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The Association Between Inflammatory Bowel Disease and Prostate Cancer Risk: a Meta-Analysis - Full Text Article

Background: Patients with inflammatory bowel disease (IBD) are at increased risk of gastrointestinal and extraintestinal malignancies. However, the associations between IBD and prostate cancer (PCa) risk remain conflicting.

Methods: We conducted a systematic literature search in PubMed, EMBASE, and Web of Science databases. According to the inclusion and exclusion criteria, a total of nine studies were included in the meta-analysis. The pooled standardized incidence ratios (SIRs) or relative risks (RRs) and corresponding 95% confidence intervals (CIs) were calculated to determine the relationship of IBD and PCa risk. Results: For cohort studies, the pooled SIR was 1.33 (95% CI = 1.03–1.71). The further subgroup analysis showed that the PCa risk was higher in patients with ulcerative colitis (UC) (pooled SIR = 1.58, 95% CI = 1.08–2.30), but not in patients with Crohn’s disease (CD) (pooled SIR = 1.12, 95% CI = 0.97–1.31). Besides, for the three case-control studies, the results indicated that compared with normal group, the pooled RR of PCa was 1.81 for the patients with IBD (95% CI = 1.43–2.29). In addition, sensitivity analysis indicated that the results were robust and no significant publication bias were observed.

Conclusions: Our findings based on the large and multicenter samples strongly indicated that men with IBD especially UC have significantly elevated PCa risk. Future efforts are needed to define the mechanism underlying the link between IBD and PCa or clinically significant PCa risk.

Introduction

Inflammatory bowel disease (IBD) is a common chronic inflammatory condition of small intestine and colon, comprised of Crohn’s disease (CD) and ulcerative colitis (UC).1It is reported that about 2.5–3.0 million individuals in Europe and over 1 million patients in the USA are estimated to suffer from IBD.2,3Moreover, a recent study showed that the incidence and prevalence of IBD were increased in newly industrialized countries4and the majority of new IBD diagnoses are made in early life.5 IBD is complex and costly, and leads to a great burden on health care system.6Therefore, IBD has emerged as a growing public health problem in the world. IBD is characterized by relapsing inflammation of the gastrointestinal tract and causes the aberrant immune response against the mucosal barriers.7 Mounting evidence shows that the inflammation is a major risk factor for cancer development.8 It is noteworthy that patients with IBD are at increased risk of gastrointestinal malignancies, such as colorectal cancer.9

Emerging evidence has shown that IBD was also a risk factor for extraintestinal malignancies,10 including lymphoma, cholangiocarcinoma, melanoma.11 The risk of cancers among patients with IBD has been widely investigated in the previous cohort studies and case control studies.11,12However, there are inconclusive studies on PCa risk for patients with IBD.13,14 In the present study, we conducted a comprehensive meta-analysis to investigate the association between IBD and the PCa risk.

Material and methods

Search strategy

The PubMed, EMBASE, and Web of Science databases were used to search the relative articles from inception until May 6, 2019. The search keywords were: (Inflammatory bowel disease) AND (Prostate cancer). The systematic search and data extraction were performed using the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) guidelines  (Supplementary file 2). Two authors assessed the study eligibility and extracted the data independently. Any disagreement was resolved through discussion.

Data extraction and risk of bias assessment

Data was extracted using an agreed data extraction form. Eligible studies for inclusion were the following prespecified criteria: (1) these studies should be designed to estimate the relationship between IBD and the PCa risk; (2) the sample size should be more than 1000; (3) these studies should record PCa outcomes over more than 3 years of follow-up; (4) these studies should report the standardized incidence ratios (SIRs) or relative risks (RRs) and the corresponding 95% confidence intervals (CIs), or sufficient information to calculate them. If more than one article was published using the same population, we selected the most recent or most informative report. The primary end point was PCa. Finally, a total of nine studies were included in meta-analysis [13–21]. Data were extracted from eligible studies using a predesigned form, including PMID, the first author, country, year, type of study, period, study size, evaluating index and adjusted covariates. Furthermore, SIRs or RRs and their corresponding 95% CIs were also extracted. 

Newcastle-Ottawa Scale (NOS) was used to evaluate the methodological bias of included studies. The NOS used a ‘star system’ to assess the quality of study from three perspectives: the selection of the studies, the comparability of studies, and the assessment of outcome.

Statistical analysis

STATA version 11 (StataCorp LP, College Station, TX, USA) was used to conduct meta-analysis. Heterogeneity between studies was assessed by Cochran’ Q and I2 statistics. If heterogeneity (Q-test’s P < 0.05 or I2 > 50%) was observed between studies, the random-effect (RE) model was applied. Otherwise, fixed-effect (FE) model was used. Besides, statistical risk of publication bias was evaluated by Begg’s funnel plot and Egger’s test. The statistical analyses were two sided and P value <0.05 was treated as statistically significant. Analyses were carried out by using the ‘metaphor’ package of R software (R-3.5.1).

Results

Characteristics of study subjects 

We identified 416 reports according to our search strategies. After comprehensive evaluation, a total of nine studies were chosen in the final meta-analysis (Fig. 1). Characteristics of studies included in this meta-analysis was summarized in the Table 1 and Supplementary Table 1. There were five studies from Europe, two from Asia, and two from North America. The nine studies included six cohort studies and three case-control studies. The cohort studies included 86,137 subjects and there were 22,760 IBD cases and 300,851 IBD-free subjects in the case-control studies. The follow-up durations ranged from 4 to 40 years. 

Meta-analysis result 

For cohort studies, the pooled SIRs for each outcome are shown in Fig. 2a. Patients with IBD were at increased risk of PCa (pooled SIR = 1.33, 95% CI = 1.03–1.71, I2 = 84.7%). In the subgroup analysis, the PCa risk was higher in patients with UC (pooled SIR = 1.58, 95% CI = 1.08–2.30,I2 = 90.5%), but not in patients with CD (pooled SIR = 1.12, 95% CI = 0.97–1.31, I2 = 42.0%). For case-control studies, the results showed that compared with normal group, the pooled RR of PCa was 1.81 for the patients with IBD (95% CI = 1.43–2.29, I2 = 95.7%, Fig. 2b). Because two case-control studies lacked of information about IBD subtype, we did not conduct a subgroup analysis for UC and CD patients.

Fig. 1 - Flow diagram of identification, inclusion of eligible studies and the reasons for exclusion

Fig1_FlowDiagram.png
Table 1 - Characteristics of individual studies included in this meta-analysis
Table1_Studies_MetaAnalysis.png

Fig. 2 — Forest plots of IBD associated with PCa risk. Pooled SIRs from cohort studies (a) and pooled RRs from case-control studies (b). The black box and horizontal lines represent the study specific SIR or RR and 95% CI. The red diamond shows the pooled SIR or RR and 95% CI. If heterogeneity (Q-test’s P < 0.05 or I2 > 50%) was observed between studies, the random-effect (RE) model was applied. Otherwise, fixed-effect (FE) model was used. Analyses were carried out by using the ‘metaphor’ package of R software (R-3.5.1)

Fig2_ForestPlots_IBD.png

Fig. 3 Begg’s funnel plot for UC (a), CD (b) in cohort studies and case-control studies (c). Sensitivity analysis for UC (d), CD (e) in cohort studies and case-control studies (f)

Fig3_BeggsFunnelPlot.png

The risk of methodological bias was evaluated by Newcastle-Ottawa Scale (Supplementary Table 2). The average of NOS quality score was 6.8 for all included studies. Moreover, the results of Begg’s tests showed that there was no evidence of publication bias in the present study and the P value of Egger’s test for UC and CD patients were 0.140 and 0.626, respectively (Fig. 3a, b). Besides, no significant publication bias was observed in the three case-control studies (P = 0.569; Fig. 3c). We used sensitivity analyses to assess the change by sequentially excluding each study from the meta-analysis and the results showed that no eligible study influenced the pooled results materially (Fig. 3d, e).

Discussion

In the present meta-analysis, we assessed the effect of IBD on the development of PCa based on cohort studies, and found that IBD patients was significantly associated with an increased PCa risk. Further subgroup analysis revealed that UC patients had higher risk of PCa, but no remarkable association was observed for CD patients. In addition, the pooled results of three case-control studies indicated that compared with IBD-free patients, IBD patients were related to a significantly higher risk of PCa. Actually, there has been wide consensus that patients with IBD was at high risk of intestinal cancer.22According to the report by Herrinton et al., compared with the general population, patients with IBD had 60% higher
incidence of colorectal cancer.23 Interesting, mounting involved in the development of extraintestinal cancer, such as hematologic cancer, lung cancer and non-Hodgkin lymphoma.16,24 Previous studies have investigated the relationship between IBD and the risk of PCa, but the effect of IBD on PCa development remain debated.14,17,21 Globally, PCa is the most common cancer in men with about 1.4 million new cases and 0.38 million deaths in 2016. Moreover, the increasing incidence rates was 40% in PCa cases since 2006.25 It is well known that chronic prostatic inflammation may act as a key role in the development of PCa.8 Inflammation is involved in proliferative inflammatory atrophy, which is a putative PCa lesions. Besides, Inflammation might promote prostate mutagenesis via oxidative stress and regulate epigenetic alterations that induced neoplastic transformation.8,26 In view of the importance of chronic inflammation in PCa carcinogenesis and lack of consistent evidence about the effect of IBD on the PCa, determination of the association between IBD and PCa risk will provide information beneficial to our better understand of risk factors of PCa. In this study, we conducted a large-scale meta-analysis and found that IBD patients had a significantly higher PCa risk in comparison to IBD-free population. Therefore, the improved surveillance and management of patients with IBD, such as biopsies for cancer screening and other prophylactic treatments may benefit for patients with IBD in cancer risk.27

However, the underlying basis of the association remains unclear. There are several potential mechanisms for the link between IBD and PCa risk. A number of researches indicated that gut microbiota play a key role in the pathogenesis of IBD.28 Accumulating studies have shown that the microbiota can also affect prostate inflammation involved in PCa.26,29 A recent study demonstrated that pathogenic microorganisms involved in IBD may be introduced into the prostate through the circulatory system and stimulate cancer-promoting prostatic inflammation.27 In addition, emerging evidence indicated that immunosuppressive therapy for IBD patients was related to a higher risk of developing extraintestinal cancer.24,30 Moreover, according to the report by Burns, shared genetic risk alleles and high frequency healthcare examination may partly explain the cause association between IBD and high incidence of PCa.13

Another noteworthy finding in the present study was that the higher risk of PCa was observed in patients with UC not CD. The phenomenon was similar to the report by Derikx et al., and they found that patients with UC were at especially high risk of colorectal cancer.9All the results above suggested that patients with IBD especial UC could be considered as high-risk population of PCa. Although many clinical symptoms, epidemiologic and immunologic feature are similar between UC and CD, the microbiome level of these two subtypes of IBD are distinct, which may lead to the PCa risk difference between UC and CD.31In addition, compared with UC patients, genomic alterations of CD are discrepant,32 and relatively small sample size of CD patients may also cause the different PCa risk.

Our study has several strengths. Firstly, the present meta-analysis was conducted from population-based studies, and the sample size is very large. Secondly, our meta-analysis is nationwide, the included studies are from Europe (UK, Sweden, Finland and Denmark), Asia (China and Korea), and North America (USA). Lastly, not only prospective cohort studies but also case-control studies were considered in this study. And the longest follow-up time was up to 40 years, which ensures the reliability of results.

There are some limitations in this study. The analysis did not take account of some confounders, such as family history of PCa, prostate-specific antigen (PSA) screening test, which may influence the risk of PCa. The present results indicated that IBD was associated with a significant higher incidence of PCa, but few studies evaluated the relationship between IBD and clinically significant PCa risk. Moreover, limited evidence is available on the potential molecular mechanism of IBD involved in the development of PCa. Further large well-designed studies and functional researches are warrant to better understanding of the association between IBD and PCa risk.
In summary, we comprehensively evaluated the public studies that estimated the association between IBD and PCa risk. Our findings based on the large and multicenter samples strongly indicated that men with IBD especially UC have significant elevated PCa risk. If confirmed in larger studies, future efforts should focus on understanding the basis for the link between IBD and total PCa or clinically significant PCa risk, including the possibility that IBD leads to an altered microbiome that increases PCa risk. Additionally, our results may give suggestion to IBD patients for increasing PCa screening, more work and evidence are warrant to assess the effect of surveillance strategies on the incidence and mortality of PCa in patients with IBD.
Acknowledgments: This work was supported by the Fundamental Research Funds for the Central Universities (JUSRP11951); Public Health Research Center at Jiangnan University (JUPH201823); Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University (JUGW201802).

Compliance with ethical standards: 
Conflict of interest: The authors declare that they have no conflict of interest.
Publisher’s note:  Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Authors: Yuqiu Ge1, Qianqian Shi2, Wenxi Yao1, Yang Cheng1, Gaoxiang Ma3,4
  1. Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi 214122 Jiangsu, China
  2. Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
  3. Clinical Metabolomics Center, China Pharmaceutical University, Nanjing 211198, China
  4. State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
Received: 13 June 2019 / Revised: 7 August 2019 / Accepted: 26 August 2019 / Published online: 7 October 2019 © The Author(s), under exclusive licence to Springer Nature Limited 2019

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Read an Editorial by Stephen J Freedland, MD: The Association Between Inflammatory Bowel Disease and Prostate Cancer Risk: a Meta-Analysis - Editorial