Prognostic impact of serum interleukin-6 and 17 level in patients with bladder cancer: a systematic review and meta-analysis

Protocol and registration

This systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), Meta-analysis of Observational Studies in Epidemiology (MOOSE), and Assessing the Methodological Quality of Systematic Reviews (AMSTAR) guidelines (Page et al., 2020; Stroup et al., 2000; Shea et al., 2017). The study was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO).

Search strategy

A comprehensive search of six English and Chinese databases—PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure (CNKI), Wanfang Database, and Chinese Biomedical Literature Service System—was conducted from inception to July 10, 2024. Both subject headings and free-text terms were employed in the search strategy. Search terms include: ‘urinary bladder neoplasms’, ‘urinary bladder neoplasm’, ‘bladder neoplasms’, ‘bladder neoplasm’, ‘bladder tumors’, ‘bladder tumor’, ‘urinary bladder cancer’, ‘bladder cancer’, ‘bladder cancers’, ‘cancer of bladder’, ‘cancer of the bladder’, ‘malignant tumor of urinary bladder’, ‘interleukin-6’, ‘interleukin-17’, ‘IL-6’, ‘IL6’, ‘IL-17’, ‘IL17’, ‘prognosis’, ‘prognoses’, ‘prognostic factors’, and ‘prognostic factor’. Additionally, a manual search of the grey literature was performed. Table 1 outlines the specific search strategy for the PubMed database.

Outcomes

The primary outcome measures were disease-free survival (DFS) and overall OS. Disease-specific survival (DSS) was a secondary outcome measure. DFS was assessed based on data on disease recurrence survival (DRS), DFS, RFS, and progression-free survival (PFS). DSS was evaluated using data on DSS and CSS.

Inclusion and exclusion criteria

Inclusion criteria were as follows: (1) study population diagnosed with BCa via histopathology and aged ≥18 years; (2) measurement and categorization of serum IL-6 or IL-17 into high and low groups; (3) assessment of at least one of the following outcomes: DFS, DRS, RFS, PFS, OS, DSS, or CSS; (4) study design as an observational study (case-control or cohort); (5) sample size of ≥ 30 participants; (6) provision or calculability of 95% confidence intervals (CIs) for serum IL-6 or IL-17 levels based on presented data; and (7) publication in English or Chinese.

Exclusion criteria were as follows: (1) absence of histological diagnosis, (2) incomplete data on serum IL-6 or IL-17 measurement or outcome, (3) book, patent, thesis, conference abstract, literature review, or case report format, (4) inability to extract data, and (5) duplicate publications.

Literature screening and data extraction

The database searches were conducted by two authors in accordance with the predefined search strategy. Duplicate records were removed using Endnote software and manual methods. Subsequently, two independent researchers screened the remaining citations. Eight studies (Tong, Hu & Li, 2022; Schuettfort et al., 2021; Andrews et al., 2002; Cai et al., 2007; Gong et al., 2019; Liu et al., 2018; Wang et al., 2024; Zhang et al., 2020) were selected for full-text review, of which seven (Tong, Hu & Li, 2022; Schuettfort et al., 2021; Andrews et al., 2002; Gong et al., 2019; Liu et al., 2018; Wang et al., 2024; Zhang et al., 2020) met the inclusion criteria for the meta-analysis. Extracted data included: (1) basic study characteristics (first author, publication year, sample size, sex, age); (2) clinicopathological features (T stage, grade); (3) interleukin-related information (assessment method, interleukin type, test method, cutoff value); (4) treatment and outcome data (surgery type, median follow-up, DFS, DRS, RFS, PFS, OS, DSS, CSS); and (5) meta-analysis data (hazard ratios (HR) and 95% CI). Data extraction and study selection were performed independently by two reviewers, with discrepancies resolved through discussion or, if necessary, by a third reviewer.

Quality assessment

Two investigators independently assessed the quality of the included studies using the Newcastle-Ottawa Scale (NOS) (Stang, 2010). A total score of nine was possible, with studies categorized into three quality levels: low (0–3 points), moderate (4–6 points), and high (7–9 points). Discrepancies between reviewers were resolved through discussion or by involving a third reviewer.

Statistical analysis

Statistical analyses were performed using RevMan 5.4.1. HRs, 95% CIs, and p-values from univariate or multivariate Cox regression were extracted from each study. When relevant data were not reported, Tierney’s method was employed for calculation (Tierney et al., 2007). In instances where both univariate and multivariate analysis results were available for survival outcomes, the latter were prioritized. Heterogeneity was assessed using the I² statistic (Higgins et al., 2003). A fixed-effects model was used for meta-analysis when I² was less than 50%, indicating no significant heterogeneity; otherwise, a random-effects model was applied.

Sensitivity analyses were conducted by employing alternative statistical models. To assess the robustness of the meta-analysis results, a sensitivity analysis was performed by sequentially excluding individual studies. Subgroup analyses were conducted to evaluate the prognostic significance of interleukin levels for OS in BCa patients based on interleukin type, and for DFS in BCa patients based on interleukin type, study location, and surgical method. To assess potential heterogeneity among studies, a random-effects model was used to calculate pooled HRs. Publication bias was evaluated using funnel plots when more than seven studies were included. Statistical significance was defined as a p-value < 0.05.

Study characteristics and quality assessment

A total of 292 articles were initially identified through electronic database searches (PubMed (n = 88), Embase (n = 51), Web of Science (n = 66), CNKI (n = 72), Wanfang (n = 2), and SinoMed (n = 12)) and manual searches using the predefined search strategy. After removing duplicates using both software and manual methods, 197 articles remained. Following title and abstract screening, eight articles (Tong, Hu & Li, 2022; Schuettfort et al., 2021; Andrews et al., 2002; Cai et al., 2007; Gong et al., 2019; Liu et al., 2018; Wang et al., 2024; Zhang et al., 2020) were selected for full-text review. Ultimately, one article (Cai et al., 2007) was excluded due to insufficient data quality. The literature screening process is summarized in Fig. 1.

The NOS scores ranged from 6 to 8 points. Among the evaluated studies (n = 7) (Tong, Hu & Li, 2022; Schuettfort et al., 2021; Andrews et al., 2002; Cai et al., 2007; Gong et al., 2019; Liu et al., 2018; Wang et al., 2024; Zhang et al., 2020), six (Schuettfort et al., 2021; Andrews et al., 2002; Gong et al., 2019; Liu et al., 2018; Wang et al., 2024; Zhang et al., 2020) were deemed high quality, one (Tong, Hu & Li, 2022) was moderate quality, and none were classified as low quality.

Eligible studies and patient characteristics

A total of seven studies (Tong, Hu & Li, 2022; Schuettfort et al., 2021; Andrews et al., 2002; Cai et al., 2007; Gong et al., 2019; Liu et al., 2018; Wang et al., 2024; Zhang et al., 2020) involving 1,505 patients were included in the meta-analysis. One study (Andrews et al., 2002) was published in 2002, while the remaining six (Tong, Hu & Li, 2022; Schuettfort et al., 2021; Gong et al., 2019; Liu et al., 2018; Wang et al., 2024; Zhang et al., 2020) were conducted within the past 5 years, indicating growing interest. Table 2 summarizes the key characteristics of the included studies. Only two (Liu et al., 2018; Zhang et al., 2020) studies investigated the association between serum IL-17 and BCa, whereas the remaining studies focused on the relationship between serum IL-6 and BCa (Tong, Hu & Li, 2022; Andrews et al., 2002; Gong et al., 2019; Schuettfort et al., 2021; Wang et al., 2024). Regarding surgical interventions, patients underwent either transurethral resection of bladder tumor (TURBT) or radical cystectomy (RC).

Association interleukin levels with survival

Four studies (Schuettfort et al., 2021; Gong et al., 2019; Liu et al., 2018; Zhang et al., 2020) (n = 1,284 patients) reported the association between serum IL-6/17 and OS in BCa. Given the substantial heterogeneity, a random-effects model was employed. Meta-analysis results indicated that patients with elevated serum IL levels exhibited poorer OS (HR = 2.28, 95% CI [1.03–5.05], P = 0.04; Fig. 2A). Due to the limited number of included studies, sensitivity analyses were not performed.

Six studies (Tong, Hu & Li, 2022; Schuettfort et al., 2021; Andrews et al., 2002; Liu et al., 2018; Wang et al., 2024; Zhang et al., 2020) (n = 1,381 patients) reported the association between serum IL-6/17 levels and DFS/DRS/RFS/PFS in BCa. A random-effects model demonstrated that elevated IL levels were associated with poorer DFS/DRS/RFS/PFS (HR = 2.57; 95% CI [1.55–4.26]; P < 0.001; Fig. 2B). Sensitivity analysis demonstrated consistent pooled estimates upon removal of any individual study, supporting the robustness of the meta-analysis.

Only two studies (Schuettfort et al., 2021; Andrews et al., 2002) reported the relationship between serum IL-6/17 and DSS/CSS in BCa. A random-effects model demonstrated no association between elevated serum interleukin levels and DSS/CSS (HR = 1.58; 95% CI [1.00–2.51]; P = 0.05; Fig. 2C). Andrews et al. (2002) analyzed 51 patients who underwent RC and found that serum IL-6 was a predictor of DSS according to their preoperative Cox proportional hazards model (HR = 2.171; 95% CI [1.288–3.659]; P = 0.05). Consistent findings were reported in another study (HR = 1.33; 95% CI [1.24–1.42]; P < 0.001).

Prognostic value of interleukins in subgroup analyses

Subsequent subgroup analyses were performed to evaluate the relationship between serum interleukin subtype and OS. Patients with elevated serum IL-17 levels exhibited significantly shorter OS (HR = 3.32; 95% CI [1.25–8.80]; P = 0.02; Fig. 3). Conversely, serum IL-6 levels were not associated with OS (HR = 1.92; 95% CI [0.67–5.47]; P = 0.22; Fig. 3). However, the pooled analysis revealed an association between elevated serum IL levels and poorer OS (HR = 2.28; 95% CI [1.03–5.05]; P = 0.04; Fig. 3).

Subgroup analyses of DFS/DRS/RFS/PFS were conducted based on serum interleukin type. Four studies (Tong, Hu & Li, 2022; Schuettfort et al., 2021; Andrews et al., 2002; Wang et al., 2024) reported serum IL-6 levels, while two studies (Liu et al., 2018; Zhang et al., 2020) reported serum IL-17 levels. Patients with elevated serum IL-6 exhibited poorer DFS/DRS/RFS/PFS (HR = 2.74; 95% CI [1.37–5.46]; P = 0.004; Fig. 4). Similarly, patients with elevated serum IL-17 levels demonstrated poorer prognosis in BCa (HR = 2.32; 95% CI [1.11–4.84]; P = 0.02; Fig. 4). A stratified analysis based on the country of publication was also undertaken. Elevated serum interleukin levels consistently predicted unfavorable prognosis irrespective of geographic origin: China (HR = 4.42; 95% CI: 1.90-10.30; P < 0.001; Fig. 5) or other countries (HR = 1.32; 95% CI [1.23–1.41]; P < 0.001; Fig. 5). A subgroup analysis stratified by surgical procedure was subsequently performed. Due to the absence of surgical procedure specification in one study (Liu et al., 2018), the analysis was restricted to the remaining five studies (Tong, Hu & Li, 2022; Schuettfort et al., 2021; Andrews et al., 2002; Wang et al., 2024; Zhang et al., 2020). Patients who underwent RC with higher serum interleukin levels exhibited significantly shorter DFS/DRS/RFS/PFS (HR = 1.32; 95% CI [1.23–1.41]; P < 0.001; Fig. 6). In contrast, patients undergoing TURBT and exhibiting elevated serum interleukin levels experienced a significantly worse prognosis (HR = 6.38; 95% CI [3.70–10.99]; P < 0.001; Fig. 6).

Publication bias

Given the limited number of studies included in this meta-analysis, an assessment of publication bias was not feasible.