Prognostic value of systemic immune-inflammation index in patients with metastatic renal cell carcinoma treated with systemic therapy: a meta-analysis

Objective A novel systemic immune-inflammation index (SII), based on the neutrophils, lymphocytes, and platelet counts, is associated with the prognosis of several cancers, including non-metastatic renal cell carcinoma (RCC). In the present study, we evaluate the prognostic significance of SII in patients with metastatic RCC (mRCC) treated with systemic therapy. Method Relevant studies were searched comprehensively from Web of Science, PubMed, Embase and the Cochrane Library up to January 2024. The pooled hazard ratio (HR) and 95% confidence interval (CI) were extracted from each study to evaluate the prognostic value of SII in patients with mRCC treated with tyrosine kinase inhibitor (TKI) or immune checkpoint inhibitor (ICI). Results A total of 12 studies including 4,238 patients were included in the final analysis. High SII was significantly correlated to poor overall survival (OS, HR = 1.88; 95% CI 1.60–2.21; P < 0.001) and progression-free survival (PFS, HR = 1.66; 95% CI 1.39–1.99; P < 0.001). Stratified by therapy, high SII was also related to the poor OS (TKI: HR = 1.63, P < 0.001; ICI: HR = 2.27, P < 0.001) and PFS (TKI: HR = 1.67, P < 0.001; ICI: HR = 1.88, P = 0.002). Conclusion In conclusion, high SII could serve as an unfavorable factor in patients with mRCC treated with systemic therapy. Stratified by therapies, the elevated SII was also associated with worse prognosis. Whereas, more prospective and large-scale studies are warranted to validate our findings. Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024522831, identifier CRD42024522831.


Introduction
Renal cell carcinoma (RCC) is one of the common urological cancers, accounts for approximately 2% of all malignancies, with an estimated 431,288 new cases and 179,368 deaths in 2020 worldwide (1).Although most patients are localized disease and could undergo surgical resection with curative intent, about one-third of patients will develop metastatic disease recurrence (2,3).Furthermore, 30% of patients present regional or distant metastases at initial diagnosis (2).Over the last decades, advancements in the treatment of metastatic RCC (mRCC) improved patients' prognosis dramatically, such as the tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICIs) (4,5).
With the progress of the management of mRCC, identification of predictive markers would be of great value to patients' treatment and long-term outcomes.The International metastatic renal cell carcinoma Database Consortium (IMDC) risk model is widely used for mRCC patients' stratification and treatment selection.Recently, other potential biomarkers have been investigated for their prognostic and predictive value, including programmed cell death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), molecular and genomic signatures, and clinical factors (6).
The SII is defined as follows platelet count × neutrophil count/ lymphocyte count and has been found to be associated with the prognosis of several cancers, such as urothelial carcinoma, hepatocellular carcinoma, and non-metastatic RCC (12)(13)(14).The prognostic value of SII in mRCC patients treated with systemic therapy remains unclear.Therefore, we summarized all relevant studies and investigated the prognostic significance of SII in mRCC.

Search strategy
The present study was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement (15).Moreover, present study has been registered in PROSPERO (CRD42024522831).We comprehensively searched Embase, Web of Science, PubMed, and the Cochrane Library up to January 2024.Two independent reviewers performed the study search based on the search strategy (SII, systemic inflammation index, systemic immune-inflammation index) and (kidney cancer, renal cancer).We also screened the references of eligible studies to avoid the omission.

Inclusion and exclusion criteria
Studies finally enrolled in the present study should meet the following criteria: (1) population-based studies, (2) involved patients with mRCC, (3) patients were treated with TKI or ICI, (4) SII was defined accurately and calculated based on the formula, (5) evaluate the prognostic value of SII, (6) available data such as hazard ratio (HR) and 95% confidence interval (CI) could be extracted.The following studies were excluded: (1) did not involve SII, (2) did not evaluate the prognostic value of SII, (3) insufficient data for HR and 95% CI, and (4) patients weren't treated with systemic therapy.For the same cohort patients, we included the study with the largest and newest data.

Data extraction and quality assessment
Two reviewers extracted the relevant data from eligible studies independently based on the predefined items: publication year, participant, study design, disease, therapy, number and ages of patients, the cutoff value of SII, clinical outcomes, and duration of follow-up.The Newcastle-Ottawa Quality Assessment Scale (NOS) was used to evaluate the quality of included studies, incorporating three main aspects: selection, comparability, and exposure/ outcome.Total scores ranged from 0 to 9, a score of no less than 7 was considered as high quality.

Statistical analysis
STATA (version 12, StataCorp, College Station, TX, USA) was applied to conduct all statistical analyses.We extracted and pooled HRs and 95% CIs through the inverse-variance method to investigated the prognostic value of SII in patients with mRCC.A random-effects approach was chosen over a fixed-effects approach, because using random effects is often preferred when performing a meta-analysis to guide patient treatment decision (16,17).For the evaluation of heterogeneity across studies, the Cochran's Q test and the Higgins'I 2 statistic were calculated.If the I 2 ≥ 50% or P < 0.10, the between-study heterogeneity was considered as significant (18).The sensitivity analyses were conducted to validate the stability of the final results by omitting each study in sequence.We also performed subgroup analysis and meta-regression to explore the potential source of heterogeneity.A two-sided P-value of < 0.05 was considered significant.

Results
At first, 594 articles were identified based on the electronic database search.After excluding the 74 duplicated articles, the remaining 520 records were screened.According to the titles and abstracts, 66 studies were further reviewed detailedly.At last, a total of 12 studies incorporating 4,238 patients were included in the final analysis (19-30).The detailed information was illustrated in Figure 1 (Supplementary Table S1).

Clinical characteristic of the enrolled studies
Most studies were retrospective, while two studies were prospective (19,28).Eight of the studies were multicenter.Half of studies included mRCC patients treated with ICIs, and the other six studies involved mRCC patients treated with TKIs.Most studies have a quite large sample size, ranging from 49 to 1,034.SII was calculated based on the formula (platelet×neutrophil/lymphocyte).The cutoff value of SII in each study is not consistent.All studies reported the overall survival (OS), seven studies reported progression-free survival (PFS).All studies were regarded as high quality (Supplementary Table S2).The detailed information was summarized in Table 1.

Overall survival
All studies including 4,238 patients reported OS.We observed moderate heterogeneity among studies, so the random effect was applied (I 2 = 51.2%;P = 0.021).A higher SII was significantly related to the worse OS compared with lower SII (HR = 1.88; 95% CI 1.60-2.21;P < 0.001; Figure 2A).

Progression-free survival
Regarding PFS, seven studies involving 2,857 patients revealed relevant data.We also observed the evidence of heterogeneity (I 2 = 48.4%;P = 0.071).Using the random-effect model, we found that the patients with higher SII had a worse PFS compared with the patients with lower SII (HR = 1.66; 95% CI 1.39-1.99;P < 0.001; Figure 2B).

Sensitivity analysis
The sensitivity analysis for OS and PFS was conducted by eliminating each study to reflect the impact of the individual to overall.Consistently, we observed that removing any single study would not dramatically alter the trend of our results (Figure 3).

Subgroup analysis and meta-regression
We performed subgroup analysis stratified by number of patients, study type, therapy, and enrollment.For the different types of studies, we both observed that high SII was significantly associated with poor OS.In the subgroup with large than 300 patients, high SII was also associated with the inferior OS and PFS, and in the <300 patients, we also detected the prognostic significance of SII.As for therapy, high SII was an unfavorable factor in patients treated with ICI or TKI.In addition, in studies from multicenter or single center, high SII was significantly related to the poor OS and PFS.Meta-regression revealed that none of these variables are significantly associated with the heterogeneity.The detailed information was summarized in Table 2.

Discussion
In the present study, we evaluate the association between SII and mRCC patients, observing that high SII was associated with the poor prognosis of mRCC.When stratified by therapies, high SII also predicts an inferior OS and PFS in mRCC patients treated with TKI or ICI.Moreover, we performed subgroup analysis and found all subgroup results are consistent with overall results.We only included the studies that provided the largest and newest data, which may affect the totality of data.However, this would likely be non-differential given the prognostic nature of the studies.
Local recurrence or metastasis is highly likely to occur in the RCC, nearly 30% of patients will develop local or distant recurrence after surgery (3).Meanwhile, one-third of patients suffer from metastasis initially (2).Although systemic therapy achieved great improvement of mRCC patients' survival, not all patients could respond to these therapies.Many efforts to explore predictive markers are continuing.
The association between inflammation and malignancy has been widely explored in the past decades.Lots of studies have revealed an immunogenic nature of RCC (31).This immunogenic microenvironment may explain the antitumor efficacy of immunerelated therapy used in mRCC treatment.While, the tumor infiltrating cells and their secretions may play a role in tumorigenesis, progression and clinical outcomes (32).It has been revealed that some peripheral markers of inflammation, NLR, PLR, and CRP were associated with prognosis of mRCC patients (33).Yucel et al. collected 706 mRCC patients treated with first-line TKI from multicenter and observed that pre-treatment high SII was considered a predictor of poor OS (HR = 1.39;P = 0.01) and PFS (HR = 1.60;P < 0.001) (23).In addition, SII might provide the similar predictive value as the IMDC and MSKCC, with the similar C-index values for OS and PFS in SII, IMDC, and MSKCC risk scores (23).Bugdayci Basal et al. demonstrated that in different IMDC risk groups, the patients with higher SII had a significantly worse OS compared with those with lower SII.And the SII may increase the predictive value of IMDC risk model in mRCC patients treated with TKI (24).Chrom et al. demonstrated that the addition of the SII to the IMDC model in place of neutrophil and Sensitivity analysis for OS (A) and PFS (B).

A B
Higher SII was associated with worse OS (A) and PFS (B) in mRCC patients treated with systemic therapies.Right side (HR > 1) favors low SII, left side (HR < 1) favors high SII.
platelet counts increased the model's prognostic performance (27).Moreover, for mRCC patients received ipilimumab plus nivolumab in the first-line setting, high SII was also an unfavorable factor for OS and PFS (22).A prospective cohort of patients with mRCC treated with nivolumab also revealed that SII independently predicted OS (HR = 2.99; P < 0.001) (28).Recently, a retrospective study of 1,034 mRCC patients from 56 centers also revealed that a high SII is associated with poor oncological outcomes in patients treated with first-line immune combinations therapy (30).Wang et al. performed a meta-analysis and explored the prognostic value of SII in cancer patients receiving ICI.They found SII could predictive OS and PFS irrespective the cancer type, ICIs type and cutoff value of SII (34).Based on the abovementioned evidence, high SII could be served as an unfavorable factor in mRCC patients treated with systemic therapies.However, more large-scale studies are required to verify our findings.
The potential mechanism for the prognostic significance of this combination might be explained by the functions of neutrophil, platelet, and lymphocyte.Neutrophils can promote cancer development through directly interacting with tumor cells.Neutrophils can secrete proinflammatory cytokine and chemokine related to the remodeling of the tumor microenvironment and have a tumor-promoting effect (35).Platelets have been reported to regulate tumor angiogenesis, protect tumor cells from cytolysis, and contribute to tumor metastasis (36).As a major cellular immunity component in humans, lymphocytes are implicated in killing the host cancer cells by cell-mediated immunization.Therefore, the decreased lymphocytes may cause a weak antitumor activity and lead to cancer progression (24).SII had significance in clinical practice.SII was calculated based on the neutrophil, platelet, and lymphocyte, which is convenient, easily obtained and commonly tested before the treatment.SII could predict the prognosis of patients, which could be used for mRCC patients' managements.However, the individual conditions should be considered during the treatment strategy decision.Our study is not devoid of shortcomings.First of all, total 12 studies consisting of 4,238 patients were included, which is not a relatively large sample and may limit the power of final results.Next, almost all studies were retrospective studies with the potential inherent bias, resulting heterogeneity.Therefore, we conducted sensitivity analysis and subgroup analysis.We only included the studies that provided the largest and newest data, which may affect the totality of data.But this would likely be non-differential given the prognostic nature of the studies.At last, although we performed subgroup analyses and meta-regression, there are several factors that are not available and may result heterogeneity such as detailed treatments and comorbidity, so we could not conduct additional analyses.

Conclusion
In conclusion, high SII could serve as an unfavorable factor in patients with mRCC treated with systemic therapy.Stratified by therapies, the elevated SII was also associated with worse prognosis.Whereas, more prospective and large-scale studies are warranted to validate our findings.

FIGURE 1 Flowchart
FIGURE 1Flowchart of the literature search.

TABLE 1
Clinical characteristics of enrolled studies.

TABLE 2
Subgroup analyses of overall survival and progression-free survival.