Periodontitis and Pancreatic Cancer Risk: A Systematic Review, Meta-Analysis, and Trial Sequential Analysis

Introduction: Pancreatic cancer is one of the most lethal malignancies worldwide, and its incidence continues to rise. Periodontitis, a highly prevalent chronic inflammatory disease, has been linked to several systemic conditions, including a potential increase in pancreatic cancer risk. However, the available epidemiological evidence remains heterogeneous and fragmented. Objective: To evaluate whether periodontitis is associated with an increased risk of pancreatic cancer through a systematic review and meta-analysis of observational studies. Materials and Methods: A comprehensive search was conducted in PubMed, EMBASE, Web of Science, Scopus, the Cochrane Library, ClinicalTrials.gov, and the WHO regional databases, following PRISMA guidelines. Cohort, case-control, and cross-sectional studies assessing periodontitis through clinical parameters, radiographic measures, or tooth loss-and reporting pancreatic cancer risk (HR, RR, or OR)-were included. Risk of bias was assessed using the Newcastle-Ottawa Scale. Random-effects meta-analyses, meta-regressions, leave-one-out sensitivity analyses, influence diagnostics, publication bias assessment, and Trial Sequential Analysis (TSA) were performed. Results: Eight observational studies (primarily cohort designs) (n = 476,245 participants) met the inclusion criteria. Periodontitis was associated with an increased risk of pancreatic cancer (pooled HR = 1.56; 95% CI: 1.28-1.89), with moderate heterogeneity (I² = 55.5%). Sensitivity and influence analyses confirmed the robustness of the estimate. TSA showed a consistent trend, although the cumulative evidence remains insufficient for a definitive conclusion. Conclusions: Observational evidence suggests a modest statistical association between periodontitis and pancreatic cancer risk. However, the absolute risk increase is very small, and Trial Sequential Analysis indicates that cumulative evidence remains insufficient to establish causality or to support preventive or clinical recommendations. Further large-scale prospective studies with standardized periodontal assessments are required.