Although several studies have previously reported the association of SII with urinary system cancers, we found that there were some slight inconsistencies in the various results. In this meta-analysis, we systematically evaluated the potential value of SII for predicting the clinicopathological features and prognosis of urinary system cancer patients who underwent non-surgical or surgical treatment. The statistical analysis results of our study showed that elevated levels of pretreatment SII are more likely to be associated with some poor survival outcomes, such as shorter OS, PFS, and CSS, and some undesirable pathological features, such as large tumour size, poor differentiation grade, and advanced tumour stage. To our knowledge, this meta-analysis is the first to investigate whether SII can be used as an independent prognostic marker for patients with urinary system cancer regardless of the treatment strategy.
As early as 1863, Virchow found abnormal leucocyte cells in cancerous tissues and built a hypothesis that there was a correlation between the inflammatory response and cancer progression.[32] Later, an increasing number of studies began to explore the potential mechanisms by which inflammation affects tumours through animal models and clinical trials.[33, 34] SII, as a new inflammatory index that is simple, economic, and easily detected, has been proposed and has received more attention in recent years; it is calculated based on the counts of peripheral neutrophils, platelets, and lymphocytes. SII has been reported to be related to the occurrence, progression, and prognosis of several diseases, such as bleeding disorders, connective tissue diseases, and various malignant tumours in humans.[35–37]
In 2014, through retrospective and prospective studies, Hu and his colleagues first demonstrated that SII was a great prognostic indicator of adverse outcomes for hepatocellular carcinoma (HCC) patients and could be used as a promising tool to aid in the decision making of therapeutic strategies for HCC.[38] Although the precise mechanism by which SII affects cancer prognosis has not been fully clarified at present, it is related to the three inflammatory biomarkers involved in the SII calculation at least. First, neutrophils can secrete various inflammatory factors, such as vascular endothelial growth factor, interleukin (IL)-6, IL-10, and prostaglandin, to accelerate the construction of the tumour microenvironment, which plays a critical role in promoting tumour angiogenesis, enhancing tumour cell adhesion and facilitating distant metastasis.[11, 12] Second, platelets, as the shield of circulating tumour cells, may prevent them from endogenous and exogenous immune attacks, leading to the multiplication, invasion and metastasis of the tumour.[39] At the same time, platelets can also release several chemokines and cytokines and have a similar effect to neutrophils in vivo.[40] Thus, the enhanced neutrophil and platelet counts reflect the opening of immune pathways and activation of the immune state in the organism. In contrast, lymphocytes, especially tumour-infiltrating lymphocytes, may induce the apoptosis of tumour cells and eliminate them through specific cellular immunity and humoral immunity, which is essential for immune defence and immune surveillance in the host.[41, 42] Based on the above mechanisms, it easily understandable that high SII indirectly symbolizes the inadequate immunological function of cancer patients and the intensification of tumour invasiveness. Therefore, this kind of compound immunity index is more likely to predict the undesirable pathological features and worse survival of cancer patients.
Previously, several studies have explored the prognostic impact of SII in tumours of different organs and systems by systematic reviews and meta-analyses. In 2017, Zhong et al. first demonstrated that high SII predicted poor outcomes of patients with solid tumours and could be considered a new cost-effective prognostic indicator.[43] Zhang and his colleagues provided evidence in 2018 that SII, as an easily obtained and noninvasive biomarker, was observably associated with short OS (HR: 1.52, 95% CI: 1.29–1.74, p < 0.01), DFS (HR: 2.28, 95% CI: 1.46–3.10, p < 0.01) and recurrence-free survival (RFS) (HR: 1.60, 95% CI: 1.19-2.00, p < 0.01) in patients with gastrointestinal (GI) cancers and could become a powerful tool in predicting the survival of GI cancers in clinical practice.[44] Not long ago, the prognostic value of pretreatment SII in non-small cell lung cancer patients was also proven by Wang et al. They supported that this immune parameter was helpful for physicians to develop therapeutic strategies, and patients with high SII should be recommended for immunotherapy compared to those with low SII.[45] In recent years, a vast number of studies have successively explored the correlation between SII and urinary malignant tumours. An Italian scientific research team performed a retrospective study involving 335 patients with terminal RCC receiving sunitinib and suggested that SII and its changes during immunological therapy could effectively predict the prognosis of patients with metastatic RCC.[26] In patients with UTUC undergoing radical nephroureterectomy, the results of Zheng's study supported that patients with high SII before surgery might have a markedly shorter OS, PFS, and CSS than those with low SII (all p < 0.05).[20] The findings of Man et al. and Fan et al. directly proved that pretreatment SII could assist in predicting the survival of metastatic castration-resistant PC patients treated with chemotherapy in both the training and validation cohorts, which combined with other indices (prostate-specific antigen, albumin, and fibrinogen) might guide clinicians in the identification of high-risk populations and selection of the best treatment protocols.[30, 18] In 2020, Yılmaz et al. found that SII as well as other parameters, such as NLR, prognostic nutritional index, and red cell distribution, were all associated with poor survival outcomes in patients with muscle-invasive bladder cancer (MIBC) in univariate analysis. Unfortunately, SII was not found to be an independent prognostic indicator for either OS (HR: 1.551, 95% CI: 0.877–2.774, p = 0.131) or PFS (HR: 1.240, 95% CI: 0.670–2.294, p = 0.493) in multivariate analysis.[28] However, in a similar study of MIBC, Zhang et al revealed that elevated preoperative SII could be considered an independent predictor for patients undergoing radical cystectomy in both univariate and multivariate Cox regression analyses, and SII was more predictive than NLR and PLR.[29] The existence of heterogeneity may be caused by the difference in study regions, the inconsistency of SII cut-off values, and the variety of tumour types. The results of our meta-analysis further confirmed the critical prognostic value of SII for urinary system cancers. Therefore, we recommend that SII should be brought into the prognostic risk assessment system for urinary system cancer patients.
Nevertheless, there were still several limitations in the present meta-analysis. First, most of the articles included in our meta-analysis were retrospective studies, which inevitably led to potential defects and deviations in the original data. Second, only 13 studies involving 15 datasets comprising 3974 patients were enrolled, which might cause bias due to the limited sample size. Third, because of the difference in cut-off selection, the critical values of SII have not yet been unified. Fourth, the treatment strategies are not exactly the same in various cancer types, and these inconsistencies might have an influence on the survival of patients and thus give rise to some heterogeneity. Finally, potential publication bias cannot be avoided entirely. Therefore, the prognostic role of pretreatment SII in urinary system cancers needs to be further explored by conducting more large-scale and high-quality prospective trials in the future.