The Association between Systemic Immune-Inflammation Index and Cardiotoxicity Related to 5-Fluorouracil in Colorectal Cancer

Abstract Background and aims: The cardiotoxicity related to 5-fluorouracil（5-FU） in cancer patients has garnered widespread attention. The systemic immune-inflammation index (SII) has recently been identified as a novel predictive marker for developing cardiovascular diseases in healthy individuals. However, it remains unclear whether the increasing SII leads to a higher risk of cardiotoxicity related to 5-FU. This study aims to address this gap by investigating the association between SII and cardiotoxicity related to 5-FU in a colorectal cancer cohort. Methods: From January 1, 2018 to December 31, 2020, colorectal cancer patients who underwent 5-FU-based chemotherapy at affiliated cancer hospital of Guizhou Medical University were included. After adjustment for confounders and stratification by tertiles of the interactive factor, linear regression analyses, curve fitting and threshold effect analyses were performed. Results: Of the 754 participants included final analysis, approximately 21% (n=156) of participants ultimately experienced cardiotoxicity related to 5-FU. Monocyte (M) was identified as an interactive factor for SII on cardiotoxicity related to 5-FU. In the low tertile of M (T1: M≤0.38×109/L), increasing log SII was positively correlated with cardiotoxicity related to 5-FU (Odds Ratio [OR], 8.04; 95% confidence interval [95%CI], 1.68 to 38.56). However, a non-linear relationship between log SII and cardiotoxicity was observed in the middle tertile of M (T2: 0.38<M≤0.52 × 109/L). Elevated log SII was correlated with decrease of cardiotoxicity risk when log SII>1.37 (OR, 0.14; 95%CI, 0.02 to 0.88) but with a threshold effect. In the high tertile of M (T3: M>0.52 × 109/L), a trend towards a negative linear correlation between the log SII and cardiotoxicity was observed (OR, 0.85; 95%CI, 0.37 to 1.98). Conclusion: Our findings suggest that SII may serve as a potential biomarker for predicting cardiotoxicity related to 5-FU in colorectal cancer patients. SII is an independent risk factor for cardiotoxicity related to 5-FU with low monocyte levels (T1). Conversely, in the middle monocyte levels (T2), SII is a protective factor for cardiotoxicity related to 5-FU but with a threshold effect.