close to 90% of the carotenoids, in the diet and the 
human body, is represented by alpha-carotene, beta- 
carotene, lutein, beta-cryptoxanthin, and lycopene [9]. 
Higher consumption of tomato products, dietary lycopene 
intake, and circulating lycopene concentrations were found 
to be inversely associated with prostate cancer risk [ 10,111 . 
Many epidemiological studies have investigated the 
association between prostate cancer and carotenoids, 
however, results have been inconsistent [ 12,131 . 
Consequently, In the current study, we aimed to investigate 
the relationship between dietary intake or blood 
concentrations of these carotenoids and their potential 
preventive effect on PC. 

2. MATERIAL AND METHODS 


2.1 Search strategy 

The current meta-analysis was performed in accordance 
with PRISMA guidelines [14]. The literature search was 
independently undertaken by two authors (H.B and M.B). 
The author (S.E) made the final decision in case of any 
discrepancy. A comprehensive literature search was 
conducted using the PubMed database 
[https://www.ncbi.nlm.nih.gov/pubmed1 to identify 
relevant English published articles on the relationship 
between carotenoids dietary intake or supplementation 
and the risk of PC. Using medical subject heading (Mesh), 
with the key terms: "carotenoids" and "prostatic 
neoplasms". English full texts were searched with no 
population restriction (the final search was performed on 
13 May 2018). 

2.2 Study selection 

Studies that met the following criteria were included in the 
meta-analysis: (a) the study design was a cohort, and case- 
control ; (b) the primary outcome was clearly defined as 
prostate cancer; (c) studies that assessed the relationship 
between carotenoids (lycopene, p-carotene, a-carotene, p- 
cryptoxanthin, and lutein/zeaxanthin) and PC risk ; (d) the 
exposure of interest was carotenoids intake and 
supplementation ; (e) the study provided Odds Ratios (OR) 
with 95% confidence intervals (Cl) for exposure categories. 
Furthermore, letters, comments, and articles, not published 
as full text, reviews, meta-analyses, animal studies, cellular 
culture, reports, and articles with missing or not 
appropriate data, were excluded. 

2.3 Data extraction 

Data collection form, for each publication, was as follow: 
first author's name, year of publication, country of origin, 


outcomes, recruitment and intervention periods, study 
type, number of cases, controls, total number, and age of 
participants in the study, exposure values of carotenoids 
(serum and/or intake), and the adjusted confounders. 

2.4 Summary measures 

Review Manager 5.3 was utilized to analyze the data [ 151 . 
The pooled OR with 95% Cl is given both for the fixed 
effects model and the random effects model. If value 1 is 
not within the 95% Cl, then the OR is statistically significant 
at the 5% level (P < 0.05) [16]. We used the study-specific 
OR for the highest versus lowest categories of dietary 
carotenoids intake or carotenoids concentration exposure 
for the meta-analysis. The study selection, data extraction, 
and statistical analysis were independently undertaken by 
two authors (H.B and M.B), a third author (S.E) made the 
final decision in case of any disagreement. 

2.5 Publication bias 

Publication bias and the small study effect were assessed 
using Begg's [17] rank correlation test and Egger's 
regression test [18], following a visual assessment of funnel 
plots. The R program was used for assessing the bias risk 
across studies [ 191 . 

2.6 Sensitivity and subgroup analyses 

Pre-Specified subgroup analyses were performed allowing 
for study types, location, methods used, and the adjusted 
confounders. Furthermore, sensitivity analyses were 
performed by excluding one dataset at a time with the 
purpose of analyzing the influence of each study on the 
effect estimates and the heterogeneity. 

3 RESULTS 


3.1 Study selection 

The literature search yielded a total of 754 publications. 
After screening, 13 studies were included and 741 were 
excluded, among the 741 excluded articles, 470 did not 
meet the criteria, 194 reviews, and meta-analysis, and 34 
letters to editorial and comments, and 43 not appropriate 
or missing data (Figure 1). 

3.2 Study characteristics 

Table 1 summarizes properties of the included studies. Two 
cohort and 11 case-control studies were included. Seven 
studies were carried out in the USA [ 12, 13, 20-241 , three in 
Australia [25-271 , two in Europe [28, 291 , and one in 
Asia [30]. Among the included studies, eleven studies 
reported the effects of dietary intake or serum 
concentrations of lycopene and p-Carotene on PC. With 
the exception of five studies, almost all adjusted analyses 


A lor. Afr. J. Food Nutr. Res. January - June 2019 Volume 03 Issue 05 









Benkhadda et al.: Carotenoids and prostate cancer 


133 


included age as a potential confounder and four studies 
controlled for family history of PC and body mass index 
(BMI). 



Figure 1: Flowchart of study selection 


3.3 Relationship between carotenoids and risk of PC 

The results of the meta-analysis, of highest versus lowest 
categories of carotenoids intake and serum concentrations, 
are summarized in table 2 and figure 2. A total of 44.861 
participants from these studies were assigned to 
intervention or control groups. The number of participants 
in each case-control and cohort ranged from 321 to 29.361. 
The effects of lycopene and (3-carotene were examined 
singly or in combination in six studies and in combination 
with other carotenoids in seven studies. 

The summary effect of the main analysis on PC was 
statistically significant with an OR of 0.88 (95% Cl 0.81-0.96), 
with moderate heterogeneity (I 2 = 56%). Thus, we conclude 
that carotenoids intake decreased the overall relative risk 
of PC. 

Nonetheless, we observed, after performing a sensitivity 
analysis, that one study (Jian et al, 2004) [30] constituted 
the major source of heterogeneity in our meta-analysis and 
after neglecting this study, I 2 dropped to only 2%. 

3.3.1 Lycopene 

A total of 11 studies with 15 datasets, on the relationship 
between lycopene and prostate cancer, were included. Our 
results showed that lycopene significantly reduced the 
prostate cancer risk (OR = 0.88; 95% Cl 0.78-1.00), with 
moderate heterogeneity (I 2 = 44 %). 


According to further subgroup analysis, as shown in Table 
3, we did not identify significant associations between PC 
risk and lycopene for cohort studies (P = 0.56). However, 
case-control studies indicated that lycopene significantly 
decreased PC risk (OR = 0.87; 95% Cl 0.77-0.99). Moreover, 
studies conducted in Australia and North American 
countries showed a stronger inverse relationship than 
European studies (OR = 0.76; 95% Cl 0.53-1.09), (OR = 0.90; 
95% Cl 0.83-0.99, P (Z-test) = 0.03), and (OR = 0.94; 95% 
Cl 0.75-1.16) respectively. Five studies with seven datasets 
reported data about dietary lycopene supplementation 
and PC risk. A statistically significant negative association 
was observed (OR = 0.83; 95% Cl 0.70-0.99). A less strong 
and yet statistically non-significant inverse relationship was 
found between serum lycopene concentrations and PC (OR 
= 0.96; 95% Cl 0.81-1.15). 

3.3.2 a-Carotene 

Regarding the overall pooled estimates of the association 
between a-carotene and PC risk, we noticed a statistically 
non-significant negative association with an OR of 0.80 
(95% Cl 0.60-1.07) and a moderate heterogeneity (I 2 = 59 
%). Alpha carotene was found to decrease PC risk in case- 
control studies and in studies conducted in North American 
countries (OR = 0.86; 95% Cl 0.64-1.15) and (OR = 0.87; 
95% Cl 0.59-1.29) respectively, although the associations 
were not statistically significant. The same pattern was 
noticed for studies investigating the effect of highest versus 
lowest categories of a-carotene intake (OR = 0.87; 95% Cl 
0.59-1.29) and serum concentrations (OR = 0.65; 95% Cl 
0.33-1.27). 

3.3.3 |3-Carotene 

A total of 11 studies, including 15 datasets, reported data on 
p-carotene and PC risk. Comparing the highest with the 
lowest dietary intake or blood concentrations, a statistically 
non-significant inverse association was found with an OR 
of 0.95 (95% Cl 0.78-1.11) and moderate heterogeneity 
(l 2 =54%). The main analysis was stratified according to 
study type, population, and methods used to assess the 
relationship. Therefore, nine studies with 13 datasets of 
case-control studies were pooled (OR = 0.95; 95% Cl 0.78- 
1.16), and two cohort studies (OR = 0.79; 95% Cl 0.46-1.35), 
suggesting a statistically non-significant negative 
association between p-carotene and PC risk. Our findings 
suggest that p-carotene has no effect on PC risk among 
North American (OR = 1.02; 95% Cl 0.83-1.26), and 
Australian populations (OR = 1.00; 95% Cl 0.76-1.31) and 
studies examining the effect of highest versus lowest 
categories of serum concentrations of p-carotene on PC 
(OR = 1.01; 95% Cl 0.84-1.23). 


Nor. Afr. J. Food Nutr. Res. January - June 2019 Volume 03 Issue 05 














Table 1: Characteristics of included studies 


Benkhadda et al.: Carotenoids and prostate cancer 


134 


I 


e * 
-ora 

E ■£ 

CD 

O 

.> eg 


-a & 

CD to 
O 

a3 Q- 

c "o 
cd 

u >> 

>, o 


§ 


O 3 

_Q "a 


c ° 

o ^ 


< E 


V Q- 
=o- b 




eg to . ~ 

, ^ ro 

03 ^ N 


3 ^ ^ 

to O O 
O ~Q "O 
Q- C C 
X eg eg 


C eg 

§ I 

eg 

u u & 

- GO. —I 


CD. 

cd' 

c CD 
CD C 
CL CD 

S o 

b eg 
U 




O 

o 

(3 


O — 
^ o 

OJ eg 
-Q u 

If 

to .g 
£ "o 


TO CD 


£ E Js 


a —i 

CD' C 


y eg 

S o 
“i: 

CD u 
CD CO. 

8 c 

^3 


3 


1 


b 

O 


■g 

'o 


£ Q 






° o 
u y 
>p eg 
- 1 U 


1 




c 


CD 


E 


c 


_gi 


'to 


to 


eg 


_c 




•q_ 


to 


eg 


TD 


CD 


N 


'E 


o 


"O 


c 


eg 




"O 


c 


eg 


CD' 


CD 


eg 


dS 


c 


Iv 


O 

< 

E 


on 

z 

CD 

CD 

c 

CD 

c 


CD 

o 

Q_ 

eg 

u 

O 

u 

X 


_1 

CCL 


E 

b 

3 

cd 

eg 

O) 

on 

Q 

'st 

o 

cm 

CM 

\ 

to 

no 

or 

CM 

or 

no 

CO 

no 

no 



00 


CO 

O 

cr> 

O 


CM 

CM 

no 

00 

or 

cr> 

CTT 



< 

< 

on 

oo 

3 

3 

CD 

CD 

_c 

_C 

1— 

1— 


M 

[ill 

or 

[ill 

to 

C7T 

O 

or 

O 


CM 

'c$ 

'c$ 

Qj 

qj 

O 

_£= 

to 

o 


u 

\2 


b 

O 


c ^ ; 
o - 


to CD 
O CD 


E E 


it! -a =3 | 


to ro 

O 1 


CO. 

CD £ 


Nor. Afr. J. Food Nutr. Res. January - June 2019 Volume 03 Issue 05 


Nordstrom eta/. 2016 [28] The USA 2000-2007 112/559 Serum p-carotene, Lycopene, a- N /A 

carotene 





















Benkhadda et al.: Carotenoids and prostate cancer 


135 


Table 2: Summary of results 






Heterogeneity 


Publication bias 
(P value) 





/ 2 (%) Tau 2 

Chi 2 


Begg’s Egger’s 

test test 

Lycopene 

11 (15) [22-24, 26-29, 31-341 RE 0.88 [0.78-1.00] 1 g 7 

70 0.12 

19.74, df=6 
(. P= 0.003) 


0.9605 0.678 

(3-Carotene 

11 (151 [22-26. 28-32. 341 RE 

0.93 [0.78-1.11] {p ° = 7 q 8 A3) 

54 0.06 

30.12, df=14 
(P= 0.007) 

0.216 0.522 

Lutein/Zeaxanthin 

6 (91 [22-24. 26. 32. 341 RE 

0.86 [0.64-1.15] ( ;f a31) 

72 0.13 

28.26, df=8 
{P= 0.0004) 

NA 

(3-cry ptoxanthin 

6 (71 [22-24, 26.32. 341 RE 0.80 [0.58-1.091 . ] A2 ,.. 

(, P- 0.16) 

70 0.12 

19.74, df=6 
(P= 0.003) 


NA 

a-Carotene 

6 (61 [23. 24. 26. 28. 32. 341 RE 0.80 [0.60-1.071 . 1-47 |4 

59 0.07 

12.16, df=5 
(P= 0.03) 


NA 

NA not applicable. 

OR odds ratio. 

RE random effects. 







Table 3: Subgroup analysis results of the association between Lycopene and prostate cancer 





N2 of 






Heterogeneity 

Subgroups 

(No of 
datasets) 

References 

Model OR [95% Cl] 

Z- test 

I 2 

(%) 

T 2 

X 2 

All studies 

11 (15) 

[22-24, 26-29, 
31-34] 

RE 

0.88 [0.78-1.00] 

1.97 

(P= 0.05) 

44 

0.02 

24.93, df = 14 
(P = 0.04) 

Study type 

Cohort 

1(1) 

[28] 

RE 

1.22 [0.62-2.40] 

0.58 

(P= 0.56) 



N/A 

Case-control 

12 (14) 

[22-24. 26. 27. 

29. 31-341 

RE 

0.87 [0.77-0.99] 

2.08 

(P= 0.04) 

46 

0.02 

24.06, df = 13 
(P= 0.03) 

Study location 

Asia 

KD 

[34] 

RE 

0.18 [0.08-0.40] 

4.08 

(P< 0.0001) 



N/A 

Europe 

2(2) 

[32^33] 

FE 

0.94 [0.75-1.16] 

0.59 

{P= 0.56) 

0 

N/A 

0.00, df = 1 
(P= 0.96) 

North America 

6(10) 

[22-24, 26- 
28] 

FE 

0.90 [0.83-0.99] 

2.22 

(P= 0.03) 

5 

N/A 

9.43, df = 9 
(P= 0.40) 

Australia 

2(2) 

[29, 31] 

FE 

0.76 [0.53-1.09] 

1.47 

{P= 0.14) 

0 

N/A 

0.00, df = 1 
(P= 0.98) 

Methods 

Serum 

6(8) 

[22-24. 26. 28. 

29] 

FE 

0.96 [0.81-1.15] 

0.41 

(P= 0.68) 

0 

N/A 

6.31, df = 7 
(P= 0.50) 

Dietary 

5(7) 

[27, 31-34] 

RE 

0.83 [0.70-0.99] 

2.05 

(P= 0.04) 

66 

0.03 

17.49, df = 6 
(P= 0.008) 

Adjusted confounders 

Age 

8(12) 

[22-24. 27. 29. 

31. 32. 341 

RE 

0.88 [0.76-1.01] 

1.77 {P= 0.08) 

52 

0.03 

22.85, df = 11 
(P = 0.02) 

Family history of 

PC 4 ^ 

[22. 26. 32. 

34] 

RE 

0.70 [0.44-1.13] 

1.45 (P= 0.15) 

76 

0.20 

16.96, df = 4 
(P= 0.005) 

BMI 

4(5) 

[22. 26. 32. 

34] 

RE 

0.70 [0.44-1.13] 

1.45 

(P= 0.15) 

76 

0.20 

16.96, df = 4 
(P= 0.005) 

Education 

3(4) 

[22. 32. 341 

RE 

0.71 [0.39-1.30] 

1.10 

(P= 0.27) 

82 

0.28 

16.37, df = 3 
(P= 0.0010) 

Study Center 

3(3) 

[23. 24. 321 

FE 

1.01 [0.85-1.21] 

0.16 

(P= 0.87) 

0 

N/A 

0.82, df = 2 
(P= 0.67) 

Smoking 

2(2) 

[23, 26] 

FE 

0.83 [0.57,1.21] 

0.96 

(P= 0.34) 

28 

N/A 

1.38, df = 1 
(P= 0.24) 

Height 

2(2) 

[26, 31] 

FE 

0.72 [0.51,1.01] 

1.91 

(P= 0.06) 

0 

N/A 

0.17, df = 1 
(P= 0.68) 

Caloric intake 

2(2) 

[3^34] 

RE 

0.43 [0.09, 2.17] 

1.02 

(P= 0.31) 

93 

1.27 

13.99, df = 1 
(P= 0.0002) 


BMI Body mass index, df degree of freedom, FE fixed effects, N/A not-applicable, PC prostate cancer, OR odds ratio, RE random effects. 


A lor. Afr. J. Food Nutr. Res. January - June 2019 Volume 03 Issue 05 
























































Benkhadda et al.: Carotenoids and prostate cancer 


136 


Study or Subgroup 

log[Odds Ratio] 

SE 

Weight IV, Random, 95% Cl 

1.1.1 c-carotene 

Bosetti 2004 

-0.1574 

0.1347 

3.0% 

0.85 [0.66, 1.11] 

Goodman 2003 

0.1655 

0.2812 

1.6% 

1.18 [0.68, 2.05] 

Jian 2004 

-0.8555 

0.3564 

1.2% 

0.43 [0.21,0.85] 

Nordstrom 201 6 

-0.6633 

0.3315 

1.3% 

0.52 [0.27, 0.99] 

Peters 2007 

0.1655 

0.1674 

2.6% 

1.18 [0.85, 1.64] 

Wu 2004 

-0.4075 

0.2539 

1.8% 

0.67 [0.40, 1.09] 

Subtotal (95% Cl) 



11.4% 

0.80 [0.60, 1.07] 

Heterogeneity: Tau 3 = 

0.07; Chi 3 = 12.16, 

df = 5 (P 

= 0.03); l 3 = 

59% 

Test for overall effect: Z = 1.47 (P= 0.14) 




1.1.2 P-carotene 

Ambrosini 2007 

-0.0101 

0.2254 

2.0% 

0.99 [0.64, 1.54] 

Beilby 2010 

-0.181 

0.315 

1.4% 

0.83 [0.45, 1.55] 

Bosetti 2004 

-0.3285 

0.1374 

3.0% 

0.72 [0.55, 0.94] 

Cook 1999 

0.2869 

0.1972 

2.3% 

1.33 [0.91,1.96] 

Cook 1999 

0.2851 

0.2957 

1.5% 

1.33 [0.74, 2.37] 

Cook 1999 

-0.0015 

0.2906 

1.5% 

1.00 [0.56, 1.76] 

Gill 2009 

-0.2107 

0.1933 

2.3% 

0.81 [0.55, 1.18] 

Gill 2009 

-0.3589 

0.4067 

0.9% 

0.70 [0.31,1.55] 

Goodman 2003 

-0.1624 

0.2863 

1.5% 

0.85 [0.49, 1.49] 

Jian 2004 

-1.0788 

0.3611 

1.1% 

0.34 [0.1 7. 0.69] 

Nordstrom 201 6 

-0.5754 

0.329 

1.3% 

0.56 [0.30, 1.07] 

Norrish 2000 

0.0862 

0.2084 

2.2% 

1.09 [0.72, 1.64] 

Peters 2007 

0.2624 

0.1717 

2.6% 

1.30 [0.93, 1.82] 

Peters 2007 

0.5128 

0.2489 

1.8% 

1.67 [1.03, 2.72] 

Wu 2004 

-0.2485 

0.2426 

1.9% 

0.78 [0.48, 1.25] 

Subtotal (95% Cl) 



27.4% 

0.93 [0.78, 1.11] 

Heterogeneity: Tau 3 = 

0.06; Chi 3 = 30.12, 

df = 1 4 (P = 0.007); I s 

’= 54% 


Odds Ratio 
IV, Random, 95% Cl 


1.1.3 P-cryptoxanthin 


Bosetti 2004 

-0.1059 

0.1319 

3.0% 

0.90 

[0.69, 

1.16] 

Gill 2009 

-0.0305 

0.198 

2.3% 

0.97 

[0.66, 

1.43] 

Gill 2009 

-0.1393 

0.4196 

0.9% 

0.87 

[0.38. 

1.98] 

Goodman 2003 

-0.2107 

0.29 

1.5% 

0.81 

[0.46, 

1.43] 

Jian 2004 

-1.9065 

0.4223 

0.9% 

0.15 

[0.06, 

0.34] 

Peters 2007 

0.0862 

0.1697 

2.6% 

1.09 

[0.78, 

1.52] 

Wu 2004 

-0.0619 

0.265 

1.7% 

0.94 

[0.56, 

1.58] 

Subtotal (95% Cl) 



12.9% 

0.80 [0.58, 

1.09] 

Heterogeneity: Tau 3 = 0.12; Chi 3 = 19.74, 

df= 6 (P 

= 0.003); I 3 : 

= 70% 


Test for overall effect: Z = 

1.42 (P= 0.16) 






1.1.4 Lutein/zeaxaiithin 

Bosetti 2004 

-0.0943 

0.1411 

2.9% 

0.91 

[0.69, 

1.20] 

Gill 2009 

0.0773 

0.2035 

2.2% 

1.08 

[0.73, 

1.61] 

Gill 2009 

0.708 

0.4353 

0.9% 

2.03 

[0.86, 

4.76] 

Goodman 2003 

-0.1512 

0.2923 

1.5% 

0.86 

[0.48, 

1.52] 

Goodman 2003 

-0.2485 

0.3021 

1.4% 

0.78 

[0.43, 

1.41] 

Jian 2004 

-3.7987 

0.7633 

0.3% 

0.02 

[0.01, 

0.10] 

Peters 2007 

-0.0834 

0.1657 

2.6% 

0.92 

[0.66, 

1.27] 

Peters 2007 

-0.0202 

0.1709 

2.6% 

0.98 

[0.70, 

1.37] 

Wu 2004 

-0.1863 

0.2667 

1.7% 

0.83 

[0.49, 

1.40] 

Subtotal (95% Cl) 



16.2% 

0.86 [0.64, 

1.15] 

Heterogeneity: Tau 3 = 0.13; Chi 3 = 28.26, 

df= 8 (P 

= 0.0004); l : 

’= 72% 


Test for overall effect: Z = 

1.01 (P= 0.31) 






1.1.5 Lycopene 

Beilby 2010 

-0.2614 

0.3299 

1.3% 

0.77 

[0.40, 

1.47] 

Bosetti 2004 

-0.0619 

0.1372 

3.0% 

0.94 

[0.72, 

1.23] 

Gill 2009 

-0.2182 

0.1958 

2.3% 

0.80 

[0.55, 

1.18] 

Gill 2009 

0.6206 

0.5352 

0.6% 

1.86 

[0.65, 

5.31] 

Goodman 2003 

0.0392 

0.2713 

1.7% 

1.04 

[0.61, 

1.77] 

Jian 2004 

-1.7148 

0.42 

0.9% 

0.18 

[0.08, 

0.41] 

Key 1997 

-0.0726 

0.1901 

2.4% 

0.93 

[0.64, 

1.35] 

Kirsh 2006 

-0.1267 

0.0747 

3.7% 

0.88 

[0.76, 

1.02] 

Kirsh 2006 

0.001 

0.1092 

3.3% 

1.00 

[0.81, 

1.24] 

Kirsh 2006 

-0.2357 

0.0994 

3.4% 

0.79 

[0.65, 

0.96] 

Nordstrom 2016 

0.2007 

0.3444 

1.2% 

1.22 

[0.62, 

2.40] 

Norrish 2000 

-0.2718 

0.2192 

2.1% 

0.76 

[0.50, 

1.17] 

Peters 2007 

0.131 

0.1665 

2.6% 

1.14 

[0.82, 

1.58] 

Peters 2007 

-0.0101 

0.2353 

1.9% 

0.99 

[0.62, 

1.57] 

Wu 2004 

-0.4155 

0.2753 

1.6% 

0.66 

[0.38, 

1.13] 

Subtotal (95% Cl) 



32.0% 

0.88 

[0.78, 

1.00] 


Heterogeneity: Tau 3 = 0.02; 
Test for overall effect: Z= 1 


Chi 3 = 24.93, df= 14 (P= 0.04); l== 44% 
97 (P= 0.05) 


Total (95% Cl) 100.0% 0.88 [0.81, 0.96] 

Heterogeneity: Tau 3 = 0.05; Chi 3 = 116.21, df= 51 (P < 0.00001); l 3 = 56% 

Test for overall effect: Z = 2.83 (P = 0.005) 

Test for subgroup differences: Chi 3 = 1.16. df= 4 (P = 0.88), l a = 0% _ 


0.05 0.2 

Favours [experimental] Favours [control] 


Figure 2: Forest plot for the association between Carotenoids and PC risk 


3.3.4 Lutein/Zeaxanthin 

Aiming to investigate the relationship between 
lutein/zeaxanthin and PC risk, the summary of ORs of six 
case-control studies with nine datasets was estimated. We 
observed a statistically non-significant decrease in PC risk 


with an OR of 0.86 (95% Cl 0.64-1.15) with high 
heterogeneity (I 2 = 72%). A slight decrease and yet 
statistically not-significant was noticed within North 
American populations and for studies using serum 
concentrations of lutein/zeaxanthin to investigate the 
association (OR = 0.96; 95% Cl 0.81-1.14). 


A lor. Afr. J. Food Nutr. Res. January - June 2019 Volume 03 Issue 05 





































Benkhadda et al.: Carotenoids and prostate cancer 


137 


3.3.5 (3-cryptoxanthin 

In a pooled analysis of six case-control studies reporting 
data about the effect of (3-cryptoxanthin on PC risk, an OR 
of 0.80 (95% Cl 0.58-1.09, I 2 = 70%) was found, indicating a 
statistically non-significant inverse association. A slight 
decrease and yet statistically not-significant was noticed 
within North American populations and for studies using 
serum concentrations of p-cryptoxanthin to investigate the 
association (OR = 0.98; 95% Cl 0.80-1.20). 

3.4 Publication bias 

The funnel plots put in the Supplementary figures show no 
sign of asymmetry. Among the five meta-analyses, the risk 
of bias assessment was available for two analyses since they 
included a number of datasets > 10. Both analyses showed 
no evidence of small study effect. The analysis of lycopene 
and PC (Begg's test P = 0.9605, Egger's test P = 0.678) and 
the analysis of p-Carotene and PC (Begg's test P = 0.216, 
Egger's test P = 0.522). 

4 DISCUSSION 


The current meta-analysis, which included 13 studies, 
provided evidence that carotenoids could prevent against 
PC. To sum up, the overall analysis demonstrated a 
significant decrease in PC incidence. The same pattern was 
noticed for all types of carotenoids investigated in our 
study i.e. lycopene p-carotene, a-carotene, (3- 
cryptoxanthin, and lutein/zeaxanthin. 

In vitro and animal, studies have provided evidence that 
carotenoids may protect against several types of cancer 
[31 - 341 . Additionally, the World Cancer Research Fund 
(WCRF) released a comprehensive report on food and 
cancer prevention in 2007 highlighting that foods 
containing carotenoids are probably protective against 
lung, mouth, pharynx, and larynx cancers [ 351 . 

Stahl and Sies [36] stated that carotenoids and/or their 
metabolites influence the expression of certain genes or 
may act as regulatory enzymes inhibitors in context with 
cancer preventive properties of these compounds. 

The mechanism underlying the beneficial effect of 
lycopene on PC risk can be explained by this carotenoid 
high biological activity through antioxidant properties as 
preventing DNA damage by scavenging free radicals [8] 
and modulating gene expression related to PC growth [ 371 . 
Furthermore, Yang et al, [38] showed that this non¬ 
provitamin A carotenoid inhibits PC cell proliferation via the 
PPARy-LXRa - ABCA1 pathway. According to Stahl and Sies 
[361 and Gerster [39], lycopene was found to hamper the 
progression of PC via apoptosis induction and 
angiogenesis suppression. 


The current analysis provides support for future studies 
using carotenoid-based dietary or supplementation 
interventions and plays a key role in PC survivorship 
including treatment. 

Concerning the risk of PC, our results agree with some 
previous studies. Wang et al [40], reported in a meta¬ 
analysis of 34 studies, that lycopene (RR = 0.88; 95% Cl 
0.76-1.02), but not (3-carotene (RR = 0.90; 95% Cl 0.81-1.01), 
were inversely associated with the risk of PC. 

Nonetheless, both Chen et al (2015) [41], llic et al [42] 
found a positive association between lycopene 
consumption (RR = 0.91; 95% Cl 0.81-1.01) and (OR = - 0.34; 
95% Cl - 2.01-1.32) respectively with the risk of PC. 
Controversially to our analysis, Wang et al [40] stated that 
a-carotene (RR = 0.87; 95% Cl 0.76-0.99) was positively 
associated with the risk of developing PC. 

However, similar to dietary carotene intake, Van Hoang et 
al [43] observed in a case-control study no relationship 
between (3-cryptoxanthin intake as well as lutein and 
zeaxanthin with adjusted ORs of 1.29 (95% Cl 0.79-2.09) 
and 0.73 (95% Cl 0.44-1.20) respectively with PC risk. 

The type of studies (cohort and case-control), populations 
(Asia, Europe, Australia, and the USA) slightly influenced 
the odds estimate. However, sensitivity analysis further 
showed that when omitting the studies conducted by (Jian 
et al, 2004) [30], the results noticeably changed. 

To the best of our knowledge, this is the first meta-analysis 
undertaken to highlight the relationship between 
carotenoids and PC risk. However, some limitations should 
be considered as the limited number of articles included in 
our analysis. Moreover, our analyses showed heterogeneity 
evidence. However, subgroup analysis demonstrated 
sources of heterogeneity that could be attributable to 
including different study designs in the analyses. 

5 CONCLUSION 


The current meta-analysis has been undertaken to assess 
available evidence for treatment and prevention of PC, to 
show the contribution of carotenoids, their intake or 
supplementation, and to perform a comparison between 
their relationships with PC risk. 

Our results showed that all types of carotenoids 
investigated in our study may contribute to the prevention 
of PC. To determine whether they are clinically relevant, 
more laboratory and clinical trials are needed on the effects 
of these compounds on the behavior of prostate cancer 
cells and tissues. Moreover, the lack of evidence and data 
supports the call for publishing more research in this area 
to investigate the effectiveness of carotenoids for the 
prevention and treatment of PC. 


Nor. Afr. J. Food Nutr. Res. January - June 2019 Volume 03 Issue 05 





Benkhadda et al.: Carotenoids and prostate cancer 


138 


6 REFERENCES 


1. 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(6). 
doi:10.3322/caac.21492 

2. Ferlay J, Colombet M, Soerjomataram I, Mathers C, 
Parkin DM, Pineros M, Znaor A, Bray F. Estimating the 
global cancer incidence and mortality in 2018: 
GLOBOCAN sources and methods. Int. J. Cancer. 
2018;0(0). doi:10.1002/iic.31937 

3. O'Neill ME, Carroll Y, Corridan B, Olmedilla B, Granado 
F, Blanco I, Van den Berg H, Hininger I, Rousell AM, 
Chopra M, Southon S, Thurnham Dl. A European 
carotenoid database to assess carotenoid intakes and 
its use in a five-country comparative study. Br. J. Nutr. 
2001;85(4):499-507. doi:10.1079/BJN2000284 

4. Gaziano JM, Manson JE, Branch LG, Colditz GA, Willett 

WC, Buring JE. A prospective study of consumption of 
carotenoids in fruits and vegetables and decreased 
cardiovascular mortality in the elderly. Annals of 
Epidemiology. 1995;5(4):255-60. doi:10.1016/1047- 

2797(94)00090-G 

5. Block G, Patterson B, Subar A. Fruit, vegetables, and 
cancer prevention: A review of the epidemiological 
evidence. Nutr. Cancer. 1992;18(1):1-29. 
doi:10.1080/01635589209514201 

6. Ziegler RG. A Review of Epidemiologic Evidence that 
Carotenoids Reduce the Risk of Cancer. J. Nutr. 
1989;119(1):116-22. doi:10.1093/in/119.1.116 

7. Hennekens CH. Micronutrients and Cancer Prevention. 
N. Engl J. Med. 1986;315(20):1288-89. 
doi:10.1056/N EJ M198611133152009 

8. Krinsky Nl. The Antioxidant and Biological Properties 
of the Carotenoids. Ann. N. Y. Acad. Sci. 
1998;854(1):443-7. doi:10.1111/i.1749-6632.1998.tb09923.x 

9. Bolhassani A. Cancer Chemoprevention by Natural 
Carotenoids as an Efficient Strategy. Anticancer 
Agents Med. Chem. 2015;15(8):1026-31. 
doi:10.2174/1871520615666150302125707 

10. Giovannucci E. A Review of Epidemiologic Studies of 

Tomatoes, Lycopene, and Prostate Cancer. Exp. Bioi 
Med. (Maywood). 2002;227(10):852-59. 

doi:10.1177/153537020222701003 

11. Tan H-L, Thomas-Ahner JM, Grainger EM, Wan L, 
Francis DM, Schwartz SJ, Erdman JW Jr, Clinton SK. 
Tomato-based food products for prostate cancer 
prevention: what have we learned? Cancer Metastasis 
Rev. 2010;29(3):553-68. doi:10.1007/s10555-010-9246-z 

12. Peters U, Leitzmann MF, Chatterjee N, Wang Y, 
Albanes D, Gelmann EP, Friesen MD, Riboli E, Hayes 
RB. Serum Lycopene, Other Carotenoids, and Prostate 


Cancer Risk: A Nested Case-Control Study in the 
Prostate, Lung, Colorectal, and Ovarian Cancer 
Screening Trial. Cancer Epidemiol Biomarkers Prev. 
2007;16(5):962-68. doi: 10.1158/1055-9965.EPI-06-0861 

13. Wu K, Erdman JW, Schwartz SJ, Platz EA, Leitzmann M, 
Clinton SK, DeGroff V, Willett WC, Giovannucci E. 
Plasma and Dietary Carotenoids, and the Risk of 
Prostate Cancer. Cancer Epidemiol Biomarkers Prev. 
2004;13(2):260-69. doi:10.1158/1055-9965.EPI-03-0012 

14. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA 

Group. Preferred Reporting Items for Systematic 
Reviews and Meta-Analyses: The PRISMA Statement. 
PLOS Med. 2009;6(7): e1000097. doi: 

10.1371/iournal.pmed.1000097 

15. Review Manager (RevMan). Version 5.3. Copenhagen: 
The Nordic Cochrane Centre, The Cochrane 
Collaboration] 2014. 

16. Higgins J, Green S, eds. Cochrane Handbook for 
Systematic Reviews of Interventions Version 5.1.0 
[Updated March 2011]. The Cochrane Collaboration] 
2011. www.cochrane-handbook.org . 

17. Begg CB, Mazumdar M. Operating Characteristics of a 
Rank Correlation Test for Publication Bias. Biometrics. 
1994;50(4):1088-1101. doi:10.2307/2533446 

18. Egger M, Davey Smith G, Schneider M, Minder C. Bias 
in meta-analysis detected by a simple, graphical test. 
Br. Med. J. 1997;315(7109):629-34. 
doi:10.1136/bmi.315.7109.629 

19. R Core Team. R: A Language and Environment for 
Statistical Computing. Vienna, Austria: R Foundation 
for Statistical Computing; 2018. https://www.r- 
project.org/ . 

20. Gill JK, Franke AA, Morris J, Cooney RV, Wilkens LR, Le 
Marchand L, Goodman MT, Henderson BE, Kolonel LN. 
Association of selenium, tocopherols, carotenoids, 
retinol, and 15-isoprostane F(2t) in serum or urine with 
prostate cancer risk: the multiethnic cohort. Cancer 
Causes Control. 2009;20(7):1161-71. doi:10.1007/s10552- 
009-9304-4 

21. Goodman GE, Schaffer S, Omenn GS, Chen C, King I. 
The Association between Lung and Prostate Cancer 
Risk, and Serum Micronutrients. Cancer Epidemiol 
Biomarkers Prev. 2003;12(6):518-26. PMID: 12814997 

22. Cook NR, Stampfer MJ, Ma J, Manson JE, Sacks FM, 
Buring JE, Hennekens CH. (3-carotene 
supplementation for patients with low baseline levels 
and decreased risks of total and prostate carcinoma. 
Cancer. 2000;86(9):1783-92. doi:10.1002/(SICI)1097- 
0142U9991101)86:9<1783::AID-CNCR21>3.0.CQ;2-N 

23. Kirsh VA, Mayne ST, Peters U, Chatterjee N, Leitzmann 
MF, Dixon LB, Urban DA, Crawford ED, Hayes RB. A 
Prospective Study of Lycopene and Tomato Product 
Intake and Risk of Prostate Cancer. Cancer Epidemiol 


Nor. Afr. J. Food Nutr. Res. January - June 2019 Volume 03 Issue 05 





























Benkhadda et al.: Carotenoids and prostate cancer 


139 


Biomarkers Prev. 2006;15(1):92-8. doi:10.1158/1055- 
9965.EPI-05-0563 

24. Nordstrom T, Van Blarigan EL, Ngo V, Roy R, Weinberg 
V, Song X, Simko J, Carroll PR, Chan JM, Paris PL. 
Associations Between Circulating Carotenoids, 
Genomic Instability and the Risk of High-Grade 
Prostate Cancer. Prostate. 2016;76(4):339-48. 
doi:10.1002/pros.23125 

25. Beilby J, Ambrosini GL, Rossi E, de Klerk NH, Musk AW. 
Serum levels of folate, lycopene, (3-carotene, retinol 
and vitamin E and prostate cancer risk. EurJCUn Nutr. 
2010; 64(10)1235-8. doi:10.1038/eicn.2010.124 

26. Ambrosini GL, de Klerk NH, Fritschi L, Mackerras D, 
Musk B. Fruit, vegetable, vitamin A intakes, and 
prostate cancer risk. Prostate Cancer Prostatic Dis. 
2008; 11(1):61-6. doi:10.1038/si.pcan.4500979 

27. Norrish AE, Jackson RT, Sharpe SJ, Skeaff CM. Prostate 
Cancer and Dietary Carotenoids. Am. J. Epidemiol. 
2000;151 (2):119-23. doi:10.1093/oxfordiournals.aie.a010176 

28. Bosetti C, Talamini R, Montella M, Negri E, Conti E, 
Franceschi S, La Vecchia C. Retinol, carotenoids and 
the risk of prostate cancer: A case-control study from 
Italy. int. J. Cancer. 2004;112(4):689-92. 
doi:10.1002/iic.20486 

29. Key TJ, Silcocks PB, Davey GK, Appleby PN, Bishop DT. 
A case-control study of diet and prostate cancer. Br. J. 
Cancer. 1997;76(5):678-87. doi:10.1038/bic.1997.445 

30. Jian L, Du C-J, Lee AH, Binns CW. Do dietary lycopene 
and other carotenoids protect against prostate 
cancer? Int. J. Cancer. 2004;113(6):1010-14. 
doi:10.1002/iic.20667 

31. Mayne ST. Beta-carotene, carotenoids, and disease 
prevention in humans. EASES J. 1996;10(7):690-701. 
doi:10.1096/fasebi.10.7.8635686 

32. Tan H-L, Thomas-Ahner JM, Moran NE, Cooperstone 
JL, Erdman JW Jr, Young GS, Clinton SK. (3-Carotene 
9',10' Oxygenase Modulates the Anticancer Activity of 
Dietary Tomato or Lycopene on Prostate 
Carcinogenesis in the TRAMP Model. Cancer Prev. Res. 
(Phila). 2017;10(2):161-9. doi:10.1158/1940-6207.CAPR- 
15-0402 

33. Assar EA, Vidalle MC, Chopra M, Hafizi S. Lycopene 
acts through inhibition of IkB kinase to suppress NF- 
kB signaling in human prostate and breast cancer cells. 
Tumor Bioi 2016;37(7):9375-85. doi:10.1007/s13277- 
016-4798-3 


34. Holzapfel NP, Holzapfel BM, Theodoropoulos C, 
Kaemmerer E, Rausch T, Feldthusen J, Champ S, 
Clements JA, Hutmacher DW, Loessner D. Lycopene's 
Effects on Cancer Cell Functions within Monolayer and 
Spheroid Cultures. Nutr. Cancer. 2016;68(2):350-63. 
doi:10.1080/01635581.2016.1150498 

35. Wiseman M. The Second World Cancer Research 
Fund/American Institute for Cancer Research Expert 
Report. Food, Nutrition, Physical Activity, and the 
Prevention of Cancer: A Global Perspective: Nutrition 
Society and BAPEN Medical Symposium on 'Nutrition 
support in cancer therapy.' Proc. Nutr. Soc. 
2008;67(3):253-6. doi:10.1017/S002966510800712X 

36. Stahl W, Sies H. Bioactivity and protective effects of 
natural carotenoids. Biochim. Biophys. Acta. 
2005;1740(2):101-7. doi:10.1016/i.bbadis.2004.12.006 

37. Rafi MM, Kanakasabai S, Reyes MD, Bright JJ. Lycopene 
modulates growth and survival associated genes in 
prostate cancer. J. Nutr. Biochem. 2013;24(10):1724-34. 
doi:10.1016/i.inutbio.2013.03.001 

38. Yang C-M, Lu Y-L, Chen H-Y, Hu M-L. Lycopene and 

the LXRa agonist T0901317 synergistically inhibit the 
proliferation of androgen-independent prostate 
cancer cells via the PPARy-LXRa-ABCAl pathway. J. 
Nutr. Biochem. 2012;23(9):1155-62. 

doi:10.1016/i.inutbio.2011,06.009 

39. Gerster H. Anticarcinogenic Effect of Common 
Carotenoids, int. J. Vitam. Nutr. Res. 1993; 63(2):39-121. 
PMID: 8407171 

40. Wang Y, Cui R, Xiao Y, Fang J, Xu Q. Effect of Carotene 
and Lycopene on the Risk of Prostate Cancer: A 
Systematic Review and Dose-Response Meta-Analysis 
of Observational Studies. PLoS One. 2015 ;10(9): 
e0137427. doi:10.1371/iournal.pone.0137427 

41. Chen P, Zhang W, Wang X, Zhao K, Negi DS, Zhuo L, 

Qi M, Wang X, Zhang X. Lycopene and Risk of Prostate 
Cancer: A Systematic Review and Meta-Analysis. 
Medicine (Baltimore). 2015;94(33): e1260. 

doi:10.1097/MD.0000000000001260 

42. Ilic D, Forbes KM, Hassed C. Lycopene for the 

prevention of prostate cancer. Cochrane Database 
Syst Rev. 2011;(11) :CD008007 

doi:10.1002/14651858.CD008007.pub2 

43. Van Hoang D, Pham NM, Lee AH, Tran DN, Binns CW. 
Dietary Carotenoid Intakes and Prostate Cancer Risk: 
A Case-Control Study from Vietnam. Nutrients. 
2018,10(1) pii: E70. doi:10.3390/nu10010070 


Cite this article as: Benkhadda H, Bouchentouf M and El Herrag S.E. Association between carotenoids and prostate cancer risk: A Meta-Analysis. Nor. 
Afr. J. Food Nutr. Res. January - June (2019); 03 (05): 131-39. https://doi.org/10.5281/zenodo.2575438 


Nor. Afr. J. Food Nutr. Res. January - June 2019 Volume 03 Issue 05