Abstract
BACKGROUND: Systemic inflammation and nutritional status play critical roles in determining clinical outcomes across multiple disease entities, particularly malignancies. Significantly, these two pathophysiological factors exhibit dynamic interplay through shared pathobiological mechanisms. This study sought to investigate the independent and combined prognostic capacity of the systemic inflammatory response index (SIRI) and prognostic nutritional index (PNI) in predicting all-cause, cancer-specific, and non-cancer mortality among cancer survivors. METHODS: Utilizing the National Health and Nutrition Examination Survey (NHANES) data from 2005 to 2018, 3,289 adult cancer survivors (weighted population: 20,795,493) were analyzed. Restricted cubic splines (RCS) delineated mortality risk nonlinearity. Survival trajectories were assessed via Kaplan-Meier (KM) analysis with complex survey adjustments. Weighted Cox proportional hazards models quantified independent and joint associations. RESULTS: Eight hundred seventy-four deaths were identified over a median follow-up of 6.5 years. By RCS analyses, SIRI exhibited a linear association with all-cause mortality, whereas PNI demonstrated a nonlinear relationship with all-cause mortality. Weighted Cox regression analysis demonstrated increased all-cause, cancer-specific, and non-cancer mortality risks in cancer survivors with high-SIRI or with undernutrition (PNI ≤ 48). Joint analysis showed that cancer survivors with concurrent high-SIRI and undernutrition had the highest risk for all-cause (HR 3.169, 95%CI 2.324-4.321), cancer-specific (HR 2.578, 95%CI 1.308-5.080) and non-cancer (HR 2.197, 95%CI 1.480-3.261) mortality, respectively, relative to the reference group with concurrent low-SIRI and PNI > 48. Subgroup and interaction analysis confirmed the stability of the core results. CONCLUSION: SIRI and PNI emerged as independent prognostic predictors with synergistic mortality prediction capacity in cancer survivors. Cancer survivors with concurrent high level of systemic inflammation and poor nutritional status was associated with the highest mortality risk for all-cause, cancer-specific, and non-cancer.