Pretreatment creatinine-to-cystatin c ratio as a prognostic marker in digestive tract cancers: a meta-analysis with reconstructed individual patient data and trial sequential analysis.

BACKGROUND: Sarcopenia, characterized by loss of skeletal muscle, is associated with unfavorable clinical outcomes in patients with cancer. The creatinine-to-cystatin C ratio (CCR) has emerged as a readily available marker related to muscle reserve. This meta-analysis aimed to examine the prognostic utility of baseline CCR levels in patients with digestive tract cancers. METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane Library from database inception through 22 October 2025. Original cohort studies that enrolled adults with histologically proven digestive tract cancers, reported pretreatment CCR with overall survival hazard ratios, and classified patients using a specific CCR cut-off were included. Risk of bias was evaluated with the Newcastle-Ottawa Scale and the Quality in Prognostic Studies tool. Pooled hazard ratios for overall survival were synthesized. Patient-level survival data were reconstructed from published Kaplan-Meier curves. No original patient-level datasets were obtained from study investigators. Trial sequential analysis (TSA) was performed as an exploratory robustness assessment. RESULTS: Nine independent cohorts comprising 3,073 patients were included. Lower CCR was significantly associated with shorter OS (HR = 1.71; 95% CI: 1.45-2.02; p < 0.001). Stratified analyses showed consistent prognostic associations in esophageal cancer (HR = 2.21; 95% CI: 1.35-3.61; p = 0.002), biliary tract cancer (HR = 2.62; 95% CI: 1.31-5.23; p = 0.006), and gastrointestinal cancers (HR = 1.65; 95% CI: 1.34-2.05; p < 0.001). Reconstructed IPD analysis also showed shorter OS in the low-CCR group (HR = 1.48; 95% CI: 1.32-1.67; p < 0.001). Exploratory trial sequential analysis was consistent with the pooled OS association under prespecified assumptions. CONCLUSION: Pretreatment CCR was associated with overall survival in patients with digestive tract cancers. However, further prospective studies are needed to confirm these findings. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD420261290556.