A ﬂowchart of the literature selection process is shown in Figure 1. The initial search of electronic databases identiﬁed 1,284 records according to the searching criteria; after duplicates were removed, 611 papers remained. Four hundred and sixteen papers were then excluded by screening titles and abstracts. Ten 195 full-text articles were further examined and 173 articles were excluded because 18 same cohort of patients and 155 lacking enough data for further research. At last, 22 articles [8, 15-35] published between 2009 and 2018 were included in this meta-analysis.
Features of included studies
Summary of major characteristics of these studies are shown in Table 1 and Table 2. All the studies were of retrospective study design. The sample size ranged from 144 to 12,515, and a total of 44,144 patients were included. A total of 10.457 PCa patients with PSMs were included in our study, which accounts for 23.7% of all patients. Geographically, 8 studies were conducted in North America, 6 in Asian, 5 in Europe, 2 in Australia and 1 in Multi-center. All patients had received RP as primary treatment for PCa. According to NOS quality assessment, all studies in this study were categorized as of high quality. (Supplementary Table S1)
The pooled results from the included studies indicated that PSMs were associated with pathological GS (< 6/ ≥7) (RE model, pooled OR= 2.34; 95% CI:2.02–2.71; P<0.001,Figure 2), pathological stage (<T2/ ≥T2) (RE model, pooled OR=4.68; 95% CI:3.90–5.61; P<0.001,Figure 3), biopsy GS (< 6/ ≥7) (RE model, pooled OR=1.51; 95% CI:1.26–1.86; P<0.001,Figure 4), p-PSA (FE model, pooled SMD=0.44; 95% CI:0.35–0.54; P<0.001,Figure 5a), positive lymph node (PLN) (RE model, pooled OR=3.12; 95% CI:1.94–5.01; P<0.001,Figure 5b), extraprostatic extension (EPE) (RE model, pooled OR=4.86; 95% CI:3.11–7.51; P<0.001,Figure 5c) and seminal vesicle invasion(SVI) (RE model, pooled OR=3.56; 95% CI:2,26–5.62; P<0.001,Figure 5d).
The results of meta-analysis for PSMs showed that no significant associations were found in age (RE model, pooled SMD=-0.01; 95%CI:-0.07–0.04; P=0.754,Figure 6a), nerve sparing (RE model, pooled OR=0.94; 95% CI: 0.68–1.29; P=0.705,Figure 6b), body mass index(BMI) (FE model, pooled SMD=0.06; 95%CI: -0.03–0.15; P=0.173,Figure 6c) and prostate volume (RE model, pooled SMD=-0.28; 95% CI: -0.62–0.05; P=0.444,Figure 6d).
Considering that no significant heterogeneity in p-PSA and BMI, besides, the number of studies that evaluated EPE, SVI and prostate volume was relatively small, we only conducted subgroup analysis for biopsy GS, pathological GS, pathological stage, PLN, age and nerve sparing (Table 3). The subgroup analyses were conducted according to geographical region (Asian vs. non-Asian), year of publication (≥ 2014 vs. < 2014), No. of patients (≥ 1000 vs. < 1000) and median follow-up (≥ 70 months vs. < 70 months). The results of subgroup analysis are roughly same as the overall results. Besides, the heterogeneity decreased significantly in some subgroup analysis, such as geographical region in Asian, year of publication< 2014 and No. of patients < 1000 cases.
Sensitivity analysisTo validate the reliability of our results, sensitivity analysis was performed. As is shown in Supplementary Figure S1, the combined ORs for biopsy GS ranged from 1.44 (95% CI: 1.20 -1.75) to 1.59 (95% CI: 1.34-1.89) (Supplementary Figure S1a), for pathological GS ranged from 2.21 (95% CI: 1.94-2.51) to 2.41 (95% CI: 2.08-2.79) (Supplementary Figure S1b), for pathological stage ranged from 4.47 (95% CI: 3.74 – 5.35) to 2.85 (95% CI: 4.04-5.83) (Supplementary Figure S1c), for PLN ranged from 2.71 (95% CI: 1.59 -4.65) to 3.83 (95% CI: 2.54-5.77) (Supplementary Figure S1d) and for nerve sparing ranged from 0.84 (95% CI: 0.62-1.14) to 1.05 (95% CI: 0.79 -1.39) (Supplementary Figure S1e). The pooled SMD for p-PSA ranged from 0.42 (95% CI: 0.33 - 0.52) to 0.47 (95% CI: 0.37-0.58) (Supplementary Figure S2a), for age ranged from -0.04 (95% CI: -0.12 - 0.05) to 0.00 (95% CI: -0.09-0.11) (Supplementary Figure S2b). These data suggesting the results were statistically robust. Because the number of the included studies for BMI, EPE, SVI and prostate volume were small, the sensitivity analysis were not valuable.Publication bias
The shape of funnel plots did not reveal any evidence of asymmetry (Figure 7). The statistical results of Begg’s test still did not show publication bias for biopsy GS (p- Begg = 0.593, Figure 7a), pathological GS (p- Begg = 0.772, Figure 7b), pathological stage (p- Begg = 0.435, Figure 7c), p-PSA (p- Begg = 0.519, Figure 7d), PLN (p- Begg = 0.658, Figure 7e), EPE (p- Begg = 0.694, Figure 7f), SVI (p- Begg = 0.688, Figure 7g), age (p- Begg = 0.990, Figure 7h) and nerve sparing (p- Begg = 0.456, Figure 7i). For the number of studies in prostate volume and BMI were limited, the publication bias were not assessed.