Pretreatment creatinine-to-cystatin C ratio as a prognostic marker in solid cancers: a systematic review and meta-analysis with trial sequential analysis and reconstructed time-to-event validation

Abstract

The creatinine-to-cystatin C ratio (CCR) has been proposed as an indirect laboratory marker related to muscle mass and systemic health status. This systematic review and meta-analysis evaluated the association between pretreatment CCR and survival outcomes in patients with solid cancers. PubMed, Embase, Web of Science, and the Cochrane Library were searched for studies reporting pretreatment CCR and survival outcomes in solid cancers until October 22, 2025. The risk of bias in each included study was assessed using the Risk of Bias in Non-randomized Studies of Exposures (ROBINS-E) tool. Overall survival (OS) was the primary outcome, and recurrence-free survival (RFS) and progression-free survival (PFS) were secondary outcomes. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to evaluate survival outcomes. For OS, both fixed-effects and random-effects models were fitted. Trial sequential analysis (TSA) and reconstructed time-to-event analysis based on published Kaplan–Meier curves were prespecified as complementary approaches. Of 340 records identified through systematic database searching, 15 reports describing 16 independent cohorts comprising 5,020 patients were included in the qualitative synthesis. Lower CCR was associated with shorter OS compared with higher CCR (low vs. high CCR: HR = 1.71; 95% CI: 1.52–1.92; p < 0.001). Similar associations were observed for RFS (low vs. high CCR: HR = 1.88; 95% CI: 1.30–2.71; p = 0.001) and PFS (low vs. high CCR: HR = 1.51; 95% CI: 1.25–1.83; p < 0.001). A DerSimonian–Laird random-effects analysis yielded a concordant OS estimate. TSA and reconstructed time-to-event data corroborated the pooled analysis. However, these findings should be interpreted cautiously as exploratory, given the observational nature of the included evidence and the lack of original patient-level data. Pretreatment CCR is associated with survival outcomes in patients with solid cancers. However, further prospective studies are still warranted to validate its role as a clinical decision-making marker.