Pretreatment systemic inflammatory ratios and survival in osteosarcoma and other primary bone sarcomas: a systematic review and meta-analysis

Abstract Background Evidence for neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) in primary bone sarcoma is dominated by osteosarcoma and has been affected by inconsistent endpoint and effect-size extraction. We re-extracted eligible estimates from the primary reports and evaluated their independent prognostic associations. Methods MEDLINE, Embase, Web of Science, Scopus, and Cochrane CENTRAL were searched for cohort studies reporting pretreatment NLR, PLR, or LMR in primary bone sarcoma. The primary analysis required clinically multivariable-adjusted, categorical high-versus-low hazard ratios (HRs). Overall survival (OS) was analyzed separately from progression-free survival (PFS), disease-free survival (DFS), event-free survival (EFS), and disease-specific mortality. Random-effects models used restricted maximum likelihood (REML) estimation and Hartung-Knapp confidence intervals. Histology- and Newcastle-Ottawa Scale (NOS)-based subgroup analyses were prespecified when at least two studies were available. Results Ten studies remained in the systematic review, and nine contributed at least one source-verifiable endpoint-specific adjusted estimate to quantitative synthesis. Seven NLR-OS cohorts yielded a pooled HR of 1.64 (95% CI 1.15–2.33; I² = 81.4%). The osteosarcoma-only subgroup remained significant (five cohorts; HR 1.70, 95% CI 1.03–2.81; I² = 86.6%). Excluding Huang X 2019 from the strict dataset yielded HR 1.84 (95% CI 1.44–2.36; I² = 0%); the reviewer-specified comparison against the previous eight-estimate set, retaining Yang Q 2020 only as a source-reported sensitivity input, yielded HR 1.90 (95% CI 1.47–2.45; I² = 5.9%). PLR was not associated with OS (four cohorts; HR 1.07, 95% CI 0.67–1.72; I² = 56.0%). LMR showed a non-significant protective trend (three cohorts; HR 0.70, 95% CI 0.38–1.27; I² = 0%). Conclusions Higher pretreatment NLR is associated with poorer OS, including in the strict osteosarcoma-only analysis. The direction remained stable in every leave-one-out analysis, while the marked reduction in heterogeneity after excluding Huang X 2019 identifies one dominant statistical influence. Retrospective designs and residual heterogeneity limit clinical application. PLR and LMR findings remain inconclusive, and whether NLR-guided management improves outcomes is untested.