Precision leak detection in the golden window: emerging biomarker strategies for anastomotic integrity monitoring after low anterior resection

Anastomotic leakage (AL) following low anterior resection for rectal cancer is a devastating complication affecting 1-30% of patients, with profound clinical, oncological, and psychological implications. Early diagnosis of AL is crucial for timely intervention. We adopted a tiered evidence synthesis approach, prioritizing existing meta-analyses and systematic reviews while supplementing others with relevant primary studies, categorizing biomarkers by healing phase (inflammation, proliferation, and remodeling). Our analysis reveals that C-reactive protein [CRP; cutoff: 140-159 mg/L on postoperative days (POD) 3-5] and procalcitonin (PCT; cutoff: 0.7-1.3 ng/mL on POD3-5) offer high negative predictive value (NPV) in blood, enabling early discharge within enhanced recovery after surgery (ERAS) pathways. Drainage fluid biomarkers [e.g., IL-6, IL-10, matrix metalloproteinase-9 (MMP9), and bile acids (BAs)] demonstrate superior site-specificity, with MMP9 and IL-10 elevation on POD1 showing particular promise for incipient leak detection. Novel approaches include ischemia markers [lactate and intestinal fatty acid binding protein (I-FABP)], collagenolytic microbiota profiling ( Enterococcus faecalis ), and excretion-derived biomarkers [urinary volatile organic compounds (VOCs)], though these require further validation. Critically, drainage fluid analysis capitalizes on existing clinical infrastructure, while combinatorial multi-marker surveillance appears essential to overcome the limitations of singular biomarkers. Future efforts must prioritize integrated diagnostic platforms embedding dynamic biomarker profiling, mechanistic drivers [reactive oxygen species/formyl peptide receptor (ROS/FPR) pathways, enteric dysbiosis, and genetic polymorphisms], and real-time interventions to transition from reactive rescue to personalized AL prevention.