Diagnostic efficacy of blood biomarkers for differentiating early-stage pancreatic cancer from chronic pancreatitis: A systematic review and network meta-analysis

• Carbohydrate antigen 19–9 (CA199) demonstrated only moderate diagnostic discrimination between pancreatic cancer (PC) and chronic pancreatitis (CP), with reduced efficacy in early-stage PC. • Tumor polypeptide antigen (TPA), microRNAs, extracellular vesicle long RNAs (exLRs), metabolites panel, and carcinoembryonic antigen (CEA) showed unique strengths in their diagnostic ability. • The application of multi-marker panels, particularly those that incorporate miRNAs and exLRs, for early detection of PC in CP holds significant clinical value for improving patient management. Early diagnosis of pancreatic cancer (PC) remains challenging, particularly in patients with chronic pancreatitis (CP). Currently, imaging is often inaccurate and biopsy is inherently invasive. This is the first network meta-analysis (NMA) comparing blood-based biomarkers for differentiating PC from CP. PubMed and EMBASE were searched for studies evaluating blood-based biomarkers for distinguishing PC from CP. Risk of bias was assessed with QUADAS-2. We conducted individual biomarker meta-analysis with generalized bivariate models. For the NMA, we applied a Bayesian inference approach via a Markov-chain Monte Carlo random effects model. The surface under the cumulative ranking curve was used to rank the diagnostic performance of the biomarkers. Across 139 enrolled studies, 49 biomarkers or panels were analyzed. For differentiating PC from CP, tumor polypeptide antigen (TPA) had the highest area under the summary receiver operating characteristic curve (AUSROC) (0.92). The NMA revealed that microRNA-196b (miR-196b) ranked highest in sensitivity (OR 3.74e+27), while the combination of carbohydrate antigen 19–9 (CA199) and a panel of eight extracellular vesicle long RNAs (exLRs) exhibited the highest specificity (OR 3.78). For early-stage (stage I and II) PC, the eight exLRs showed the highest relative sensitivity (OR 7.00), and carcinoembryonic antigen (CEA) demonstrated the highest specificity (OR 4.70). CA199 demonstrated only moderate diagnostic discrimination between PC and CP, with reduced efficacy in early-stage PC. Combining CA199 and eight exLRs exhibited promising differential diagnostic efficacy with both high sensitivity and specificity.