Colorectal Cancer—One Disease, Two Fires: Distinct Inflammatory Landscapes in Colon and Rectal Cancer

<b>Background:</b> Systemic inflammatory indices are increasingly used to predict prognosis in colorectal cancer (CRC), yet direct comparisons between colon cancer (CC) and rectal cancer (RC) remain limited. <b>Methods:</b> We conducted a retrospective matched-cohort study including 296 patients (148 with CC and 148 with RC) surgically treated between January 2018 and December 2024. Patients were matched by tumor stage, sex, and age (±3 years). Preoperative blood samples were used to calculate several inflammatory markers, including Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), Monocyte-to-Lymphocyte Ratio (MLR), Systemic Inflammation Response Index (SIRI), Systemic Immune-Inflammation Index (SII), and Aggregate Index of Systemic Inflammation (AISI). Subgroup analyses were performed based on the Charlson Comorbidity Index (>3 vs. ≤3), surgical context (elective vs. emergency), and tumor stage (T1-T2 vs. T3-T4). <b>Results:</b> Colon cancer patients exhibited significantly higher levels of systemic inflammation compared to those with rectal cancer, with notable differences in NLR (3.99 vs. 2.84, <i>p</i> < 0.001), PLR (219.8 vs. 163.3, <i>p</i> < 0.001), SIRI (3.7 vs. 1.91, <i>p</i> = 0.004), SII (1533.8 vs. 847.8, <i>p</i> < 0.001), and AISI (1714.7 vs. 593.6, <i>p</i> = 0.009). These differences remained statistically significant in key subgroups. In elective surgeries, CC patients had elevated PLR (<i>p</i> < 0.001), SIRI (<i>p</i> = 0.003), SII (<i>p</i> < 0.001), and AISI (<i>p</i> = 0.013). Among patients with advanced tumors (T3-T4), CC was associated with higher SII (<i>p</i> < 0.001), AISI (<i>p</i> = 0.008), PLR (<i>p</i> < 0.001), and SIRI (<i>p</i> = 0.004). For those with a Charlson index > 3, CC patients showed significantly higher PLR (<i>p</i> < 0.001), NLR (<i>p</i> < 0.001) and SIRI (<i>p</i> = 0.001). <b>Conclusions:</b> colon cancer presents with a markedly stronger systemic inflammatory response than rectal cancer, particularly in patients with advanced disease, elective surgical treatment, and higher comorbidity burden. These findings suggest that indices such as SIRI, SII, and PLR may serve as valuable stratification tools beyond tumor location in CRC.