Prognostic significance of pretreatment systemic immune-inflammation index in patients with prostate cancer: a meta-analysis

Apart from being the 2nd commonly diagnosed carcinoma, prostate cancer (PCa) also represents the 5th leading cause of carcinoma-associated mortality among males globally [1]. Based on GLOBOCAN 2020 estimates, there were 1,414,259 new PCa cases and 375,304 PCa-associated deaths in 2020 around the world [1]. The global incidence of PCa varies more than 25-fold, with a higher prevalence in Western countries and a lower prevalence in Asian countries [2]. The last few decades have witnessed an elevation in the global PCa incidence [3]. Its prognosis is heterogeneous, according to tumor stage. Most PCa cases have localized disease, and the 5-year rate of survival is nearly 100% in these populations. However, the patients with metastatic castration-resistant PCa (mCRPC) have poor prognosis, whose median time of survival is 24 months and 5-year rate of survival 30% [4, 5]. Prognostic biomarkers are important for improving the survival outcomes of patients with PCa [6]. For example, a recent study (PRIMERA trial) including 44 patients revealed that androgen receptor (AR), prostate-specific antigen (PSA), and prostate-specific membrane antigen (PSMA) expression in circulating tumor cells (CTC)+ had no significant impact on PSA drop and survival in mCRPC patients [7]. The PRIMERA trial validated the predictive importance of CTC detection in mCRPC patients as a result [7]. Hence, identification of novel biomarkers and treatment targets is imperative, in order to enhance the prognosis for patients with PCa.

As indicated by growing evidence, the systemic inflammatory reactions are significant determinants of cancer development and survival outcomes in various cancer types [8]. Many serum inflammatory parameters, including the ratios of neutrophils/lymphocytes [9], platelets/lymphocytes [10], C-reactive proteins/albumin [11], and the SII (systemic immune-inflammation index) [12], have been reported to be effective prognostic markers in different cancer types. The SII was calculated as follows: platelet quantity × neutrophil quantity/lymphocyte quantity. Its role as a prominent prognostic biomarker has been demonstrated in numerous types of carcinomas, such as the hepatocellular [13], pancreatic [14], breast [15], and non-small cell lung [16] carcinomas. Despite the prior explorations on SII’s prognostic significance among the PCa population, unconformable results have been yielded [17‐26]. High SII in PCa has been considered a valid prognostic biomarker for the poor outcome by several researchers [19, 21, 24], whereas others have denied this association [20]. Hence, the objective of the present meta-analysis is to evaluate SII’s prognostic value in PCa based on current evidence.

In former researches, the potential of SII as a prognostic biomarker has been explored for the PCa population [17‐26], despite the unconformable results. In our current meta-analysis, the exact prognostic role of SII in PCa was clarified by pooling the data from 10 studies involving 8133 patients. According to our findings, a high SII represented an independent prognostic biomarker for PFS/bRFS and OS among the PCa patients. Besides, SII exhibited a reliable prognostic power across varying subgroups. However, elevated SII also not correlated with LN metastasis, T stage, Gleason score, or age in PCa. Based on the evidence obtained from this meta-analysis, we recommend the application of SII as a cost-efficient new biomarker for guiding the management and follow-up for the PCa population.

Increasing evidence has suggested the tight linkage of immunoreactions to the cancer occurrence, development, and metastasis [29, 30]. Tumor-derived proinflammatory cytokines like IL (interleukin)-6, IL-8, VEGF, tumor necrosis factor-α, and interferon-γ can be secreted into the tumor microenvironment, leading to chronic inflammation, thus facilitating tumor progression [31]. The SII is a combination of neutrophil, lymphocyte, and platelet counts; thus, it can be elevated in the event of high quantities of neutrophils, platelets, and/or a low quantity of lymphocytes. Current evidence indicates that a microenvironment is offered by the tumor-infiltrating neutrophils, which facilitates the tumor cell growth; they also promote angiogenesis and cell mobility [32]. By constraining the cytolytic potential of various immunocytes, high neutrophil counts inhibit the immunity system [29]. Platelets can release various matrix metalloproteinases to facilitate the degradation of the extracellular matrix, thereby promoting metastasis of cancer cells [33]. In addition, through the proangiogenic cytokine discharge inside the microvasculature of cancer cells, the platelet aggregation is capable of facilitating the tumor growth [34]. In contrast, for the tumor development suppression, lymphocytes are involved critically in the immunosurveillance for cancer [35]. Lymphocytes, including subsets such as CD8+ and CD3+ T cells, correlated with good prognosis in various cancers [36]. Therefore, a high SII is a promising indicator of a combination of neutrophils, lymphocytes, and platelets.

The exact prognostic significance of PSA (prostate-specific antigen), the most extensively applied PCa biomarker [37], in PCa has been reported in several important latest studies [38‐40]. A study on 148 patients showed the validity of PSA as a biomarker for forecasting the PCa prognosis when its levels were from 20 to 70 ng/mL [38]. According to another study focusing on PCa sufferers having low levels of PSA, the tumor stage was more advanced when the PSA level at diagnosis was < 3.5 ng/ml compared to that between 3.5 and 10 ng/ml [39]. As suggested by a study enrolling 90 PCa patients whose PSA levels were > 100 ng/mL, the differences in OS or CSS were insignificant among the 3 PSA groups, namely the slightly high (100–200 ng/mL), moderately high (200–1000 ng/mL), and considerably high (> 1000 ng/mL) groups [40]. According to the results of our current meta-analysis, the prognosis of patients was poor when their SII was high. SII is an independent risk factor for PCa and could be a better screening method for PCa before biopsy [41]. Therefore, the SII could be used as a biomarker for improving the diagnostic and prognostic accuracy of PSA. Furthermore, a recent study suggested that the level of CCL2 (serum CC motif (chemokine) ligand 2) is a valid prognostic indicator for poor survival in PCa [42]. Patients with serum CCL2 levels ≥ 320 pg/mL had relatively worse OS, CSS, and CRPC-free survival than those with CCL2 concentrations < 320 pg/mL [42]. The relationship between CCL2 levels and the SII needs to be investigated in future studies.

Notably, this meta-analysis included four studies with the endpoint of PFS [19, 20] and bRFS [24, 25]. Two studies enrolled patients with mCRPC [19, 20], whereas two studies recruited the localized PCa patients [24, 25]. The definition of these endpoints in four studies is not all the same. In Fan’s study [19] with mCRPC patients, PFS referred to an interval from the commencement of the first mCRPC therapy (i.e., docetaxel-prednisone or abiraterone) until the time of radiographic progression. In Kobayashi, H.’s work [20] with mCRPC patients, an interval from the disease diagnosis to progression was regarded as PFS. Besides, disease was considered progressed when the serum level of PSA was elevated by > 2 ng/mL, the rise over nadir was 50%, and/or a new lesion emerged, or the known lesions classified as per the RECIST (ver. 1.1) increased by one or more [43]. In Rajwa’ s study with localized PCa patients, bRFS was defined as the interval from radical prostatectomy to the first PSA rise of two consecutive PSA values > 0.2 ng/ml [24]. Although the definitions are not all the same, our results demonstrated that in PCa, a high SII was a prominent prognostic biomarker for poor PFS/bRFS (Table 3). To probe deeper into SII’s prognostic function among patients with different metastatic status, subgroup analysis was conducted. The results showed that a high SII was not associated with poor PFS/bRFS in localized PCa patients (p = 0.160), as well as not with worse PFS/bRFS in mCRPC patients (p = 0.183) (Table 3). Because of the relatively small size of samples, our results still need be verified through large-scale researches.

SII’s prominent prognostic value has been pinpointed for varying solid tumors by extensive recent meta-analyses [44‐47]. As suggested by a meta-analysis involving 7 studies, an elevated pretreatment SII was linked to inferior carcinoma-specific survival/DFS/PFS and poor OS in pancreatic carcinoma patients [44]. According to another meta-analysis covering 4236 patients, a high pretreatment SII forecasted poor OS in gastric carcinoma [48]. A high SII was also reported to be linked to the poor OS among the renal cell carcinoma sufferers [47]. Through a meta-analysis involving 2,796 patients, Wang et al. reported that elevated pretreatment SII was related to lower OS and earlier time-to-recurrence in hepatocellular carcinoma [49]. As indicated by a latest meta-analysis enrolling 12 studies, high levels of SII were correlated pronouncedly with worse PFS and OS among the colorectal cancer population [50]. Our present results on SII’s prognostic role agree with those in other types of carcinomas.

Regarding several shortcomings of our meta-analysis, first of all, the optimal SII cut-off was not determined. The included studies used different cutoff thresholds, which might have contributed to the heterogeneity among studies. Second, majority of the enrolled studies were retrospective, while there was merely 1 enrolled prospective study. Thus, differences in unadjusted factors could lead to selection bias. Third, our meta-analysis included qualified published studies in English or Chinese only, while failing to enroll relevant articles in other languages, which is also likely to result in inherent heterogeneity.

Conclusively, the present meta-analysis suggests the correlation of an elevated pretreatment SII with the shortened PFS/bRFS and OS among the PCa population. SII monitoring could be a potentially effective approach for improving the survival of patients with PCa.