European Journal of Clinical Nutrition (2014) 68, 330–337 & 2014 Macmillan Publishers Limited All rights reserved 0954-3007/14 www.nature.com/ejcn
ORIGINAL ARTICLE
Coffee consumption and risk of prostate cancer: an up-to-date meta-analysis S Zhong1, W Chen2, X Yu3, Z Chen4, Q Hu5 and J Zhao1 BACKGROUND/OBJECTIVES: Epidemiologic findings concerning the association between coffee consumption and prostate cancer risk yielded mixed results. We aimed to investigate the association by performing a meta-analysis of all available studies. SUBJECTS/METHODS: We searched PubMed, Web of Science and EMBASE for studies published up to July 2013. We calculated the summary relative risk (RR) and 95% confidence intervals (CIs) for ever, moderate and highest consumption of coffee vs non/lowest consumption. The dose–response relationship was assessed by restricted cubic spline model and multivariate random-effect metaregression. RESULTS: A total of 12 case–control studies and 12 cohort studies with 42 179 cases were selected for final meta-analysis. No significant associations were found among overall analysis. A borderline positive association was found for highest drinkers in five small hospital-based case–control (HCC) studies involving 2278 cases. However, compared with non/lowest drinkers, the summary RRs were 0.92 (95% CI ¼ 0.85–0.99) for ever drinkers, 0.92 (95% CI ¼ 0.85–1.00) for moderate drinkers and 0.83 (95% CI ¼ 0.72–0.96) for highest drinkers from 12 cohort studies, comprising a total of 34 424 cases. An increase in coffee intake of two cups/day was associated with a 7% decreased risk of prostate cancer according to cohort studies. A significant inverse relationship was also found for fatal prostate cancers and high-grade prostate cancers. CONCLUSIONS: Case–control studies especially HCC ones might be prone to selection bias and recall bias that might have contributed to the conflicting results. Therefore, the present meta-analysis suggests a borderline significant inverse association between coffee consumption and prostate cancer risk based on cohort studies. European Journal of Clinical Nutrition (2014) 68, 330–337; doi:10.1038/ejcn.2013.256; published online 4 December 2013 Keywords: coffee; caffeine; prostate cancer; meta-analysis
INTRODUCTION Prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in men globally.1 In 2013, prostate cancer alone is expected to account for B28% of all new cancer cases among men of the United States.2 Coffee, the most common beverage in the Western world, can potentially impact the etiology of cancer of various sites along multiple pathways, ranging from carcinogenesis to cellular apoptosis. A number of epidemiological studies have sought to establish a relationship between coffee consumption and prostate cancer risk in the past three decades but with varying results. Two studies have shown an increased prostate cancer risk among coffee drinkers.3,4 However, the reduced risk of prostate cancer in coffee drinkers was observed in several studies.5–7 A meta-analysis,8 including the results of eight case–control studies and four cohort studies, found an overall relative risk (RR) of 1.16 (95% confidence interval (CI) ¼ 1.01–1.33) for highest vs lowest coffee drinkers, but the combination of four cohort studies demonstrated no association (RR ¼ 1.06; 95% CI ¼ 0.83–1.35). Another meta-analysis,9 combining five cohort studies, showed an inverse association of prostate cancer risk with high coffee intake (RR ¼ 0.79; 95% CI ¼ 0.61–0.98). However, both compared only lowest with highest intakes and neither included all the published studies available at the time of their compilations. Furthermore, many studies were
published after the previous meta-analysis. Therefore, we systematically conducted a meta-analysis by combining all available data of both case–control and cohort studies to derive a more precise estimation of this association. Besides, we also performed a dose–response analysis, because categories of coffee consumption differed between studies that might complicate the interpretation of the pooled results across study populations with different categories.
MATERIALS AND METHODS Search strategy In order to identify all the previous published studies on coffee consumption and risk of prostate cancer, PubMed, Web of Science and EMBASE were searched with the following keywords: ‘coffee’ and ‘prostate’ by two independent investigators (last search update: 7 July 2013). Reference lists were examined manually to further identify potentially relevant studies. All the studies matching the eligible criteria listed below were included in our meta-analysis.
Inclusion criteria The following inclusion criteria were used in selecting literature for further meta-analysis: (1) the exposure of interest was coffee consumption; (2) the outcome of interest was prostate cancer; (3) the type of study was
1 Center of Clinical Laboratory Science, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, China; 2The Fourth Clinical College of Nanjing Medical University, Nanjing, China; 3Department of Hematology (Key Department of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Nanjing, China; 4Department of General Surgery, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, China and 5Teaching and Research Office of General Surgery, Xuzhou Medical College, Xuzhou, China. Correspondence: J Zhao, Center of Clinical Laboratory Science, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing 210009, China. E-mail: [email protected] Received 13 July 2013; revised 30 October 2013; accepted 31 October 2013; published online 4 December 2013
Coffee consumption and prostate cancer risk S Zhong et al
331 case–control or cohort; and (4) the RR with their 95% CIs were reported (or information to calculate them).
Data extraction Two investigators extracted the data independently. Discrepancies were adjudicated by the third investigator until consensus was achieved on every item. The following information was abstracted from each included articles: the name of first author, year of publication, country origin, study period, study design, sample size (cases and noncases), the exposure to coffee consumption, the RRs and corresponding 95% CIs for each category of coffee consumption and confounders adjusted for in multivariate analysis, respectively.
Assessment of methodological quality The methodological quality of the included studies was independently evaluated by two investigators using the Newcastle–Ottawa Scale (NOS).10 Each study was assessed based on three broad perspectives: selection, comparability and exposure with a score ranging from 0 to 9. A score of X7 indicated that one study was of high quality. Discrepancies were adjudicated through discussion and re-evaluation of the methodology of the study in question.
Statistical methods All statistical analyses were done with Stata software (Version 12; Stata Corporation, College Station, TX, USA), and all tests were two sided. For a study that provided two OR or RR estimates based on population and cancer controls, we used the estimates derived from the population controls.11 If a study provided separate OR or RR estimates by age or subtype of the disease, we treated them as different studies.6,12 Risk estimates were extracted from each study, and log RRs were weighted by the inverse of their variances to obtain a pooled RR and its 95% CI. For each study, non/lowest drinkers represented the reference category, highest drinkers represented the greatest coffee consumption, moderate drinkers represented in-between coffee consumption and ever drinkers represented both greatest and moderate coffee consumption. First, we compared the risk of prostate cancer in ever coffee drinkers with non/ lowest drinkers. For studies that did not report a risk estimate for ever drinkers, a summary estimate was calculated using reported risk estimate for each coffee consumption category. Second, estimates comparing the highest with the non/lowest coffee consumption were calculated. Third, estimates were also calculated for moderate coffee consumption. A summary estimate was also calculated for studies that did not report a risk estimate for moderate drinkers. Statistical heterogeneity among studies was assessed with the Q and I2 statistics;13 a Po0.1 was considered significant.14 The fixed-effect model (the Mantel–Haenszel method)15 was used to access the pooled RRs if the heterogeneity was not significant, otherwise the random-effect model (the DerSimonian and Laird method)16 was used. Subgroup analyses were performed based on study design (hospital-based case–control (HCC) study, population-based case–control study and cohort study), geographic region (America, Asia and Europe), methodological quality (high (with a score X7) and low (with a score o7)) and subtype of prostate cancer (fatal, local, advanced, high grade (Gleason score 47) and low grade (Gleason score o7) prostate cancer) to explore the source of heterogeneity. Meta-regression17 was conducted to further explore the heterogeneity quantitatively among the studies (the analysis was based on highest vs non/lowest coffee consumption). Sensitivity analyses were performed to reflect the influence of the individual data on the summary RRs. Publication bias was evaluated using the Begg’s funnel plot and Egger’s test.18 A two-stage random-effects dose–response meta-analysis was performed to compute the trend from the correlated log RR estimates across levels of coffee consumption taking into account the between-study heterogeneity.19 For each study, we calculated the median cups of coffee consumption for each category by assigning the midpoint of upper and lower boundaries in each category as the average consumption. When the highest category was open ended, we assigned the lower end value of the category multiplied by 1.5. We examined a potential nonlinear dose– response relationship between coffee intake and risk of prostate cancer by modeling coffee levels using restricted cubic splines with three knots at percentiles 25, 50 and 75% of the distribution.20 A P-value for nonlinearity was calculated by testing the null hypothesis that the coefficient of the second spline is equal to 0. & 2014 Macmillan Publishers Limited
Studies were not eligible if the required data were not reported or could not be estimated. If coffee consumption was indicated by ml (or g),21,22 we defined 250 ml (or 250 g) of coffee equal to 1 cup. If coffee consumption was measured in a times/day (or occasions/day or drinks/day) scale,11,23,24 we assumed the scale equals to cups/day.
RESULTS Characteristics of the studies Figure 1 outlines the search strategy used to obtain relevant literature. A total of 313 titles and abstracts were identified and screened, and 36 studies were reviewed in detail. Six studies associated with benign prostatic hyperplasia were excluded. Three articles were excluded as their subjects were overlapped in other publications. One study was also excluded because it was not case–control or cohort design. After further excluding 2 reviews, 12 cohort studies6,7,22–31 and 12 case–control studies3,5,11,12,21,32–38 involving 527 486 participants and 42 179 cases of prostate cancer were selected for meta-analysis. The characteristics of the included studies are shown in Table 1. Supplementary Tables S1 and S2 present the methodological quality of studies included in the final analysis. The NOS results showed that the average score was 5.8 (range 4–8) for case–control studies and 7.5 (range 4–9) for cohort studies, indicating that the methodological quality of cohort studies was generally good. Evidence synthesis The pooled RRs of prostate cancer for the ever, moderate and highest coffee drinkers vs non/lowest drinkers are presented in Table 2. Compared with non/lowest drinkers, the summary RR was 0.98 (95% CI ¼ 0.92–1.03) for ever drinkers, 0.96 (95% CI ¼ 0.90–1.02) for moderate drinkers and 0.94 (95% CI ¼ 0.85–1.05) for highest drinkers. In the subgroup analyses by study design and subtype of prostate cancer, a statistically significant inverse association was observed for ever, moderate and highest coffee consumption in cohort studies (RR ¼ 0.92, 95% CI ¼ 0.85–0.99; RR ¼ 0.92, 95% CI ¼ 0.85–1.00; and RR ¼ 0.83, 95% CI ¼ 0.72–0.96, respectively) and fatal prostate cancers (RR ¼ 0.79, 95% CI ¼ 0.72–0.87;
Figure 1. Flowchart of the selection of publications included in the meta-analysis. European Journal of Clinical Nutrition (2014) 330 – 337
Coffee consumption and prostate cancer risk S Zhong et al
332 Table 1.
Characteristics of studies included in the meta-analysis
First author
Year
Country
Follow-up period
Study design
Cases
Noncases
Coffee consumption
Relative risk (95% CI)
Wilson5
2013
Sweden
2001–2002
PCC
1489
1112
o1 cup/day 1 to o2 cups/day 2 to o4 cups/day 4–5 cups/day 45 cups/day
OR 1.00 0.97 (0.62–1.52) 0.98 (0.65–1.49) 1.06 (0.69–1.62) 0.97 (0.60–1.57)
Age, region, smoking, BMI, education and intake of calcium, zinc and total energy
Geybels38
2013
USA
2002–2005
PCC
894
860
p1 cup/week 2–6 cups/week 1 cup/day 2–3 cups/day X4 cups/day
OR 1.00 1.22 (0.88–1.69) 1.13 (0.84–1.51) 1.16 (0.90–1.50) 1.16 (0.82–1.63)
Age, race, first-degree family history of prostate cancer, smoking status and history of prostate cancer screening
Polesel32
2012
Italy
1991–2002
HCC
1294
1451
o1 cup/day 1–2 cups/day 3–4 cups/day 45 cups/day
OR 1.00 1.05 (0.83–1.32) 1.11 (0.86–1.43) 1.05 (0.70–1.58)
Center, age, education, occupational physical activity, family history of prostate cancer, diabetes, smoking habits, drinking habits, nonalcohol energy intake, BMI, BMI at age 30 years
Deneo-Pellegrini37
2012
Uruguay
1996–2004
HCC
326
640
I tertile II tertile III tertile
OR 1.00 1.54 (0.91–2.59) 1.37 (0.82–2.29)
Age, residence, urban/rural status, education, family history of prostate cancer among first degree relatives, BMI and total energy intake
Ganesh36
2011
India
1999–2001
HCC
123
167
No Yes
OR 1.00 1.3 (0.6–2.7)
Chen3
2005
China
1996–1998
HCC
237
481
No Yes
OR 1.00 1.88 (1.07–3.30)
Sharpe11
2002
Canada
1979–1985
PCC
398
476
None 1–2 drinks/day 3–4 drinks/day X5 drinks/day
OR 1.00 1.1 (0.6–1.9) 1.1 (0.6–1.9) 0.9 (0.5–1.7)
Age, ethnicity, respondent status, family income, BMI, cumulative cigarette smoking and cumulative alcohol consumption
Hsieh35
1999
Greece
1994–1997
HCC
298
214
None o1 cup/day 1 to o2 cups/day 2 to o3 cups/day 3 þ cups/day
OR 1.00 0.38 (0.15–0.99) 0.72 (0.35–1.45) 0.57 (0.29–1.12) 1.15 (0.53–2.47)
Age, height, BMI and years of schooling
Villeneuve34
1999
Canada
1994–1997
PCC
1410
1397
None o1 cup/day 1 to o4 cups/day X4 cups/day
OR 1.00 0.8 (0.6–1.1) 1.0 (0.7–1.3) 1.1 (0.8–1.5)
Age, province of residence, race, years since quitting smoking, cigarette packyears, BMI, rice and pasta, coffee, grains and cereals, alcohol, fruit and fruit juices, tofu, meat, income and family history of cancer
Jain21
1998
Canada
1989–1993
PCC
617
636
0 g/day 40–500 g/day 4500 g/day
OR 1.00 0.84 (0.58–1.22) 0.97 (0.65–1.44)
Age and total energy intake
Gronberg33
1996
Sweden
1959–1989
PCC
311
910
0 cup/day 1–2 cups/day 3–5 cups/day 6–9 cups/day
OR 1.00 1.77 (0.65–5.09) 1.99 (0.78–5.46) 1.91 (0.73–5.30)
Specific food items, smoking habits and alcohol consumption.
Slattery12
1993
USA
1984–1985
PCC
358
679
p67 years 0 cup/week 1–20 cups/week 420 cups/week 467 0 cup/week 1–20 cups/week 420 cups/week
Discacciati6
2013
Sweden
1998–2010
Cohort
European Journal of Clinical Nutrition (2014) 330 – 337
3801
40 812
Localized PCa None o1 cup/day 1–3 cups/day 4–5 cups/day X6 cups/day Advanced PCa None o1 cup/day 1–3 cups/day 4–5 cups/day X6 cups/day Fatal PCa a None o1 cup/day 1–3 cups/day 4–5 cups/day X6 cups/day
Covariate adjustment
Age, religion and education Age and BMI
Age OR 1.00 0.99 (0.68–1.47) 1.09 (0.75–1.60) OR 1.00 1.09 (0.73–1.61) 0.88 (0.58–1.34) RR 1.00 1.02 (0.82–1.28) 0.89 (0.74–1.08) 0.69 (0.57–0.85) 0.52 (0.41–0.65)
Age, tea, alcohol, BMI, personal history of diabetes, family history of PCa, smoking status, physical activity, education and total energy intake
RR 1.00 1.56 (1.06–2.35) 1.29 (0.93–1.86) 0.81 (0.56–1.19) 0.55 (0.36–0.86) RR 1.00 1.39 (0.88–2.26) 0.93 (0.63–1.42) 0.60 (0.38–0.95) 0.36 (0.20–0.64)
& 2014 Macmillan Publishers Limited
Coffee consumption and prostate cancer risk S Zhong et al
333 Table 1. (Continued ) First author
Year
Country
Follow-up period
Study design
Cases
Noncases
Coffee consumption
Relative risk (95% CI)
Bosire31
2013
USA
1995–2006
Cohort
23 335
265 056
None o1 cup/day 1 cup/day 2–4 cups/day 4–5 cups/day X6 cups/day
HR 1.00 1.03 (0.98–1.08) 1.00 (0.95–1.06) 1.00 (0.96–1.05) 1.00 (0.94–1.06) 0.94 (0.87–1.02)
Age, race, height, BMI, physical activity, smoking, history of diabetes, family history of prostate cancer, PSA testing, intakes of tomato sauce, a-linolenic acid and total energy intake
Li29
2013
Japan
1995–2005
Cohort
318
18 217
Never Occasionally 1–2 cups/day X3 cups/day
HR 1.00 0.82 (0.62–1.08) 0.74 (0.54–1.01) 0.63 (0.39–1.00)
Age, education level, BMI, time engaging in sports or exercise, marital status, time spent walking, smoking status, family history of cancer, consumption of tea, job status, daily total energy intake, passive smoking, alcohol drinking, daily consumption of miso soup
Shafique30
2012
UK
1970–2007
Cohort
318
5699
0 cup/day 1–2 cups/day X3 cups/day
HR 1.00 0.95 (0.72–1.24) 0.93 (0.66–1.31)
Age at screening, cholesterol, systolic blood pressure, BMI, alcohol intake, tea consumption, smoking status, social class
Wilson7
2011
USA
1986–2006
Cohort
5035
42 876
None o1 cup/day 1–3 cups/day 4–5 cups/day X6 cups/day
RR 1.00 0.94 (0.85–1.05) 0.94 (0.86–1.04) 0.93 (0.83–1.04) 0.82 (0.68–0.98)
Race, height, BMI at age 21, current BMI, vigorous physical activity, smoking, diabetes, family history of prostate cancer in father or brother, multivitamin use, intakes of processed meat, tomato sauce, calcium, a-linolenic acid, supplemental vitamin E, alcohol intake, energy intake and history of PSA testing
Nilsson24
2010
Sweden
1992–2007
Cohort
653
30 930
o1 occasions/day 1–3 occasions/day X4 occasions/day
HR 1.00 0.92 (0.70–1.21) 1.03 (0.77–1.38)
Age, sex, BMI, smoking, education and recreational physical activity
Ellison22
2000
Canada
1969–1993
Cohort
145
3255
0 ml/day 40–250 ml/day 4250–500 ml/day 4500–750 ml/day 4750 ml/day
RR 1.00 1.14 (0.66–1.97) 1.42 (0.80–2.52) 1.35 (0.75–2.43) 1.42 (0.77–2.61)
Five-year age group, wine consumption
Le Marchand27
1994
USA
1975–1980
Cohort
198
8881
1 2 3 4
Stensvold25
1994
Norway
1977–1990
Cohort
38
21 697
p2 3–4 5–6 X7
Hsing28
1990
USA
1966–1986
Cohort
149
17 633
o3 cups/day 3–4 cups/day X5 cups/day
RR 1.00 0.8 (0.6–1.2) 1.0 (0.6–1.6)
Age
Severson23
1989
USA
1965–1986
Cohort
174
7824
p1 times/week 2–4 times/week X5 times/week
RR 1.00 0.96 (0.39–2.37) 0.92 (0.59–1.44)
Age
Jacobsen26
1986
Norway
1964–1978
Cohort
260
13 404
p2 cup/day 3–4 cups/day 5–6 cups/day X7 cups/day
RR 1.00 0.61 (0.39–0.95) 0.64 (0.45–0.90) 0.88 (0.66–1.18)
Age, residence and cigarette smoking
Quantile Quantile Quantile Quantile cups/day cups/day cups/day cups/day
RR 1.00 0.9 (0.6–1.4) 1.2 (0.8–1.8) 1.1 (0.7–1.7) RR 1.00 0.34 (0.10–1.10) 0.61 (0.23–1.69) 0.47 (0.17–1.35)
Covariate adjustment
Age, ethnicity and income
Age, cigarettes per day and county of residence
Abbreviations: BMI, body mass index; CI, confidence interval; HCC, hospital-based case–control study; HR, hazard ratio; OR, odds ratio; PCa, prostate cancer; PCC, population-based case–control study; PSA, prostate-specific antigen; RR, relative risk. aThe subgroup was only included in the subgroup analysis by subtype of prostate cancer as its subjects were overlapped in the other two subgroups.
RR ¼ 0.80, 95% CI ¼ 0.73–0.88; and RR ¼ 0.61, 95% CI ¼ 0.42–0.90, respectively) and for highest coffee consumption in high-grade prostate cancers (RR ¼ 0.70, 95% CI ¼ 0.52–0.94). However, a borderline positive association was found for highest coffee consumption in HCC studies (RR ¼ 1.29, 95% CI ¼ 1.01–1.65; Figure 2). No significant associations were found in other subgroups (not all data shown). We assessed the dose–response relationship between coffee levels and the risk of prostate cancer with 18 studies.5–7,11,12,21–26,29–31,33–35,38 Statistically significant departure from linearity was found for all studies (P ¼ 0.04; Figure 3a), but not for cohort studies (P ¼ 0.07; Figure 3b) and case–control & 2014 Macmillan Publishers Limited
studies (P ¼ 0.38). A 2 cups/day increment in coffee consumption level conferred an RR of 0.97 (95% CI ¼ 0.94–1.01) for overall result, 0.93 (95% CI ¼ 0.88–0.99) for cohort studies and 1.04 (95% CI ¼ 1.00–1.08) for case–control studies. Sensitivity analysis and publication bias From the results of the leave-one-out sensitivity analysis, the summary RRs were not materially altered (data not shown). We explored the source of heterogeneity by study design (HCC, population-based case–control and cohort studies), geographic region (America, Asia and Europe) and methodological quality European Journal of Clinical Nutrition (2014) 330 – 337
Coffee consumption and prostate cancer risk S Zhong et al
European Journal of Clinical Nutrition (2014) 330 – 337
Abbreviations: CI, confidence interval; HCC, hospital-based case–control study; High grade, Gleason score 47; Low grade, Gleason score o7; PCC, population-based case–control study; Ph, P-value of Q-test for heterogeneity test (random-effects model was used when P-value for heterogeneity test was o0.1, otherwise fix-effects model was used); RR, relative risk. Values in bold font indicate statistical significance (Po0.05). aIf a study provided separate OR or RR estimates by age or subtype of the disease, we treated them as different studies.6,12
61.4 79.4 75.8 34.9 0.0 0.61 (0.42–0.90) 0.74 (0.47–1.17) 0.71 (0.47–1.08) 0.70 (0.52–0.94) 1.07 (0.89–1.29) 2530 4191 5227 1367 4137 Subtype of prostate cancer Fatal 5 Local 4 Advanced 5 High-grade 5 Low-grade 5
0.79 (0.72–0.87) 0.95 (0.79–1.13) 0.90 (0.75–1.09) 0.87 (0.60–1.24) 1.06 (0.99–1.14)
0.60 0.07 0.00 0.00 0.25
0.0 58.1 78.3 88.3 25.3
5 4 5 5 5
2430 3835 4988 1292 3871
0.80 (0.73–0.88) 1.00 (0.89–1.11) 0.94 (0.79–1.12) 0.91 (0.64–1.31) 1.06 (0.98–1.14)
0.78 0.23 0.00 0.00 0.39
0.0 30.8 74.6 85.2 2.4
5 4 5 5 5
484 801 721 285 847
0.04 0.00 0.00 0.19 0.67
66.5 0.0 0.87 (0.75–1.01) 1.07 (0.94–1.22) 35 035 7144 Methodological quality High 15 Low 11
0.95 (0.88–1.03) 1.03 (0.96–1.10)
0.00 0.15
67.9 31.4
15 11
33 052 5797
0.95 (0.87–1.03) 1.01 (0.93–1.09)
0.00 0.11
63.4 36.9
15 11
5659 2513
0.00 0.84
4.8 0.0 0.0 66.5 1.11 (0.98–1.26) 1.05 (0.90–1.22) 1.29 (1.01–1.65) 0.83 (0.72–0.96) 7755 5477 2278 34 424 13 8 5 13 Study design Case–control PCC HCC Cohort
1.07 (0.96–1.18) 1.05 (0.96–1.14) 1.16 (0.86–1.56) 0.92 (0.85–0.99)
0.06 0.29 0.02 0.00
41.1 18.0 64.8 65.3
10 8 2 11
6142 4414 1707 32 728
1.02 (0.91–1.16) 1.04 (0.94–1.15) 0.98 (0.61–1.56) 0.92 (0.85–1.00)
0.06 0.34 0.01 0.00
43.2 11.8 79.2 61.4
13 8 5 13
2801 1871 930 5371
0.80 0.88 0.59 0.00
53.8 0.00 0.94 (0.85–1.05) 42 179 26 All studies
0.98 (0.92–1.03)
0.00
57.9
21
38 849
0.96 (0.90–1.02)
0.00
53.9
26
8172
Ph RR (95% CI) Cases, n Ph RR (95% CI) Cases, n Study, na
Cases, n
RR (95% CI)
Ph
I2,%
Study, n
Moderate drinkers vs non/lowest drinkers Ever drinkers vs non/lowest drinkers Variables
Table 2.
Summary risk estimates and 95% CIs for coffee consumption and risk of prostate cancer
I2,%
Study, n
Highest drinkers vs non/lowest drinkers
I2,%
334 (continuous variable) with meta-regression. The results for the highest vs non/lowest coffee consumption revealed that study design (P ¼ 0.04) and methodological quality (P ¼ 0.01) but not geographic region (P ¼ 0.10) contributed to the source of heterogeneity. Begg’s funnel plot and Egger’s test were used to assess the publication bias of included studies. The graphical funnel plots for all the three comparisons appeared to be symmetrical (Figure 4). Then, Egger’s test was used to provide statistical evidence of funnel plot symmetry. The results still did not show any evidence of publication bias in the overall meta-analysis for the ever, moderate and highest coffee drinkers vs non/lowest drinkers (t ¼ 0.30, P ¼ 0.77; t ¼ 0.96, P ¼ 0.35; and t ¼ 0.83, P ¼ 0.42, respectively). DISCUSSION This meta-analysis investigated the association between coffee consumption and prostate cancer risk on the basis of previously published researches involving 527 486 participants and 42 179 cases of prostate cancer. The overall summary results indicated no association of coffee consumption with prostate cancer risk. However, an inverse association between coffee consumption and risk of prostate cancer was observed in cohort studies, whereas no association was observed from case–control studies. Interestingly, the five HCC studies with only 2278 cases showed an increased risk of prostate cancer among highest coffee drinkers (Figure 2 and Table 2). We noted that there were four HCC studies3,32,36,37 with smallest sample size that was o1000. In addition, a more precise scale (for example, cups/day) was not used to measure the coffee consumption in three HCC studies,3,36,37 two3,36 of which only quantified coffee consumption as ‘yes’ or ‘no’ (Table 1). We also noted that the HCC study conducted in China reported an extremely significant result, and the number of coffee consumers in the sample was very low, consisting of 31 cases (13.1%) and 36 controls (7.5%).3 After removing this study, the significant result of HCC studies disappeared. In the previous meta-analysis by Park et al.,8 case–control and cohort studies also showed different association results (RR ¼ 1.21, 95% CI ¼ 1.03–1.43; and RR ¼ 1.06, 95% CI ¼ 0.83–1.35, respectively). Their conflicting results might be because of the study mentioned above3 and another study by Gallus et al.4 that was excluded in present meta-analysis because its subjects were overlapped by a larger study.32 In the study by Gallus et al.,4 the authors reported an increased risk of prostate cancer for highest coffee consumption with 219 cases and 431 controls. However, the larger study32 showed no association anymore with 1294 cases and 1451 controls. Case–-control studies especially HCC ones give a lower level of evidence than cohort studies and might provide spurious results because of selection bias and recall bias that might have contributed to the conflicting results in the present meta-analysis. In addition to what is mentioned above, we could easily find that the methodological quality of case–control studies was generally lower (Supplementary Table S1). More than half the studies did not use a representative case population, and almost all ascertained the exposure to coffee without blinding to case–control status. Therefore, the results might have suffered from biases, thus contributing to spurious results. Taking account of all the above-mentioned aspects, we concluded that coffee consumption is associated with decreased risk of prostate cancer. Several studies have explored coffee consumption and incidence of prostate cancer by subtype of the disease.5–7,28–32,38 The results from the subgroup analysis showed a strong inverse association between coffee consumption and fatal or high-grade prostate cancer risk, suggesting that coffee may be implicated in preventing progression of prostate cancer. A recent study indicated that higher prediagnostic coffee consumption was associated with a lower risk of prostate cancer recurrence/progression.39 The authors defined & 2014 Macmillan Publishers Limited
Coffee consumption and prostate cancer risk S Zhong et al
335
Figure 2. Summary relative risks of prostate cancer for highest coffee consumption vs non/lowest coffee consumption. The squares and horizontal lines correspond to the study-specific RR and 95% CIs. The area of the squares reflects the study-specific weight. The diamond represents the pooled RR and 95% CI.
recurrence/progression as patients who died of prostate cancer, developed metastasis, received secondary treatment or had a rising prostate-specific antigen. Nevertheless, they evaluated daily coffee consumption (X1 cup/day vs o1 cup/day) in relation to prostate cancer-specific mortality and observed a nonsignificant 23% lower risk, which might be because of the limited sample size. Therefore, additional large prospective studies of the relationship between coffee consumption and prostate cancer outcomes, including recurrence/progression and prostate cancer-specific mortality, are urgently needed to confirm whether coffee intake is beneficial for secondary prevention. Because the categories of coffee consumption differed between studies, which might complicate the interpretation of the pooled results across study populations with different categories, we also performed dose–response analyses. A nonlinear and not significant dose–response association was found between coffee consumption and prostate cancer risk, and a 2 cups/day increment in coffee consumption level was associated with a 0.97-fold reduced prostate cancer risk. When restricted to cohort studies, a linear and significant dose–response association was found, and the risk of prostate cancer was decreased by 7% for every 2 cups/ day increment in coffee consumption. & 2014 Macmillan Publishers Limited
Numerous investigations in animals and in vitro cell cultures have tried to establish a link between coffee and cancer. Coffee contains a large number of compounds, some of which have been identified as having potentially chemopreventive effects. Caffeine, one of the major components of coffee, could slightly stimulate apoptosis of prostate cancer cells through activating ryanodine receptor.40 Studies,7,31 however, showed that regular and decaffeinated coffee showed no difference on risk of prostate cancer, suggesting that noncaffeine components of coffee may play more important roles in preventing prostate cancer development. Coffee is also a major source of antioxidants that have been indicated to have an inhibitory effect on carcinogenesis of prostate cancer.41 Coffee has been observed to be associated with increased total testosterone and sex hormone-binding globulin concentrations.42 Evidences suggested that free testosterone was inversely associated with the risk of advanced prostate cancer,43 and sex hormone-binding globulin decreased prostate cancer risk in younger men.44,45 Coffee has also been observed to increase the level of plasma adiponectin46 that was associated with decreased prostate cancer risk.47 A study reported that p53 and bcl-2, two key regulators of apoptosis, were modulated by adiponectin in prostate cancer cells.48 It has been European Journal of Clinical Nutrition (2014) 330 – 337
Coffee consumption and prostate cancer risk S Zhong et al
336
Figure 3. The dose–response analysis between coffee intake and prostate cancer risk with restricted cubic splines in a multivariate randomeffects dose–response model for (a) all studies and (b) cohort studies. The solid line and the long dash line represent the estimated RR and its 95% CI. Short dash line represents the linear relationship.
further prospective cohort studies with larger sample size, wellcontrolled confounding factors, long enough follow-up time and more accurate assessment of coffee consumption is essential. CONFLICT OF INTEREST The authors declare no conflict of interest.
REFERENCES
Figure 4. Begg’s funnel plot of studies on coffee consumption and prostate cancer risk for ever drinkers versus non/lowest drinkers. The solid line in the center is the natural logarithm of pooled RR, and two oblique lines are pseudo 95% CIs.
shown that serum adiponectin was inversely correlated with serum insulin-like growth factor 1.49 There were evidences to suggest that elevated blood levels of insulin-like growth factor 1 have been associated with several cancers, most commonly with prostate cancer.50 Combined with our results, it seems that coffee intervened in prostate cancer development. The potential limitations of our study should be considered when interpreting the results. First, the possibility of bias and confounding cannot be excluded for all observational studies of diet and disease. Second, our results are likely to be affected by some misclassification of coffee consumption. Coffee exposure is mostly assessed regarding the number of cups of coffee consumed daily or weekly. However, cup size and brew strength may vary considerably. In addition, there can be important differences in the concentration of coffee components, depending on the coffee variety. Third, our search was restricted to published studies, whereas unpublished studies or original data were not searched. Finally, studies included in this meta-analysis were major conducted in Western countries, and hence the results should be extrapolated to other populations with caution. In conclusion, our data suggest that coffee consumption or an increased coffee consumption may influence the risk of prostate cancer based on the findings of cohort studies. Regarding the significant heterogeneity among included studies, confirmation in European Journal of Clinical Nutrition (2014) 330 – 337
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337 17 Sharp S. sbe23: meta-analysis regression. Stata Technical Bulletin 1998; 42: 16–22. 18 Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629–634. 19 Orsini N, Li R, Wolk A, Khudyakov P, Spiegelman D. Meta-analysis for linear and nonlinear dose-response relations: examples, an evaluation of approximations, and software. Am J Epidemiol 2012; 175: 66–73. 20 Harrell Jr FE, Lee KL, Pollock BG. Regression models in clinical studies: determining relationships between predictors and response. J Natl Cancer Inst 1988; 80: 1198–1202. 21 Jain MG, Hislop GT, Howe GR, Burch JD, Ghadirian P. Alcohol and other beverage use and prostate cancer risk among Canadian men. Int J Cancer 1998; 78: 707–711. 22 Ellison LF. Tea and other beverage consumption and prostate cancer risk: a Canadian retrospective cohort study. Eur J Cancer Prev 2000; 9: 125–130. 23 Severson RK, Nomura AM, Grove JS, Stemmermann GN. A prospective study of demographics, diet, and prostate cancer among men of Japanese ancestry in Hawaii. Cancer Res 1989; 49: 1857–1860. 24 Nilsson LM, Johansson I, Lenner P, Lindahl B, Van Guelpen B. Consumption of filtered and boiled coffee and the risk of incident cancer: a prospective cohort study. Cancer Causes Control 2010; 21: 1533–1544. 25 Stensvold I, Jacobsen BK. Coffee and cancer: a prospective-study of 43,000 norwegian men and women. Cancer Causes Control 1994; 5: 401–408. 26 Jacobsen BK, Bjelke E, Kvale G, Heuch I. Coffee drinking, mortality, and cancer incidence: results from a Norwegian prospective study. J Natl Cancer Inst 1986; 76: 823–831. 27 Le Marchand L, Kolonel LN, Wilkens LR, Myers BC, Hirohata T. Animal fat consumption and prostate cancer: a prospective study in Hawaii. Epidemiology (Cambridge, Mass.) 1994; 5: 276–282. 28 Hsing AW, McLaughlin JK, Schuman LM, Bjelke E, Gridley G, Wacholder S et al. Diet, tobacco use, and fatal prostate cancer: results from the Lutheran Brotherhood Cohort Study. Cancer Res 1990; 50: 6836–6840. 29 Li Q, Kakizaki M, Sugawara Y, Tomata Y, Watanabe T, Nishino Y et al. Coffee consumption and the risk of prostate cancer: the Ohsaki Cohort Study. Br J Cancer 2013; 108: 2381–2389. 30 Shafique K, McLoone P, Qureshi K, Leung H, Hart C, Morrison DS. Coffee consumption and prostate cancer risk: further evidence for inverse relationship. Nutr J 2012; 11: 42. 31 Bosire C, Stampfer MJ, Subar AF, Wilson KM, Park Y, Sinha R. Coffee consumption and the risk of overall and fatal prostate cancer in the NIH-AARP Diet and Health Study. Cancer Causes Control 2013; 24: 1527–1534. 32 Polesel J, Zucchetto A, Talamini R, Dal Maso L, Serraino D, La Vecchia C et al. Re: coffee consumption and prostate cancer risk and progression in the health professional follow-up study. J Natl Cancer Inst 2012; 104: 1684–1686. 33 Gronberg H, Damber L, Damber JE. Total food consumption and body mass index in relation to prostate cancer risk: a case-control study in Sweden with prospectively collected exposure data. J Urol 1996; 155: 969–974. 34 Villeneuve PJ, Johnson KC, Kreiger N, Mao Y. Risk factors for prostate cancer: results from the Canadian National Enhanced Cancer Surveillance System.
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Supplementary Information accompanies this paper on European Journal of Clinical Nutrition website (http://www.nature.com/ejcn)
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European Journal of Clinical Nutrition (2014) 330 – 337
ORIGINAL ARTICLE
Coffee consumption and risk of prostate cancer: an up-to-date meta-analysis S Zhong1, W Chen2, X Yu3, Z Chen4, Q Hu5 and J Zhao1 BACKGROUND/OBJECTIVES: Epidemiologic findings concerning the association between coffee consumption and prostate cancer risk yielded mixed results. We aimed to investigate the association by performing a meta-analysis of all available studies. SUBJECTS/METHODS: We searched PubMed, Web of Science and EMBASE for studies published up to July 2013. We calculated the summary relative risk (RR) and 95% confidence intervals (CIs) for ever, moderate and highest consumption of coffee vs non/lowest consumption. The dose–response relationship was assessed by restricted cubic spline model and multivariate random-effect metaregression. RESULTS: A total of 12 case–control studies and 12 cohort studies with 42 179 cases were selected for final meta-analysis. No significant associations were found among overall analysis. A borderline positive association was found for highest drinkers in five small hospital-based case–control (HCC) studies involving 2278 cases. However, compared with non/lowest drinkers, the summary RRs were 0.92 (95% CI ¼ 0.85–0.99) for ever drinkers, 0.92 (95% CI ¼ 0.85–1.00) for moderate drinkers and 0.83 (95% CI ¼ 0.72–0.96) for highest drinkers from 12 cohort studies, comprising a total of 34 424 cases. An increase in coffee intake of two cups/day was associated with a 7% decreased risk of prostate cancer according to cohort studies. A significant inverse relationship was also found for fatal prostate cancers and high-grade prostate cancers. CONCLUSIONS: Case–control studies especially HCC ones might be prone to selection bias and recall bias that might have contributed to the conflicting results. Therefore, the present meta-analysis suggests a borderline significant inverse association between coffee consumption and prostate cancer risk based on cohort studies. European Journal of Clinical Nutrition (2014) 68, 330–337; doi:10.1038/ejcn.2013.256; published online 4 December 2013 Keywords: coffee; caffeine; prostate cancer; meta-analysis
INTRODUCTION Prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in men globally.1 In 2013, prostate cancer alone is expected to account for B28% of all new cancer cases among men of the United States.2 Coffee, the most common beverage in the Western world, can potentially impact the etiology of cancer of various sites along multiple pathways, ranging from carcinogenesis to cellular apoptosis. A number of epidemiological studies have sought to establish a relationship between coffee consumption and prostate cancer risk in the past three decades but with varying results. Two studies have shown an increased prostate cancer risk among coffee drinkers.3,4 However, the reduced risk of prostate cancer in coffee drinkers was observed in several studies.5–7 A meta-analysis,8 including the results of eight case–control studies and four cohort studies, found an overall relative risk (RR) of 1.16 (95% confidence interval (CI) ¼ 1.01–1.33) for highest vs lowest coffee drinkers, but the combination of four cohort studies demonstrated no association (RR ¼ 1.06; 95% CI ¼ 0.83–1.35). Another meta-analysis,9 combining five cohort studies, showed an inverse association of prostate cancer risk with high coffee intake (RR ¼ 0.79; 95% CI ¼ 0.61–0.98). However, both compared only lowest with highest intakes and neither included all the published studies available at the time of their compilations. Furthermore, many studies were
published after the previous meta-analysis. Therefore, we systematically conducted a meta-analysis by combining all available data of both case–control and cohort studies to derive a more precise estimation of this association. Besides, we also performed a dose–response analysis, because categories of coffee consumption differed between studies that might complicate the interpretation of the pooled results across study populations with different categories.
MATERIALS AND METHODS Search strategy In order to identify all the previous published studies on coffee consumption and risk of prostate cancer, PubMed, Web of Science and EMBASE were searched with the following keywords: ‘coffee’ and ‘prostate’ by two independent investigators (last search update: 7 July 2013). Reference lists were examined manually to further identify potentially relevant studies. All the studies matching the eligible criteria listed below were included in our meta-analysis.
Inclusion criteria The following inclusion criteria were used in selecting literature for further meta-analysis: (1) the exposure of interest was coffee consumption; (2) the outcome of interest was prostate cancer; (3) the type of study was
1 Center of Clinical Laboratory Science, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, China; 2The Fourth Clinical College of Nanjing Medical University, Nanjing, China; 3Department of Hematology (Key Department of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Nanjing, China; 4Department of General Surgery, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, China and 5Teaching and Research Office of General Surgery, Xuzhou Medical College, Xuzhou, China. Correspondence: J Zhao, Center of Clinical Laboratory Science, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing 210009, China. E-mail: [email protected] Received 13 July 2013; revised 30 October 2013; accepted 31 October 2013; published online 4 December 2013
Coffee consumption and prostate cancer risk S Zhong et al
331 case–control or cohort; and (4) the RR with their 95% CIs were reported (or information to calculate them).
Data extraction Two investigators extracted the data independently. Discrepancies were adjudicated by the third investigator until consensus was achieved on every item. The following information was abstracted from each included articles: the name of first author, year of publication, country origin, study period, study design, sample size (cases and noncases), the exposure to coffee consumption, the RRs and corresponding 95% CIs for each category of coffee consumption and confounders adjusted for in multivariate analysis, respectively.
Assessment of methodological quality The methodological quality of the included studies was independently evaluated by two investigators using the Newcastle–Ottawa Scale (NOS).10 Each study was assessed based on three broad perspectives: selection, comparability and exposure with a score ranging from 0 to 9. A score of X7 indicated that one study was of high quality. Discrepancies were adjudicated through discussion and re-evaluation of the methodology of the study in question.
Statistical methods All statistical analyses were done with Stata software (Version 12; Stata Corporation, College Station, TX, USA), and all tests were two sided. For a study that provided two OR or RR estimates based on population and cancer controls, we used the estimates derived from the population controls.11 If a study provided separate OR or RR estimates by age or subtype of the disease, we treated them as different studies.6,12 Risk estimates were extracted from each study, and log RRs were weighted by the inverse of their variances to obtain a pooled RR and its 95% CI. For each study, non/lowest drinkers represented the reference category, highest drinkers represented the greatest coffee consumption, moderate drinkers represented in-between coffee consumption and ever drinkers represented both greatest and moderate coffee consumption. First, we compared the risk of prostate cancer in ever coffee drinkers with non/ lowest drinkers. For studies that did not report a risk estimate for ever drinkers, a summary estimate was calculated using reported risk estimate for each coffee consumption category. Second, estimates comparing the highest with the non/lowest coffee consumption were calculated. Third, estimates were also calculated for moderate coffee consumption. A summary estimate was also calculated for studies that did not report a risk estimate for moderate drinkers. Statistical heterogeneity among studies was assessed with the Q and I2 statistics;13 a Po0.1 was considered significant.14 The fixed-effect model (the Mantel–Haenszel method)15 was used to access the pooled RRs if the heterogeneity was not significant, otherwise the random-effect model (the DerSimonian and Laird method)16 was used. Subgroup analyses were performed based on study design (hospital-based case–control (HCC) study, population-based case–control study and cohort study), geographic region (America, Asia and Europe), methodological quality (high (with a score X7) and low (with a score o7)) and subtype of prostate cancer (fatal, local, advanced, high grade (Gleason score 47) and low grade (Gleason score o7) prostate cancer) to explore the source of heterogeneity. Meta-regression17 was conducted to further explore the heterogeneity quantitatively among the studies (the analysis was based on highest vs non/lowest coffee consumption). Sensitivity analyses were performed to reflect the influence of the individual data on the summary RRs. Publication bias was evaluated using the Begg’s funnel plot and Egger’s test.18 A two-stage random-effects dose–response meta-analysis was performed to compute the trend from the correlated log RR estimates across levels of coffee consumption taking into account the between-study heterogeneity.19 For each study, we calculated the median cups of coffee consumption for each category by assigning the midpoint of upper and lower boundaries in each category as the average consumption. When the highest category was open ended, we assigned the lower end value of the category multiplied by 1.5. We examined a potential nonlinear dose– response relationship between coffee intake and risk of prostate cancer by modeling coffee levels using restricted cubic splines with three knots at percentiles 25, 50 and 75% of the distribution.20 A P-value for nonlinearity was calculated by testing the null hypothesis that the coefficient of the second spline is equal to 0. & 2014 Macmillan Publishers Limited
Studies were not eligible if the required data were not reported or could not be estimated. If coffee consumption was indicated by ml (or g),21,22 we defined 250 ml (or 250 g) of coffee equal to 1 cup. If coffee consumption was measured in a times/day (or occasions/day or drinks/day) scale,11,23,24 we assumed the scale equals to cups/day.
RESULTS Characteristics of the studies Figure 1 outlines the search strategy used to obtain relevant literature. A total of 313 titles and abstracts were identified and screened, and 36 studies were reviewed in detail. Six studies associated with benign prostatic hyperplasia were excluded. Three articles were excluded as their subjects were overlapped in other publications. One study was also excluded because it was not case–control or cohort design. After further excluding 2 reviews, 12 cohort studies6,7,22–31 and 12 case–control studies3,5,11,12,21,32–38 involving 527 486 participants and 42 179 cases of prostate cancer were selected for meta-analysis. The characteristics of the included studies are shown in Table 1. Supplementary Tables S1 and S2 present the methodological quality of studies included in the final analysis. The NOS results showed that the average score was 5.8 (range 4–8) for case–control studies and 7.5 (range 4–9) for cohort studies, indicating that the methodological quality of cohort studies was generally good. Evidence synthesis The pooled RRs of prostate cancer for the ever, moderate and highest coffee drinkers vs non/lowest drinkers are presented in Table 2. Compared with non/lowest drinkers, the summary RR was 0.98 (95% CI ¼ 0.92–1.03) for ever drinkers, 0.96 (95% CI ¼ 0.90–1.02) for moderate drinkers and 0.94 (95% CI ¼ 0.85–1.05) for highest drinkers. In the subgroup analyses by study design and subtype of prostate cancer, a statistically significant inverse association was observed for ever, moderate and highest coffee consumption in cohort studies (RR ¼ 0.92, 95% CI ¼ 0.85–0.99; RR ¼ 0.92, 95% CI ¼ 0.85–1.00; and RR ¼ 0.83, 95% CI ¼ 0.72–0.96, respectively) and fatal prostate cancers (RR ¼ 0.79, 95% CI ¼ 0.72–0.87;
Figure 1. Flowchart of the selection of publications included in the meta-analysis. European Journal of Clinical Nutrition (2014) 330 – 337
Coffee consumption and prostate cancer risk S Zhong et al
332 Table 1.
Characteristics of studies included in the meta-analysis
First author
Year
Country
Follow-up period
Study design
Cases
Noncases
Coffee consumption
Relative risk (95% CI)
Wilson5
2013
Sweden
2001–2002
PCC
1489
1112
o1 cup/day 1 to o2 cups/day 2 to o4 cups/day 4–5 cups/day 45 cups/day
OR 1.00 0.97 (0.62–1.52) 0.98 (0.65–1.49) 1.06 (0.69–1.62) 0.97 (0.60–1.57)
Age, region, smoking, BMI, education and intake of calcium, zinc and total energy
Geybels38
2013
USA
2002–2005
PCC
894
860
p1 cup/week 2–6 cups/week 1 cup/day 2–3 cups/day X4 cups/day
OR 1.00 1.22 (0.88–1.69) 1.13 (0.84–1.51) 1.16 (0.90–1.50) 1.16 (0.82–1.63)
Age, race, first-degree family history of prostate cancer, smoking status and history of prostate cancer screening
Polesel32
2012
Italy
1991–2002
HCC
1294
1451
o1 cup/day 1–2 cups/day 3–4 cups/day 45 cups/day
OR 1.00 1.05 (0.83–1.32) 1.11 (0.86–1.43) 1.05 (0.70–1.58)
Center, age, education, occupational physical activity, family history of prostate cancer, diabetes, smoking habits, drinking habits, nonalcohol energy intake, BMI, BMI at age 30 years
Deneo-Pellegrini37
2012
Uruguay
1996–2004
HCC
326
640
I tertile II tertile III tertile
OR 1.00 1.54 (0.91–2.59) 1.37 (0.82–2.29)
Age, residence, urban/rural status, education, family history of prostate cancer among first degree relatives, BMI and total energy intake
Ganesh36
2011
India
1999–2001
HCC
123
167
No Yes
OR 1.00 1.3 (0.6–2.7)
Chen3
2005
China
1996–1998
HCC
237
481
No Yes
OR 1.00 1.88 (1.07–3.30)
Sharpe11
2002
Canada
1979–1985
PCC
398
476
None 1–2 drinks/day 3–4 drinks/day X5 drinks/day
OR 1.00 1.1 (0.6–1.9) 1.1 (0.6–1.9) 0.9 (0.5–1.7)
Age, ethnicity, respondent status, family income, BMI, cumulative cigarette smoking and cumulative alcohol consumption
Hsieh35
1999
Greece
1994–1997
HCC
298
214
None o1 cup/day 1 to o2 cups/day 2 to o3 cups/day 3 þ cups/day
OR 1.00 0.38 (0.15–0.99) 0.72 (0.35–1.45) 0.57 (0.29–1.12) 1.15 (0.53–2.47)
Age, height, BMI and years of schooling
Villeneuve34
1999
Canada
1994–1997
PCC
1410
1397
None o1 cup/day 1 to o4 cups/day X4 cups/day
OR 1.00 0.8 (0.6–1.1) 1.0 (0.7–1.3) 1.1 (0.8–1.5)
Age, province of residence, race, years since quitting smoking, cigarette packyears, BMI, rice and pasta, coffee, grains and cereals, alcohol, fruit and fruit juices, tofu, meat, income and family history of cancer
Jain21
1998
Canada
1989–1993
PCC
617
636
0 g/day 40–500 g/day 4500 g/day
OR 1.00 0.84 (0.58–1.22) 0.97 (0.65–1.44)
Age and total energy intake
Gronberg33
1996
Sweden
1959–1989
PCC
311
910
0 cup/day 1–2 cups/day 3–5 cups/day 6–9 cups/day
OR 1.00 1.77 (0.65–5.09) 1.99 (0.78–5.46) 1.91 (0.73–5.30)
Specific food items, smoking habits and alcohol consumption.
Slattery12
1993
USA
1984–1985
PCC
358
679
p67 years 0 cup/week 1–20 cups/week 420 cups/week 467 0 cup/week 1–20 cups/week 420 cups/week
Discacciati6
2013
Sweden
1998–2010
Cohort
European Journal of Clinical Nutrition (2014) 330 – 337
3801
40 812
Localized PCa None o1 cup/day 1–3 cups/day 4–5 cups/day X6 cups/day Advanced PCa None o1 cup/day 1–3 cups/day 4–5 cups/day X6 cups/day Fatal PCa a None o1 cup/day 1–3 cups/day 4–5 cups/day X6 cups/day
Covariate adjustment
Age, religion and education Age and BMI
Age OR 1.00 0.99 (0.68–1.47) 1.09 (0.75–1.60) OR 1.00 1.09 (0.73–1.61) 0.88 (0.58–1.34) RR 1.00 1.02 (0.82–1.28) 0.89 (0.74–1.08) 0.69 (0.57–0.85) 0.52 (0.41–0.65)
Age, tea, alcohol, BMI, personal history of diabetes, family history of PCa, smoking status, physical activity, education and total energy intake
RR 1.00 1.56 (1.06–2.35) 1.29 (0.93–1.86) 0.81 (0.56–1.19) 0.55 (0.36–0.86) RR 1.00 1.39 (0.88–2.26) 0.93 (0.63–1.42) 0.60 (0.38–0.95) 0.36 (0.20–0.64)
& 2014 Macmillan Publishers Limited
Coffee consumption and prostate cancer risk S Zhong et al
333 Table 1. (Continued ) First author
Year
Country
Follow-up period
Study design
Cases
Noncases
Coffee consumption
Relative risk (95% CI)
Bosire31
2013
USA
1995–2006
Cohort
23 335
265 056
None o1 cup/day 1 cup/day 2–4 cups/day 4–5 cups/day X6 cups/day
HR 1.00 1.03 (0.98–1.08) 1.00 (0.95–1.06) 1.00 (0.96–1.05) 1.00 (0.94–1.06) 0.94 (0.87–1.02)
Age, race, height, BMI, physical activity, smoking, history of diabetes, family history of prostate cancer, PSA testing, intakes of tomato sauce, a-linolenic acid and total energy intake
Li29
2013
Japan
1995–2005
Cohort
318
18 217
Never Occasionally 1–2 cups/day X3 cups/day
HR 1.00 0.82 (0.62–1.08) 0.74 (0.54–1.01) 0.63 (0.39–1.00)
Age, education level, BMI, time engaging in sports or exercise, marital status, time spent walking, smoking status, family history of cancer, consumption of tea, job status, daily total energy intake, passive smoking, alcohol drinking, daily consumption of miso soup
Shafique30
2012
UK
1970–2007
Cohort
318
5699
0 cup/day 1–2 cups/day X3 cups/day
HR 1.00 0.95 (0.72–1.24) 0.93 (0.66–1.31)
Age at screening, cholesterol, systolic blood pressure, BMI, alcohol intake, tea consumption, smoking status, social class
Wilson7
2011
USA
1986–2006
Cohort
5035
42 876
None o1 cup/day 1–3 cups/day 4–5 cups/day X6 cups/day
RR 1.00 0.94 (0.85–1.05) 0.94 (0.86–1.04) 0.93 (0.83–1.04) 0.82 (0.68–0.98)
Race, height, BMI at age 21, current BMI, vigorous physical activity, smoking, diabetes, family history of prostate cancer in father or brother, multivitamin use, intakes of processed meat, tomato sauce, calcium, a-linolenic acid, supplemental vitamin E, alcohol intake, energy intake and history of PSA testing
Nilsson24
2010
Sweden
1992–2007
Cohort
653
30 930
o1 occasions/day 1–3 occasions/day X4 occasions/day
HR 1.00 0.92 (0.70–1.21) 1.03 (0.77–1.38)
Age, sex, BMI, smoking, education and recreational physical activity
Ellison22
2000
Canada
1969–1993
Cohort
145
3255
0 ml/day 40–250 ml/day 4250–500 ml/day 4500–750 ml/day 4750 ml/day
RR 1.00 1.14 (0.66–1.97) 1.42 (0.80–2.52) 1.35 (0.75–2.43) 1.42 (0.77–2.61)
Five-year age group, wine consumption
Le Marchand27
1994
USA
1975–1980
Cohort
198
8881
1 2 3 4
Stensvold25
1994
Norway
1977–1990
Cohort
38
21 697
p2 3–4 5–6 X7
Hsing28
1990
USA
1966–1986
Cohort
149
17 633
o3 cups/day 3–4 cups/day X5 cups/day
RR 1.00 0.8 (0.6–1.2) 1.0 (0.6–1.6)
Age
Severson23
1989
USA
1965–1986
Cohort
174
7824
p1 times/week 2–4 times/week X5 times/week
RR 1.00 0.96 (0.39–2.37) 0.92 (0.59–1.44)
Age
Jacobsen26
1986
Norway
1964–1978
Cohort
260
13 404
p2 cup/day 3–4 cups/day 5–6 cups/day X7 cups/day
RR 1.00 0.61 (0.39–0.95) 0.64 (0.45–0.90) 0.88 (0.66–1.18)
Age, residence and cigarette smoking
Quantile Quantile Quantile Quantile cups/day cups/day cups/day cups/day
RR 1.00 0.9 (0.6–1.4) 1.2 (0.8–1.8) 1.1 (0.7–1.7) RR 1.00 0.34 (0.10–1.10) 0.61 (0.23–1.69) 0.47 (0.17–1.35)
Covariate adjustment
Age, ethnicity and income
Age, cigarettes per day and county of residence
Abbreviations: BMI, body mass index; CI, confidence interval; HCC, hospital-based case–control study; HR, hazard ratio; OR, odds ratio; PCa, prostate cancer; PCC, population-based case–control study; PSA, prostate-specific antigen; RR, relative risk. aThe subgroup was only included in the subgroup analysis by subtype of prostate cancer as its subjects were overlapped in the other two subgroups.
RR ¼ 0.80, 95% CI ¼ 0.73–0.88; and RR ¼ 0.61, 95% CI ¼ 0.42–0.90, respectively) and for highest coffee consumption in high-grade prostate cancers (RR ¼ 0.70, 95% CI ¼ 0.52–0.94). However, a borderline positive association was found for highest coffee consumption in HCC studies (RR ¼ 1.29, 95% CI ¼ 1.01–1.65; Figure 2). No significant associations were found in other subgroups (not all data shown). We assessed the dose–response relationship between coffee levels and the risk of prostate cancer with 18 studies.5–7,11,12,21–26,29–31,33–35,38 Statistically significant departure from linearity was found for all studies (P ¼ 0.04; Figure 3a), but not for cohort studies (P ¼ 0.07; Figure 3b) and case–control & 2014 Macmillan Publishers Limited
studies (P ¼ 0.38). A 2 cups/day increment in coffee consumption level conferred an RR of 0.97 (95% CI ¼ 0.94–1.01) for overall result, 0.93 (95% CI ¼ 0.88–0.99) for cohort studies and 1.04 (95% CI ¼ 1.00–1.08) for case–control studies. Sensitivity analysis and publication bias From the results of the leave-one-out sensitivity analysis, the summary RRs were not materially altered (data not shown). We explored the source of heterogeneity by study design (HCC, population-based case–control and cohort studies), geographic region (America, Asia and Europe) and methodological quality European Journal of Clinical Nutrition (2014) 330 – 337
Coffee consumption and prostate cancer risk S Zhong et al
European Journal of Clinical Nutrition (2014) 330 – 337
Abbreviations: CI, confidence interval; HCC, hospital-based case–control study; High grade, Gleason score 47; Low grade, Gleason score o7; PCC, population-based case–control study; Ph, P-value of Q-test for heterogeneity test (random-effects model was used when P-value for heterogeneity test was o0.1, otherwise fix-effects model was used); RR, relative risk. Values in bold font indicate statistical significance (Po0.05). aIf a study provided separate OR or RR estimates by age or subtype of the disease, we treated them as different studies.6,12
61.4 79.4 75.8 34.9 0.0 0.61 (0.42–0.90) 0.74 (0.47–1.17) 0.71 (0.47–1.08) 0.70 (0.52–0.94) 1.07 (0.89–1.29) 2530 4191 5227 1367 4137 Subtype of prostate cancer Fatal 5 Local 4 Advanced 5 High-grade 5 Low-grade 5
0.79 (0.72–0.87) 0.95 (0.79–1.13) 0.90 (0.75–1.09) 0.87 (0.60–1.24) 1.06 (0.99–1.14)
0.60 0.07 0.00 0.00 0.25
0.0 58.1 78.3 88.3 25.3
5 4 5 5 5
2430 3835 4988 1292 3871
0.80 (0.73–0.88) 1.00 (0.89–1.11) 0.94 (0.79–1.12) 0.91 (0.64–1.31) 1.06 (0.98–1.14)
0.78 0.23 0.00 0.00 0.39
0.0 30.8 74.6 85.2 2.4
5 4 5 5 5
484 801 721 285 847
0.04 0.00 0.00 0.19 0.67
66.5 0.0 0.87 (0.75–1.01) 1.07 (0.94–1.22) 35 035 7144 Methodological quality High 15 Low 11
0.95 (0.88–1.03) 1.03 (0.96–1.10)
0.00 0.15
67.9 31.4
15 11
33 052 5797
0.95 (0.87–1.03) 1.01 (0.93–1.09)
0.00 0.11
63.4 36.9
15 11
5659 2513
0.00 0.84
4.8 0.0 0.0 66.5 1.11 (0.98–1.26) 1.05 (0.90–1.22) 1.29 (1.01–1.65) 0.83 (0.72–0.96) 7755 5477 2278 34 424 13 8 5 13 Study design Case–control PCC HCC Cohort
1.07 (0.96–1.18) 1.05 (0.96–1.14) 1.16 (0.86–1.56) 0.92 (0.85–0.99)
0.06 0.29 0.02 0.00
41.1 18.0 64.8 65.3
10 8 2 11
6142 4414 1707 32 728
1.02 (0.91–1.16) 1.04 (0.94–1.15) 0.98 (0.61–1.56) 0.92 (0.85–1.00)
0.06 0.34 0.01 0.00
43.2 11.8 79.2 61.4
13 8 5 13
2801 1871 930 5371
0.80 0.88 0.59 0.00
53.8 0.00 0.94 (0.85–1.05) 42 179 26 All studies
0.98 (0.92–1.03)
0.00
57.9
21
38 849
0.96 (0.90–1.02)
0.00
53.9
26
8172
Ph RR (95% CI) Cases, n Ph RR (95% CI) Cases, n Study, na
Cases, n
RR (95% CI)
Ph
I2,%
Study, n
Moderate drinkers vs non/lowest drinkers Ever drinkers vs non/lowest drinkers Variables
Table 2.
Summary risk estimates and 95% CIs for coffee consumption and risk of prostate cancer
I2,%
Study, n
Highest drinkers vs non/lowest drinkers
I2,%
334 (continuous variable) with meta-regression. The results for the highest vs non/lowest coffee consumption revealed that study design (P ¼ 0.04) and methodological quality (P ¼ 0.01) but not geographic region (P ¼ 0.10) contributed to the source of heterogeneity. Begg’s funnel plot and Egger’s test were used to assess the publication bias of included studies. The graphical funnel plots for all the three comparisons appeared to be symmetrical (Figure 4). Then, Egger’s test was used to provide statistical evidence of funnel plot symmetry. The results still did not show any evidence of publication bias in the overall meta-analysis for the ever, moderate and highest coffee drinkers vs non/lowest drinkers (t ¼ 0.30, P ¼ 0.77; t ¼ 0.96, P ¼ 0.35; and t ¼ 0.83, P ¼ 0.42, respectively). DISCUSSION This meta-analysis investigated the association between coffee consumption and prostate cancer risk on the basis of previously published researches involving 527 486 participants and 42 179 cases of prostate cancer. The overall summary results indicated no association of coffee consumption with prostate cancer risk. However, an inverse association between coffee consumption and risk of prostate cancer was observed in cohort studies, whereas no association was observed from case–control studies. Interestingly, the five HCC studies with only 2278 cases showed an increased risk of prostate cancer among highest coffee drinkers (Figure 2 and Table 2). We noted that there were four HCC studies3,32,36,37 with smallest sample size that was o1000. In addition, a more precise scale (for example, cups/day) was not used to measure the coffee consumption in three HCC studies,3,36,37 two3,36 of which only quantified coffee consumption as ‘yes’ or ‘no’ (Table 1). We also noted that the HCC study conducted in China reported an extremely significant result, and the number of coffee consumers in the sample was very low, consisting of 31 cases (13.1%) and 36 controls (7.5%).3 After removing this study, the significant result of HCC studies disappeared. In the previous meta-analysis by Park et al.,8 case–control and cohort studies also showed different association results (RR ¼ 1.21, 95% CI ¼ 1.03–1.43; and RR ¼ 1.06, 95% CI ¼ 0.83–1.35, respectively). Their conflicting results might be because of the study mentioned above3 and another study by Gallus et al.4 that was excluded in present meta-analysis because its subjects were overlapped by a larger study.32 In the study by Gallus et al.,4 the authors reported an increased risk of prostate cancer for highest coffee consumption with 219 cases and 431 controls. However, the larger study32 showed no association anymore with 1294 cases and 1451 controls. Case–-control studies especially HCC ones give a lower level of evidence than cohort studies and might provide spurious results because of selection bias and recall bias that might have contributed to the conflicting results in the present meta-analysis. In addition to what is mentioned above, we could easily find that the methodological quality of case–control studies was generally lower (Supplementary Table S1). More than half the studies did not use a representative case population, and almost all ascertained the exposure to coffee without blinding to case–control status. Therefore, the results might have suffered from biases, thus contributing to spurious results. Taking account of all the above-mentioned aspects, we concluded that coffee consumption is associated with decreased risk of prostate cancer. Several studies have explored coffee consumption and incidence of prostate cancer by subtype of the disease.5–7,28–32,38 The results from the subgroup analysis showed a strong inverse association between coffee consumption and fatal or high-grade prostate cancer risk, suggesting that coffee may be implicated in preventing progression of prostate cancer. A recent study indicated that higher prediagnostic coffee consumption was associated with a lower risk of prostate cancer recurrence/progression.39 The authors defined & 2014 Macmillan Publishers Limited
Coffee consumption and prostate cancer risk S Zhong et al
335
Figure 2. Summary relative risks of prostate cancer for highest coffee consumption vs non/lowest coffee consumption. The squares and horizontal lines correspond to the study-specific RR and 95% CIs. The area of the squares reflects the study-specific weight. The diamond represents the pooled RR and 95% CI.
recurrence/progression as patients who died of prostate cancer, developed metastasis, received secondary treatment or had a rising prostate-specific antigen. Nevertheless, they evaluated daily coffee consumption (X1 cup/day vs o1 cup/day) in relation to prostate cancer-specific mortality and observed a nonsignificant 23% lower risk, which might be because of the limited sample size. Therefore, additional large prospective studies of the relationship between coffee consumption and prostate cancer outcomes, including recurrence/progression and prostate cancer-specific mortality, are urgently needed to confirm whether coffee intake is beneficial for secondary prevention. Because the categories of coffee consumption differed between studies, which might complicate the interpretation of the pooled results across study populations with different categories, we also performed dose–response analyses. A nonlinear and not significant dose–response association was found between coffee consumption and prostate cancer risk, and a 2 cups/day increment in coffee consumption level was associated with a 0.97-fold reduced prostate cancer risk. When restricted to cohort studies, a linear and significant dose–response association was found, and the risk of prostate cancer was decreased by 7% for every 2 cups/ day increment in coffee consumption. & 2014 Macmillan Publishers Limited
Numerous investigations in animals and in vitro cell cultures have tried to establish a link between coffee and cancer. Coffee contains a large number of compounds, some of which have been identified as having potentially chemopreventive effects. Caffeine, one of the major components of coffee, could slightly stimulate apoptosis of prostate cancer cells through activating ryanodine receptor.40 Studies,7,31 however, showed that regular and decaffeinated coffee showed no difference on risk of prostate cancer, suggesting that noncaffeine components of coffee may play more important roles in preventing prostate cancer development. Coffee is also a major source of antioxidants that have been indicated to have an inhibitory effect on carcinogenesis of prostate cancer.41 Coffee has been observed to be associated with increased total testosterone and sex hormone-binding globulin concentrations.42 Evidences suggested that free testosterone was inversely associated with the risk of advanced prostate cancer,43 and sex hormone-binding globulin decreased prostate cancer risk in younger men.44,45 Coffee has also been observed to increase the level of plasma adiponectin46 that was associated with decreased prostate cancer risk.47 A study reported that p53 and bcl-2, two key regulators of apoptosis, were modulated by adiponectin in prostate cancer cells.48 It has been European Journal of Clinical Nutrition (2014) 330 – 337
Coffee consumption and prostate cancer risk S Zhong et al
336
Figure 3. The dose–response analysis between coffee intake and prostate cancer risk with restricted cubic splines in a multivariate randomeffects dose–response model for (a) all studies and (b) cohort studies. The solid line and the long dash line represent the estimated RR and its 95% CI. Short dash line represents the linear relationship.
further prospective cohort studies with larger sample size, wellcontrolled confounding factors, long enough follow-up time and more accurate assessment of coffee consumption is essential. CONFLICT OF INTEREST The authors declare no conflict of interest.
REFERENCES
Figure 4. Begg’s funnel plot of studies on coffee consumption and prostate cancer risk for ever drinkers versus non/lowest drinkers. The solid line in the center is the natural logarithm of pooled RR, and two oblique lines are pseudo 95% CIs.
shown that serum adiponectin was inversely correlated with serum insulin-like growth factor 1.49 There were evidences to suggest that elevated blood levels of insulin-like growth factor 1 have been associated with several cancers, most commonly with prostate cancer.50 Combined with our results, it seems that coffee intervened in prostate cancer development. The potential limitations of our study should be considered when interpreting the results. First, the possibility of bias and confounding cannot be excluded for all observational studies of diet and disease. Second, our results are likely to be affected by some misclassification of coffee consumption. Coffee exposure is mostly assessed regarding the number of cups of coffee consumed daily or weekly. However, cup size and brew strength may vary considerably. In addition, there can be important differences in the concentration of coffee components, depending on the coffee variety. Third, our search was restricted to published studies, whereas unpublished studies or original data were not searched. Finally, studies included in this meta-analysis were major conducted in Western countries, and hence the results should be extrapolated to other populations with caution. In conclusion, our data suggest that coffee consumption or an increased coffee consumption may influence the risk of prostate cancer based on the findings of cohort studies. Regarding the significant heterogeneity among included studies, confirmation in European Journal of Clinical Nutrition (2014) 330 – 337
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