Comment on “Prognostic Value of Systemic Immune‐Inflammation Index in Patients With Gynecological Tumors: A Systematic Review and Meta‐Analysis”

Dear Editor, We read with interest the article by Guo et al., “Prognostic Value of Systemic Immune-Inflammation Index in Patients With Gynecological Tumors: A Systematic Review and Meta-Analysis,” which synthesizes the evidence on SII as a readily available prognostic biomarker in female malignancies 1. By pooling hazard ratios for overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS), the study highlights that elevated SII is associated with poorer outcomes and argues that SII may aid risk stratification and inform individualized management in this population. We noted several methodological and conceptual issues that may limit the validity and generalizability of the conclusions, particularly regarding “gynecological tumors.” First, according to Table 1, most included cohorts involve triple-negative and HER2-positive breast cancer, with only a minority of studies in epithelial ovarian and endometrial cancer. Breast cancer is typically not classified as a gynecologic malignancy, yet studies in breast cancer are analyzed alongside ovarian and endometrial cancer, and the pooled effect is interpreted as applying to “gynecological tumors.” This mismatch between the stated target population and the actual tumor spectrum may overstate the applicability of the findings to classical gynecologic cancers. Second, the methods section describes use of the Cochrane risk-of-bias tool for randomized controlled trials, but all included studies appear to be observational (case-control or cohort), suggesting a possible misalignment between the risk-of-bias tool and study design. Third, the authors report substantial heterogeneity (I2 >50% for several pooled estimates) and evidence of publication bias from funnel-plot asymmetry, yet the conclusions remain relatively strong regarding clinical applicability without formal meta-regression to explore sources of heterogeneity (eg, tumor type, disease stage, SII cutoff definition, or adjustment for confounders). Finally, the manuscript repeatedly refers to SII as an “independent” prognostic factor, although many of the underlying studies use unadjusted or partially adjusted models; independence from established clinicopathologic predictors (FIGO stage, residual disease, molecular subtype, etc) is therefore not fully demonstrated. Recent literature does support the central premise that SII carries prognostic information in at least some gynecologic malignancies. A recent updated systematic review and meta-analysis focused specifically on ovarian cancer included 10 studies with 11 cohorts (n = 2852). The authors reported that high SII was associated with significantly worse OS (HR, 2.35; 95% CI, 1.56–3.55) and DFS (HR, 2.51; 95% CI, 1.71–3.67), with results largely robust to sensitivity analyses and broadly consistent across subgroups defined by stage, treatment, and cutoff methods 2. These findings substantiate the suggestion by Guo et al. that SII is a clinically relevant prognostic marker, at least in epithelial ovarian cancer, and they do so within a more narrowly and appropriately defined disease category. Conversely, other recent work illustrates that systemic inflammatory indices, including SII, may not always retain independent prognostic value once established factors are accounted for. One study evaluated neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and SII in 154 patients with epithelial ovarian cancer. In univariate analyses, elevated NLR and PLR were associated with worse PFS and OS, but these markers, including SII, did not remain statistically significant in multivariable models. SII showed only a non-significant trend toward poorer outcomes, and its predictive performance for platinum resistance was limited (area under the curve, 0.36) 3. This study suggests that inflammatory indices may be context-dependent and that their incremental value over standard prognostic factors is not uniform across all gynecologic settings. To strengthen the clinical message, we suggest (1) clarifying the distinction between breast and gynecologic tumors and, where possible, presenting separate pooled estimates by tumor site; (2) aligning the risk-of-bias assessment with the observational nature of the included studies; and (3) tempering claims of independence until more consistently adjusted data are available. Future research should prioritize large, prospective, site-specific cohorts (eg, ovarian, endometrial, cervical) with standardized SII measurement and cutoffs, multivariable modeling that includes established prognostic variables, and external validation, ideally embedded within randomized or real-world treatment studies. Such refinements would help define when and how SII can be incorporated into validated prognostic models and whether it meaningfully improves risk stratification and treatment decision-making in gynecologic oncology. The authors acknowledge institutional academic support. No additional assistance was received. The authors declare that no external funding was received for this work. As this manuscript is a commentary, ethical approval was not required. The authors have nothing to report. The authors declare no conflicts of interest. No new datasets were created or analyzed in this study.