ABSTRACT

Background:

Periodontal disease is reportedly associated with the risk of various systemic diseases, including pancreatic and lung cancers. However, its association with prostate cancer remains inconclusive. Herein, we explored the association of periodontal disease with the risk of prostate cancer through a meta-analysis.

Materials and Methods:

MEDLINE, Embase, Web of Sciences and Cochrane Library databases were searched for eligible publications up to April 2020. Multivariate adjusted risk estimates with corresponding 95% confidence intervals (CIs) were extracted and calculated using random- or fixed-effect models.

Results:

Nine cohort studies involving 3.353 prostate cancer cases with 440.911 participants were identified and included in the meta-analysis. We found that periodontal disease significantly increased the risk of prostate cancer by 1.40-fold (hazard ratio [HR]=1.40, 95% CI: 1.16-1.70; P=0.001; I2=76.1%) compared with normal condition. Interestingly, the risk of developing prostate cancer was not significant in patients treated with periodontal therapy (HR=1.22, 95% CI: 0.86-1.73; P=0.272; I2=65.2%). The results of subgroup analyses were also consistent and significant when stratified by study design and follow-up period, whereas conflicting results were observed in periodontal disease ascertainment stratification. These findings were robust as indicated by sensitivity analyses.

Conclusions:

Periodontal disease was associated with the increased risk of prostate cancer, whereas no significant association was observed in patients treated with periodontal therapy. Hence, the awareness and importance for maintaining oral health should be improved, and the underlying mechanisms linking periodontal disease and prostate cancer should be fully explored in future research.

Keywords:
Periodontal Diseases; Prostatic Neoplasms; Systematic Review [Publication Type]

INTRODUCTION

Prostate cancer is the most common cancer in men and the leading cause of cancer-related deaths worldwide (¹1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010; 127:2893-917., ²2. Buja A, Lange JH, Perissinotto E, Rausa G, Grigoletto F, Canova C, et al. Cancer incidence among male military and civil pilots and flight attendants: an analysis on published data. Toxicol Ind Health. 2005; 21:273-82.). Approximately 164.690 new cases of prostate cancer were diagnosed in 2019 and led to 29.430 deaths, as estimated by the American Cancer Society (³3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018; 68:7-30.). Available data show that the risk factors for prostate cancer include age, family history and race, which limit its prevention (⁴4. Eeles RA, Olama AA, Benlloch S, Saunders EJ, Leongamornlert DA, Tymrakiewicz M, et al. Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. Nat Genet. 2013; 45:385-91, 391e1-2., ⁵5. Culp SH, Schellhammer PF, Williams MB. Might men diagnosed with metastatic prostate cancer benefit from definitive treatment of the primary tumor? A SEER-based study. Eur Urol. 2014; 65:1058-66.). Periodontal disease, a complex microbial inflammatory disease of the periodontium, partly causes tooth loss. The cumulative burden of periodontal disease increased significantly between 1990 and 2015, resulting in a 64% increase in disability, which posed a great public health challenge for policy makers (⁶6. Kassebaum NJ, Smith AGC, Bernabé E, Fleming TD, Reynolds AE, Vos T, et al. GBD 2015 Oral Health Collaborators. Global, Regional, and National Prevalence, Incidence, and Disability-Adjusted Life Years for Oral Conditions for 195 Countries, 1990-2015: A Systematic Analysis for the Global Burden of Diseases, Injuries, and Risk Factors. J Dent Res. 2017; 96:380-7.). Moreover, severe periodontal disease has affected 743 million people worldwide (⁷7. Eke PI, Dye BA, Wei L, Slade GD, Thornton-Evans GO, Borgnakke WS, et al. Update on Prevalence of Periodontitis in Adults in the United States: NHANES 2009 to 2012. J Periodontol. 2015; 86:611-22.). Recently, the association between periodontal disease and the risk of cancer development has attracted research attention, especially for pancreatic, head and neck, and lung cancers (⁸8. Maisonneuve P, Amar S, Lowenfels AB. Periodontal disease, edentulism, and pancreatic cancer: a meta-analysis. Ann Oncol. 2017; 28:985-95.–¹⁰10. Zeng XT, Xia LY, Zhang YG, Li S, Leng WD, Kwong JS. Periodontal Disease and Incident Lung Cancer Risk: A Meta-Analysis of Cohort Studies. J Periodontol. 2016; 87:1158-64.).

Results about the association between periodontal disease and prostate cancer are conflicting (¹¹11. Arora M, Weuve J, Fall K, Pedersen NL, Mucci LA. An exploration of shared genetic risk factors between periodontal disease and cancers: a prospective co-twin study. Am J Epidemiol. 2010; 171:253-9.–¹³13. Güven DC, Dizdar Ö, Akman AC, Berker E, Yekedüz E, Ceylan F, et al. Evaluation of cancer risk in patients with periodontal diseases. Turk J Med Sci. 2019; 49:826-31.). For instance, Dizdar et al. (¹²12. Dizdar O, Hayran M, Guven DC, Yılmaz TB, Taheri S, Akman AC, et al. Increased cancer risk in patients with periodontitis. Curr Med Res Opin. 2017; 33:2195-2200.) suggested that periodontal disease is not associated with the increased risk of prostate cancer (hazard ratio [HR]=3.75, 95% confidence interval [CI]: 0.95-10.21), whilst Arora et al. (¹¹11. Arora M, Weuve J, Fall K, Pedersen NL, Mucci LA. An exploration of shared genetic risk factors between periodontal disease and cancers: a prospective co-twin study. Am J Epidemiol. 2010; 171:253-9.) and Guven et al. (¹³13. Güven DC, Dizdar Ö, Akman AC, Berker E, Yekedüz E, Ceylan F, et al. Evaluation of cancer risk in patients with periodontal diseases. Turk J Med Sci. 2019; 49:826-31.) reported different observations. Considering that a single epidemiological study may not be sufficient to determine the effect of periodontal disease on prostate cancer risk, we performed a systematic review and meta-analysis of previous studies to further elucidate the association between periodontal disease and prostate cancer risk.

MATERIALS AND METHODS

This systematic review and meta-analysis were conducted in line with the Cochrane Collaboration criterion (¹⁴14. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration. 2011. [Internet]. Available at. <https://training.cochrane.org/cochrane-handbook-systematic-reviews-interventions>.
https://training.cochrane.org/cochrane-h... ) and reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (Supplementary Material) (¹⁵15. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015; 4:1.).

Search Strategy

MEDLINE (via PubMed), Embase, Web of Sciences and Cochrane Library databases were searched for eligible studies that investigated the association between periodontal disease and the risk of prostate cancer up to April 2020. The combination of Medical Subject Headings (MeSH) and non-MeSH terms was used in each database, including ‘periodontal disease’, ‘periodontitis’ or ‘dental health’ and ‘prostate carcinoma’, ‘prostate cancer’, ‘prostate neoplasms’ or ‘prostate tumor’, without restriction for language, region or publication status. The reference lists from previous reviews and other relevant articles were manually searched to identify additional studies. The main search was completed by the senior author (ZL Guo), and any discrepancy was resolved by consensus or consultation with another investigator (SS Wang).

Eligibility Criteria

The inclusion criteria for original studies that investigated the association between periodontal disease and prostate cancer risk were as follows: (¹1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010; 127:2893-917.) studies reporting the risk estimate (HR, odds ratio [OR], relative risk, standardized incidence rate [SIR]) with associated 95% CIs of incident for prostate cancer (any stage) amongst participants with periodontal disease (i.e. periodontitis, tooth loss or gingivitis caused by periodontitis) compared with those free of periodontal disease; (²2. Buja A, Lange JH, Perissinotto E, Rausa G, Grigoletto F, Canova C, et al. Cancer incidence among male military and civil pilots and flight attendants: an analysis on published data. Toxicol Ind Health. 2005; 21:273-82.) the evaluation of periodontal status might vary across studies, including self-reporting, clinical diagnosis or retrieved from clinical and radiographic parameters; (³3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018; 68:7-30.) observational studies (i.e. prospective or retrospective cohort, cross-sectional or case-control study) published as original articles; and (⁴4. Eeles RA, Olama AA, Benlloch S, Saunders EJ, Leongamornlert DA, Tymrakiewicz M, et al. Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. Nat Genet. 2013; 45:385-91, 391e1-2.) studies that provide sufficient raw data for calculation if no risk estimates with associated 95% CIs were reported. For studies on the same population or subpopulation, only the largest or most recent studies with the longest follow-up duration were considered. Case series, case reports and review articles were excluded. Disagreement was resolved through discussion amongst the investigators.

Data extraction and methodological quality assessment

The title and abstract of all articles retrieved from the initial search were screened to ascertain their relevance. All potentially relevant full-text articles were further considered and assessed to determine their inclusion eligibility in the meta-analysis. Hereafter, two investigators (CM Gu and SY Li) independently extracted and crosschecked the following data of all the included studies through a predesigned evidence table: first author, study population, study design, country, participant characteristics (i.e. sample size and age), follow-up duration, periodontal disease ascertainment, therapy of periodontal disease, dental and smoking status, risk estimates with associated 95% CIs or sufficient raw data and corresponding adjusting confounding factors. If the information in the included studies was insufficient, the primary author was contacted to obtain and verify the data.

The methodological quality of the included studies was assessed by two investigators (S Gan and Y Li) on the basis of the Newcastle-Ottawa scale (NOS) (¹⁶16. GA Wells, B Shea, D O’Connell, J Peterson, V Welch, M Losos, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Hospital Research Institute. [Internet]. Available at. <www.ohri.ca/programs/clinical_epidemiology/oxford.asp>.
www.ohri.ca/programs/clinical_epidemiolo... ), which includes nine items that assess the representativeness of eligible studies. In detail, the evaluation of each item could be classified as ‘unclear’, ‘yes’ or ‘no’, which corresponded to ‘0’, ‘1’ or ‘0’, respectively. The total score ranged from 0 to 9, where 8-9 indicates high quality, 6-7 indicates moderate quality and ≤5 indicates low quality. Any disagreement was resolved by consensus or consultation with a third investigator.

Statistical Analysis

The association between periodontal disease and prostate cancer was evaluated using risk estimates, and their corresponding 95% CIs were extracted from the included studies via Stata version 15.0 (serial number: 10699393; StataCorp Wyb). For consistent definitions, the differences amongst the various measures of risk estimates could be ignored because periodontal disease-related prostate cancer is a rare event; therefore, the ORs and SIRs were directly considered as HRs in the meta-analysis (¹⁷17. Greenland S. Quantitative methods in the review of epidemiologic literature. Epidemiol Rev. 1987; 9:1-30.). I2 was used to investigate heterogeneity amongst the included studies, and high statistical heterogeneity was defined as I2 ≥50%. High heterogeneity warrants the use of random-effect inverse-variance models; otherwise, a fixed-effect model should be utilized (¹⁵15. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015; 4:1.). Statistical significance was considered at P <0.05. Subgroup analyses stratified by study design, follow-up duration, country, periodontal disease ascertainment and therapy of periodontal disease were performed. Sensitivity analysis was also performed by deleting each study individually to assess the stability and consistency of results. Meta-regression analysis was performed to investigate the potential risk factors of heterogeneity, and restricted maximum likelihood was used in the analysis. However, the use of Egger (¹⁸18. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315:629-34.) and Begg-Mazumdar (¹⁹19. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994; 50:1088-101.) tests was limited because of the limited number of studies evaluated.

RESULTS

Study identification and selection

Figure-1 presents the search and study selection process. Overall, the initial search yielded a total of 238 articles. After duplication, the titles and abstracts of 159 articles were evaluated for eligibility, where 22 full-text articles were retrieved for further evaluation and 13 were excluded for the following reasons: no prostate cancer (6 studies), no periodontal disease (5 studies), duplication (1 study) and no sufficient data for extraction (1 study). Nine articles (11-13, 20-25) involving 3.353 prostate cancer cases with 440.911 participants were identified and included in the meta-analysis according to the eligibility criteria.

Study characteristics and methodological quality

The main characteristics of the included studies are summarized in Table-1. These studies included four prospective cohorts (¹¹11. Arora M, Weuve J, Fall K, Pedersen NL, Mucci LA. An exploration of shared genetic risk factors between periodontal disease and cancers: a prospective co-twin study. Am J Epidemiol. 2010; 171:253-9., ²⁰20. Hujoel PP, Drangsholt M, Spiekerman C, Weiss NS. An exploration of the periodontitis-cancer association. Ann Epidemiol. 2003; 13:312-6., ²³23. Michaud DS, Kelsey KT, Papathanasiou E, Genco CA, Giovannucci E. Periodontal disease and risk of all cancers among male never smokers: an updated analysis of the Health Professionals Follow-up Study. Ann Oncol. 2016; 27:941-7., ²⁴24. Michaud DS, Lu J, Peacock-Villada AY, Barber JR, Joshu CE, Prizment AE, et al. Periodontal Disease Assessed Using Clinical Dental Measurements and Cancer Risk in the ARIC Study. J Natl Cancer Inst. 2018; 110:843-54.) and five retrospective cohorts (¹²12. Dizdar O, Hayran M, Guven DC, Yılmaz TB, Taheri S, Akman AC, et al. Increased cancer risk in patients with periodontitis. Curr Med Res Opin. 2017; 33:2195-2200., ¹³13. Güven DC, Dizdar Ö, Akman AC, Berker E, Yekedüz E, Ceylan F, et al. Evaluation of cancer risk in patients with periodontal diseases. Turk J Med Sci. 2019; 49:826-31., ²¹21. Hwang IM, Sun LM, Lin CL, Lee CF, Kao CH. Periodontal disease with treatment reduces subsequent cancer risks. QJM. 2014; 107:805-12., ²²22. Lee JH, Kweon HH, Choi JK, Kim YT, Choi SH. Association between Periodontal disease and Prostate cancer: Results of a 12-year Longitudinal Cohort Study in South Korea. J Cancer. 2017; 8:2959-65., ²⁵25. Wen BW, Tsai CS, Lin CL, Chang YJ, Lee CF, Hsu CH, et al. Cancer risk among gingivitis and periodontitis patients: a nationwide cohort study. QJM. 2014; 107:283-90.), which were published from 2003 to 2019. Three studies (²⁰20. Hujoel PP, Drangsholt M, Spiekerman C, Weiss NS. An exploration of the periodontitis-cancer association. Ann Epidemiol. 2003; 13:312-6., ²³23. Michaud DS, Kelsey KT, Papathanasiou E, Genco CA, Giovannucci E. Periodontal disease and risk of all cancers among male never smokers: an updated analysis of the Health Professionals Follow-up Study. Ann Oncol. 2016; 27:941-7., ²⁴24. Michaud DS, Lu J, Peacock-Villada AY, Barber JR, Joshu CE, Prizment AE, et al. Periodontal Disease Assessed Using Clinical Dental Measurements and Cancer Risk in the ARIC Study. J Natl Cancer Inst. 2018; 110:843-54.) from the United States, two (¹²12. Dizdar O, Hayran M, Guven DC, Yılmaz TB, Taheri S, Akman AC, et al. Increased cancer risk in patients with periodontitis. Curr Med Res Opin. 2017; 33:2195-2200., ¹³13. Güven DC, Dizdar Ö, Akman AC, Berker E, Yekedüz E, Ceylan F, et al. Evaluation of cancer risk in patients with periodontal diseases. Turk J Med Sci. 2019; 49:826-31.) from Turkey, two (²¹21. Hwang IM, Sun LM, Lin CL, Lee CF, Kao CH. Periodontal disease with treatment reduces subsequent cancer risks. QJM. 2014; 107:805-12., ²⁵25. Wen BW, Tsai CS, Lin CL, Chang YJ, Lee CF, Hsu CH, et al. Cancer risk among gingivitis and periodontitis patients: a nationwide cohort study. QJM. 2014; 107:283-90.) from Taiwan, one (¹¹11. Arora M, Weuve J, Fall K, Pedersen NL, Mucci LA. An exploration of shared genetic risk factors between periodontal disease and cancers: a prospective co-twin study. Am J Epidemiol. 2010; 171:253-9.) from Sweden and one (²²22. Lee JH, Kweon HH, Choi JK, Kim YT, Choi SH. Association between Periodontal disease and Prostate cancer: Results of a 12-year Longitudinal Cohort Study in South Korea. J Cancer. 2017; 8:2959-65.) from Korea were included. Moreover, the sample sizes varied from 1.250 and 187.934, and the follow-up period ranged from 7.2 years to 27 years. However, three studies did not provide information on the follow-up duration (²¹21. Hwang IM, Sun LM, Lin CL, Lee CF, Kao CH. Periodontal disease with treatment reduces subsequent cancer risks. QJM. 2014; 107:805-12., ²²22. Lee JH, Kweon HH, Choi JK, Kim YT, Choi SH. Association between Periodontal disease and Prostate cancer: Results of a 12-year Longitudinal Cohort Study in South Korea. J Cancer. 2017; 8:2959-65., ²⁵25. Wen BW, Tsai CS, Lin CL, Chang YJ, Lee CF, Hsu CH, et al. Cancer risk among gingivitis and periodontitis patients: a nationwide cohort study. QJM. 2014; 107:283-90.). Regarding the ascertainment of periodontal disease, three studies (¹¹11. Arora M, Weuve J, Fall K, Pedersen NL, Mucci LA. An exploration of shared genetic risk factors between periodontal disease and cancers: a prospective co-twin study. Am J Epidemiol. 2010; 171:253-9., ²³23. Michaud DS, Kelsey KT, Papathanasiou E, Genco CA, Giovannucci E. Periodontal disease and risk of all cancers among male never smokers: an updated analysis of the Health Professionals Follow-up Study. Ann Oncol. 2016; 27:941-7., ²⁴24. Michaud DS, Lu J, Peacock-Villada AY, Barber JR, Joshu CE, Prizment AE, et al. Periodontal Disease Assessed Using Clinical Dental Measurements and Cancer Risk in the ARIC Study. J Natl Cancer Inst. 2018; 110:843-54.) used a self-reporting method, three studies (²⁰20. Hujoel PP, Drangsholt M, Spiekerman C, Weiss NS. An exploration of the periodontitis-cancer association. Ann Epidemiol. 2003; 13:312-6., ²¹21. Hwang IM, Sun LM, Lin CL, Lee CF, Kao CH. Periodontal disease with treatment reduces subsequent cancer risks. QJM. 2014; 107:805-12., ²⁵25. Wen BW, Tsai CS, Lin CL, Chang YJ, Lee CF, Hsu CH, et al. Cancer risk among gingivitis and periodontitis patients: a nationwide cohort study. QJM. 2014; 107:283-90.) adopted a clinical diagnosis method, and three studies (¹²12. Dizdar O, Hayran M, Guven DC, Yılmaz TB, Taheri S, Akman AC, et al. Increased cancer risk in patients with periodontitis. Curr Med Res Opin. 2017; 33:2195-2200., ¹³13. Güven DC, Dizdar Ö, Akman AC, Berker E, Yekedüz E, Ceylan F, et al. Evaluation of cancer risk in patients with periodontal diseases. Turk J Med Sci. 2019; 49:826-31., ²²22. Lee JH, Kweon HH, Choi JK, Kim YT, Choi SH. Association between Periodontal disease and Prostate cancer: Results of a 12-year Longitudinal Cohort Study in South Korea. J Cancer. 2017; 8:2959-65.) used clinical radiographic parameters. Moreover, three studies (¹²12. Dizdar O, Hayran M, Guven DC, Yılmaz TB, Taheri S, Akman AC, et al. Increased cancer risk in patients with periodontitis. Curr Med Res Opin. 2017; 33:2195-2200., ²⁴24. Michaud DS, Lu J, Peacock-Villada AY, Barber JR, Joshu CE, Prizment AE, et al. Periodontal Disease Assessed Using Clinical Dental Measurements and Cancer Risk in the ARIC Study. J Natl Cancer Inst. 2018; 110:843-54., ²⁵25. Wen BW, Tsai CS, Lin CL, Chang YJ, Lee CF, Hsu CH, et al. Cancer risk among gingivitis and periodontitis patients: a nationwide cohort study. QJM. 2014; 107:283-90.) reported patients with periodontal disease and a history of periodontal treatment or currently undergoing periodontal therapy, whereas six studies (¹¹11. Arora M, Weuve J, Fall K, Pedersen NL, Mucci LA. An exploration of shared genetic risk factors between periodontal disease and cancers: a prospective co-twin study. Am J Epidemiol. 2010; 171:253-9., ¹³13. Güven DC, Dizdar Ö, Akman AC, Berker E, Yekedüz E, Ceylan F, et al. Evaluation of cancer risk in patients with periodontal diseases. Turk J Med Sci. 2019; 49:826-31., ²⁰20. Hujoel PP, Drangsholt M, Spiekerman C, Weiss NS. An exploration of the periodontitis-cancer association. Ann Epidemiol. 2003; 13:312-6.–²³23. Michaud DS, Kelsey KT, Papathanasiou E, Genco CA, Giovannucci E. Periodontal disease and risk of all cancers among male never smokers: an updated analysis of the Health Professionals Follow-up Study. Ann Oncol. 2016; 27:941-7.) did not provide this information. One study (²⁰20. Hujoel PP, Drangsholt M, Spiekerman C, Weiss NS. An exploration of the periodontitis-cancer association. Ann Epidemiol. 2003; 13:312-6.) focused on the association between gingivitis and prostate cancer risk, and another study (²²22. Lee JH, Kweon HH, Choi JK, Kim YT, Choi SH. Association between Periodontal disease and Prostate cancer: Results of a 12-year Longitudinal Cohort Study in South Korea. J Cancer. 2017; 8:2959-65.) provided information on the baseline smoking status of participants. Notably, all the included studies reported risk estimates adjusted for confounding factors.

In general, the quality of the included studies (¹¹11. Arora M, Weuve J, Fall K, Pedersen NL, Mucci LA. An exploration of shared genetic risk factors between periodontal disease and cancers: a prospective co-twin study. Am J Epidemiol. 2010; 171:253-9.–¹³13. Güven DC, Dizdar Ö, Akman AC, Berker E, Yekedüz E, Ceylan F, et al. Evaluation of cancer risk in patients with periodontal diseases. Turk J Med Sci. 2019; 49:826-31., ²⁰20. Hujoel PP, Drangsholt M, Spiekerman C, Weiss NS. An exploration of the periodontitis-cancer association. Ann Epidemiol. 2003; 13:312-6.–²⁵25. Wen BW, Tsai CS, Lin CL, Chang YJ, Lee CF, Hsu CH, et al. Cancer risk among gingivitis and periodontitis patients: a nationwide cohort study. QJM. 2014; 107:283-90.) was methodologically evaluated on the basis of NOS. Four studies (¹¹11. Arora M, Weuve J, Fall K, Pedersen NL, Mucci LA. An exploration of shared genetic risk factors between periodontal disease and cancers: a prospective co-twin study. Am J Epidemiol. 2010; 171:253-9., ²⁰20. Hujoel PP, Drangsholt M, Spiekerman C, Weiss NS. An exploration of the periodontitis-cancer association. Ann Epidemiol. 2003; 13:312-6., ²³23. Michaud DS, Kelsey KT, Papathanasiou E, Genco CA, Giovannucci E. Periodontal disease and risk of all cancers among male never smokers: an updated analysis of the Health Professionals Follow-up Study. Ann Oncol. 2016; 27:941-7., ²⁴24. Michaud DS, Lu J, Peacock-Villada AY, Barber JR, Joshu CE, Prizment AE, et al. Periodontal Disease Assessed Using Clinical Dental Measurements and Cancer Risk in the ARIC Study. J Natl Cancer Inst. 2018; 110:843-54.) acquired scores of 8 or 9 and were considered as high quality; four studies (¹³13. Güven DC, Dizdar Ö, Akman AC, Berker E, Yekedüz E, Ceylan F, et al. Evaluation of cancer risk in patients with periodontal diseases. Turk J Med Sci. 2019; 49:826-31., ²¹21. Hwang IM, Sun LM, Lin CL, Lee CF, Kao CH. Periodontal disease with treatment reduces subsequent cancer risks. QJM. 2014; 107:805-12., ²²22. Lee JH, Kweon HH, Choi JK, Kim YT, Choi SH. Association between Periodontal disease and Prostate cancer: Results of a 12-year Longitudinal Cohort Study in South Korea. J Cancer. 2017; 8:2959-65., ²⁵25. Wen BW, Tsai CS, Lin CL, Chang YJ, Lee CF, Hsu CH, et al. Cancer risk among gingivitis and periodontitis patients: a nationwide cohort study. QJM. 2014; 107:283-90.) acquired scores of 6 or 7 and were considered as moderate quality; one study (¹²12. Dizdar O, Hayran M, Guven DC, Yılmaz TB, Taheri S, Akman AC, et al. Increased cancer risk in patients with periodontitis. Curr Med Res Opin. 2017; 33:2195-2200.) obtained a score of 5 and was considered as low quality.

Periodontal disease and prostate cancer risk

The results of meta-analysis revealed that periodontal disease significantly increased the risk of developing prostate cancer by 1.40 times (HR=1.40, 95% CI: 1.16-1.70; P=0.001; I2=76.1%), and the risk was greater than those without periodontal disease. Significant statistical heterogeneity was observed. Thus, we used a random-effect model (Figure-2). Interestingly, the risk of developing prostate cancer was not significant in patients treated with periodontal therapy (HR=1.22, 95% CI: 0.86-1.73; P=0.272; I2=65.2%) compared with those who have never been treated for periodontal disease (HR=1.49, 95% CI: 1.17-1.91; P=0.001; I2=79.2%). In the subgroup analyses of study design, excess risk of prostate cancer was observed in prospective (HR=1.27, 95% CI: 1.09-1.48; P=0.003; I2=0%) and retrospective cohorts (HR=1.51, 95% CI: 1.09-2.09; P=0.013; I2=87.3%). When stratified by follow-up period, two cohorts reporting a follow-up period of more than 15 years suggested that periodontal disease can increase the risk of prostate cancer (HR=1.26, 95% CI: 1.02-1.56; P=0.030; I2=15.8%), thereby supporting the results of four cohorts with a follow-up period of less than 15 years (HR=1.64, 95% CI: 1.17-2.29; P=0.004; I2=47.5%). Regarding the diagnosis of periodontal disease, the pooled results of three studies indicated significant association based on the self-reported methods (HR=1.25, 95% CI: 1.07-1.46; P=0.005; I2=0%), whereas negative results were observed based on the other two methods (Table-2). We were unable to perform a subgroup analysis based on the smoking status of the study participants and the severity of periodontal disease because of limited data.

Sensitivity analysis validated the stability of our results by omitting every study. Notably, the results of meta-regression analyses indicated that the variables (study design, P=0.573, R-squared [R2] values=-8.67%; country, P=0.281, R2=-11.64%; follow-up period, P=0.915, R2=-12.07%; periodontal disease ascertainment, P=0.583, R2=-7.34%; periodontal disease therapy, P=0.686, R2=-4.10%) could not result in heterogeneity amongst the included studies. Moreover, the adjusted R2 values from −12.07% to −4.10% revealed that these regressors slightly contributed to the explanation of the response variables.

DISCUSSION

Main findings

The association between periodontal disease and prostate cancer was assessed using nine pooled studies, which involved 3.353 prostate cancer cases amongst 440.911 participants. The results suggest that periodontal disease is associated with increased risk of prostate cancer. Interestingly, the risk of developing prostate cancer was not significant in patients treated with periodontal therapy. Moreover, the results of subgroup analyses were consistent and significant when stratified by study design and follow-up period, whereas conflicting results were observed in periodontal disease ascertainment stratification. The results were robust as indicated by the sensitivity analysis. However, the meta-regression failed to identify the potential confounding factors that might affect the level of heterogeneity amongst the included studies.

Several studies shared conflicting results of the association between periodontal disease and prostate cancer (²⁰20. Hujoel PP, Drangsholt M, Spiekerman C, Weiss NS. An exploration of the periodontitis-cancer association. Ann Epidemiol. 2003; 13:312-6.–²²22. Lee JH, Kweon HH, Choi JK, Kim YT, Choi SH. Association between Periodontal disease and Prostate cancer: Results of a 12-year Longitudinal Cohort Study in South Korea. J Cancer. 2017; 8:2959-65.). In a prospective cohort with 67 prostate cancer cases amongst 11.328 participants, Hujoel et al. (²⁰20. Hujoel PP, Drangsholt M, Spiekerman C, Weiss NS. An exploration of the periodontitis-cancer association. Ann Epidemiol. 2003; 13:312-6.) reported a negative association between periodontitis and prostate cancer risk (OR=1.81, 95% CI: 0.76-4.34) and gingivitis (OR=1.48, 95% CI: 0.56-3.94). By contrast, Hwang et al. (²¹21. Hwang IM, Sun LM, Lin CL, Lee CF, Kao CH. Periodontal disease with treatment reduces subsequent cancer risks. QJM. 2014; 107:805-12.) and Lee et al. (²²22. Lee JH, Kweon HH, Choi JK, Kim YT, Choi SH. Association between Periodontal disease and Prostate cancer: Results of a 12-year Longitudinal Cohort Study in South Korea. J Cancer. 2017; 8:2959-65.) demonstrated that periodontal disease is associated with the excess risk of prostate cancer. Lee et al. focused on the influence of smoking status on prostate cancer risk amongst patients with periodontal disease and revealed that current smokers with periodontal disease had a significantly increased risk of prostate cancer, that is, 1.68 times (HR=1.68, 95% CI: 1.52-1.85) greater than that for non-smokers. However, our understanding of the effect of smoking status and the severity of periodontal disease on prostate cancer risk remains insufficient because of the limited studies evaluated.

Notably, a prospective cohort regarding the topic was excluded from the meta-analysis because it did not meet the inclusion criteria. We found that Michaud et al. performed two prospective cohorts in 2016 (²³23. Michaud DS, Kelsey KT, Papathanasiou E, Genco CA, Giovannucci E. Periodontal disease and risk of all cancers among male never smokers: an updated analysis of the Health Professionals Follow-up Study. Ann Oncol. 2016; 27:941-7.) and 2008 (²⁶26. Michaud DS, Liu Y, Meyer M, Giovannucci E, Joshipura K. Periodontal disease, tooth loss, and cancer risk in male health professionals: a prospective cohort study. Lancet Oncol. 2008; 9:550-8.) based on a similar population from the same database. The cohort comprising 541 prostate cancer cases with 48.375 participants was collected from the Health Professionals Follow-up Study database performed by Michaud et al. (²⁶26. Michaud DS, Liu Y, Meyer M, Giovannucci E, Joshipura K. Periodontal disease, tooth loss, and cancer risk in male health professionals: a prospective cohort study. Lancet Oncol. 2008; 9:550-8.). It revealed that periodontal disease is not significantly associated with the increased risk of prostate cancer (HR=0.90, 95% CI: 0.73-1.12). To avoid duplication, we identified cohorts with more prostate cancer cases and more comprehensive information according to the inclusion criteria. Notably, the results of the sensitivity analysis and meta-regression further consolidated our findings.

Comparison with previous study

A meta-analysis regarding the association between periodontitis and cancer risk was published by Corbella et al. (²⁷27. Corbella S, Veronesi P, Galimberti V, Weinstein R, Del Fabbro M, Francetti L. Is periodontitis a risk indicator for cancer? A meta-analysis. PLoS One. 2018; 13:e0195683.). Although the main results of our meta-analysis were consistent with those in previous studies, several differences between the results of Corbella et al. and the current work should be noted. Firstly, Corbella et al. only included two studies comprising 1.237 prostate cancer cases with 68.308 participants. By contrast, our meta-analysis included nine cohorts involving 3.353 prostate cancer cases with 440.911 participants. With the added statistical power of seven studies and at least 2116 prostate cancer cases with 372.603 participants, our meta-analysis was the latest and the most comprehensive review to date. Secondly, contrary to the study of Corbella et al., the current meta-analysis excluded a cohort performed by Michaud et al. (²⁶26. Michaud DS, Liu Y, Meyer M, Giovannucci E, Joshipura K. Periodontal disease, tooth loss, and cancer risk in male health professionals: a prospective cohort study. Lancet Oncol. 2008; 9:550-8.) to avoid duplication. Finally, meta-regression and subgroup analyses stratified by study design, country, follow-up period, periodontal disease ascertainment and periodontal disease therapy were also performed to identify the potential risk factors that might affect the level of heterogeneity amongst the included studies. Moreover, sensitivity analysis reinforced the main findings of our meta-analysis.

Implications for clinical practice

The incidence of prostate cancer is increasing year by year with the improvement of prostate biopsy technology (²⁸28. Westerman ME, Sharma V, Bailey GC, Boorjian SA, Frank I, Gettman MT, et al. Impact of time from biopsy to surgery on complications, functional and oncologic outcomes following radical prostatectomy. Int Braz J Urol. 2019;45:468-77., ²⁹29. Nassiri N, Beeder L, Nazemi A, Asanad K, Um J, Gill I, et al. Step-by-Step: Fusion-guided prostate biopsy in the diagnosis and surveillance of prostate cancer. Int Braz J Urol. 2019; 45:1277-8.). However, the etiological relationships between periodontal disease and prostate cancer remain controversial, and little is known about their underlying mechanisms. Hence, further studies on the pathogenesis of prostate cancer and clinical and epidemiological evidence are urgently needed to explore the relationships between periodontal disease and prostate cancer. Given the rising prevalence of periodontal disease worldwide, if the underlying mechanism is confirmed, this observation will be beneficial for clinicians and public health decision makers in the management of prostate cancer. Amongst the included studies, several trials used self-reported methods as an ascertainment of periodontal disease. However, any misclassification would underestimate the association between periodontal disease and prostate cancer. Periodontal disease may be worsened in patients with osteoporosis because of androgen deprivation therapy (ADT). Famili et al. (³⁰30. Famili P, Cauley JA, Greenspan SL. The effect of androgen deprivation therapy on periodontal disease in men with prostate cancer. J Urol. 2007; 177:921-4.) found that patients diagnosed with prostate cancer receiving ADT developed periodontal disease compared with those who did not receive ADT. Therefore, clinicians must consider this observation in patients receiving ADT. As the etiology of prostate cancer develops, increasing evidence suggests that chronic or recurrent inflammation may also be associated with prostate cancer risk. Moreover, the low level of persistent systemic inflammation caused by periodontal disease can induce oxidative DNA damage, uncontrolled repair procedures and eventually the occurrence of tumors in the body (³¹31. Moutsopoulos NM, Madianos PN. Low-grade inflammation in chronic infectious diseases: paradigm of periodontal infections. Ann N Y Acad Sci. 2006; 1088:251-64.–³³33. Li XC, Huang CX, Wu SK, Yu L, Zhou GJ, Chen LJ. Biological roles of filamin a in prostate cancer cells. Int Braz J Urol. 2019; 45:916-24.). Therefore, if a genetic link can be determined between periodontal disease and prostate cancer, the specific identification of genetic polymorphism may be beneficial to identifying high-risk groups and developing preventive strategies, which merits further attention. Finally, for patients with periodontal disease, a high-risk group for developing prostate cancer, increased awareness and effective periodontal therapy should be immediately applied by clinicians to reduce the risk of developing prostate cancer. Notably, patients with prostate cancer should be encouraged to pay more attention to their own oral health care, and urological clinicians and nurses should provide oral health-care tips, education, etc. to better manage patients with prostate cancer.

Strengths and limitations

Overall, our study exhibited several crucial strengths. Firstly, it was the latest and most comprehensive meta-analysis regarding the association between periodontal disease and the risk of prostate cancer. Moreover, subgroup analyses stratified by study design, country, follow-up period, periodontal disease ascertainment and periodontal disease therapy were performed to determine whether these variables affected the level of heterogeneity amongst the included studies. Secondly, all the risk estimates extracted from the included studies were adjusted for confounding factors to minimize their effect on the overall results. Finally, sensitivity analysis and meta-regression further validated and reinforced the rationality and reliability of our findings.

However, the meta-analysis was restricted by several limitations. Firstly, five studies used retrospective cohort design, which might miss data and result in a risk of bias. Secondly, significant heterogeneity was observed. Moreover, none of the variables that might affect the level of heterogeneity were identified although sensitivity analysis revealed the robustness of the overall results. Finally, we were unable to further investigate the association between smoking status and the degree of severity of periodontal disease because of the limited data. Therefore, future high-quality research should comprehensively address these issues.

CONCLUSIONS

Existing evidence suggests that periodontal disease appears to be associated with an increased risk of developing prostate cancer. Interestingly, no significant association was observed in patients who underwent periodontal therapy. Hence, patients with periodontal disease, a high-risk group for developing prostate cancer, should be treated with periodontal therapy immediately. Furthermore, the awareness and importance of maintaining oral health should be improved based on the main findings. Notably, further research should fully explore the underlying mechanisms linking periodontal disease and prostate cancer.

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