Immune-inflammatory Indices as Predictors of Complete Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer: A Systematic Review and Meta-Analysis of Observational Studies

Background: Pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer (LARC) is associated with improved survival and organ preservation. Available blood-based inflammatory indices may help to predict pCR and guide individualized treatment. Methods: We conducted a comprehensive search of PubMed, Web of Science, Scopus, and Embase, and Cochrane Library to identify studies including adult patients with pathologically confirmed LARC treated with nCRT followed by total mesorectal excision. We included studies that reported categorical analyses of pre-nCRT NLR (neutrophil-to-lymphocyte ratio), PLR (platelet-to-lymphocyte ratio), or SII (systemic immune-inflammation) in relation to pCR. Random-effects models were used to generate pooled odds ratios [1] for high versus low index values; heterogeneity, small-study effects, meta-regression, and certainty of evidence (GRADE) were assessed. Results: Twenty-four studies (20 NLR, 12 PLR, and 5 SII) met the inclusion criteria; all were rated as high quality according to the Newcastle-Ottawa Scale. Higher pre-nCRT NLR was associated with reduced odds of pCR (OR 0.60, 95% CI 0.49-0.71; I2=35.4%). Elevated PLR similarly predicted lower pCR rates (OR 0.53, 95% CI 0.37-0.69; I2=54.7%), as did higher SII (OR 0.42, 95% CI 0.26-0.58; I2=27.9%). Associations were consistent across cut-off values and geographic regions. Meta-regression suggested that age, stage, sample size, and cut-off selection partially explained between-study heterogeneity. Evidence of small-study effects was observed for NLR and PLR. Conclusions: Higher pre-nCRT NLR, PLR, and SII predict reduced pCR rates in LARC following nCRT. These inexpensive, available indices may refine pre-nCRT risk stratification and selection for organ-preserving.