Alcohol Consumption and the Risk of Prostate Cancer: A Dose-Response Meta-Analysis

Alcohol is widely consumed and is known as a major risk factor for several types of cancers. Yet, it is unclear whether alcohol consumption is associated with the risk of prostate cancer (PCa) or not. We conducted linear and non-linear dose–response meta-analyses of cohort studies on alcohol consumption and PCa risk by types of alcohol (total, wine, beer, and liquor) and PCa (non-aggressive and aggressive). Pubmed and Embase were searched through April 2020 to identify relevant studies. Summary relative risk (RR) and 95% confidence interval (CI) were estimated using a random-effects model. For non-aggressive PCa, by alcohol type, the risk increased linearly with liquor (RR per 14 g/day intake (alcohol content in standard drink) being 1.04 (95% CI = 1.02–1.06, I2 = 0%, three studies) and non-linearly with beer (Pnon-linearity = 0.045, four studies), with increased risk observed in the lower range (RR = 1.03, 95% CI = 1.01–1.05; 14 g/day), with 1.05 (95% CI = 1.01–1.08) at 28 g/day. Wine was not significantly associated with the risk of non-aggressive PCa. For aggressive PCa, a non-linear relationship of diverse shapes was indicated for all types of alcohol in the sensitivity analysis. Compared to non-drinking, a significant positive association was more apparent at lower dose for liquor (RR = 1.12, 95% CI = 1.04–1.20 at 14 g/day; RR = 1.16, 95% CI = 1.03–1.31 at 28 g/day; Pnon-linearity = 0.005, three studies) but at higher doses for wine (RR = 1.02, 95% CI = 0.90–1.16 at 28 g/day, RR = 1.35, 95% CI = 1.08–1.67 at 56 g/day; Pnon-linearity = 0.01, four studies). In contrast, decreased risks were indicated at lower doses of beer (RR = 0.85, 95% CI = 0.79–0.92 at 14 g/day; RR = 0.79, 95% CI = 0.70–0.90 at 28 g/day, Pnon-linearity < 0.001, four studies). Total alcohol consumption was not associated with both types of PCa. In this study, we found heterogeneous associations between alcohol intake and PCa by types of alcohol and PCa.

We did not employ a search software.
EndNote was used to merge retrieved articles and eliminate duplications. √

Use of hand searching
The reference lists of all the articles included in this analysis were also reviewed for additional studies.

Method of addressing articles published in languages other than English
We restricted the language to English.

Method of handling abstracts and unpublished studies
We excluded abstracts and unpublished results.

Description of any contact with authors
No author contact was made for this manuscript.

Reporting of methods should include
√ Description of relevance or appropriateness of studies assembled for assessing the hypothesis to be tested Only articles published in English were used, and no other restrictions were imposed. Abstracts and unpublished results were excluded.

Rationale for the selection and coding of data
From each study, the following information was extracted: multivariable-adjusted RR and corresponding 95% confidence interval in each category of alcohol consumption, categoryspecific range of alcohol consumption and unit, alcoholic beverage type (total, wine, beer, and liquor), PCa types (nonaggressive and aggressive), category-specific or total number of cases, non-cases and person years, first author's name, publication year, characteristics of study population (e.g., country, sex, age at enrollment), and variables adjusted for.

Assessment of confounding
We extracted the most fully adjusted RRs; conducted sensitivity analyses and meta-regression by adjustment for important confounders.

√
Assessment of study quality, including blinding of quality assessors; stratification or regression on possible predictors of study results We conducted sensitivity analyses by repeating the linear and non-linear dose-response meta-analysis among studies that provided the results for both non-aggressive and aggressive PCa.
√ Assessment of heterogeneity Potential heterogeneity in the relationship between alcohol risk and PCa risk across studies was tested by Cochran's Q test and quantified by I 2 , the percentage of total variation across studies that is attributable to true heterogeneity rather than to chance. The presence of small study effects, such as publication bias, was checked by Egger's test.
√ Description of statistical methods in sufficient detail to be replicated Description of dose-response meta-analysis was detailed in the methods.

Provision of appropriate tables and graphics
We included 5 figures (flow chart, forest plots). Additional tables and figures were also provided in online-only materials.

Reporting of results should include
√ Graph summarizing individual study estimates and overall estimate

Reporting of discussion should include
√ Quantitative assessment of bias Robustness of our findings was stated based on results from sensitivity analyses.
We assessed potential bias due to PSA testing by subgroup analysis.

Justification for exclusion
We did not make any specific exclusion to justify. √

Assessment of quality of included studies
PSA is an important confounder that we conducted a subgroup analysis, but the results were consistent.

Consideration of alternative explanations for observed results
In the paragraph for limitations, potential biases were thoroughly discussed.
√ Generalization of the conclusions Liquor may be associated with increased risk of any PCa over a wide range of intake. For wine, heavy intake may have a harmful effect on the risk of aggressive PCa. Beer might be modestly harmful for non-aggressive PCa but protective against aggressive PCa.
√ Guidelines for future research Future studies are warranted to confirm our heterogeneous findings and to explain an inverse association between beer intake and aggressive PCa.
√ Disclosure of funding source We declared no external funding for this work in the acknowledgement section.

Supplementary Figure S2. Sensitivity analyses of total alcohol intake and prostate cancer risk: (A) linear analysis with non-aggressive PCa risk; (B) non-linear analysis with non-aggressive PCa risk; (C) linear analysis with aggressive PCa risk; (D) non-linear analysis with aggressive PCa risk.
Abbreviations: CI, confidence interval; PCa, prostate cancer; RR, relative risk. Figure S2A. Figure S2B.