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World Journal of Surgical Oncology logoLink to World Journal of Surgical Oncology
. 2018 Jul 3;16:124. doi: 10.1186/s12957-018-1433-3

Positive surgical margin is associated with biochemical recurrence risk following radical prostatectomy: a meta-analysis from high-quality retrospective cohort studies

Lijin Zhang 1,✉, Bin Wu 1, Zhenlei Zha 1,#, Hu Zhao 1,#, Yuefang Jiang 1,#, Jun Yuan 1
PMCID: PMC6029044  PMID: 29970100

Abstract

Background and purpose

Although numerous studies have shown that positive surgical margin (PSM) is linked to biochemical recurrence (BCR) in prostate cancer (PCa), the research results have been inconsistent. This study aimed to explore the association between PSM and BCR in patients with PCa following radical prostatectomy (RP).

Materials and methods

In accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), PubMed, EMBASE and Wan Fang databases were searched for eligible studies from inception to November 2017. The Newcastle–Ottawa Scale was used to assess the risk of bias of the included studies. Meta-analysis was performed by using Stata 12.0. Combined hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models.

Results

Ultimately, 41 retrospective cohort studies of high quality that met the eligibility criteria, comprising 37,928 patients (94–3294 per study), were included in this meta-analysis. The results showed that PSM was associated with higher BCR risk in both univariate analysis (pooled HR = 1.56; 95% CI 1.46, 1.66; p < 0.001) and multivariate analysis (pooled HR = 1.35; 95% CI 1.27, 1.43; p < 0.001). Moreover, no potential publication bias was observed among the included studies in univariate analysis (p-Begg = 0.971) and multivariate analysis (p-Begg = 0.401).

Conclusions

Our meta-analysis demonstrated that PSM is associated with a higher risk of BCR in PCa following RP and could serve as an independent prognostic factor in patients with PCa.

Electronic supplementary material

The online version of this article (10.1186/s12957-018-1433-3) contains supplementary material, which is available to authorized users.

Keywords: Positive surgical margin, Prostate cancer, Radical prostatectomy, Biochemical recurrence, Meta-analysis

Background

Prostate cancer (PCa) is the most diagnosed malignancy and the second leading cause of cancer-related deaths among men in Western countries [1]. Radical prostatectomy (RP) has been shown to have a cancer-specific survival benefit for men with clinically localised PCa [2]. Although many patients are disease-free after surgery, nearly 30% [3] of patients still continue to experience biochemical recurrence (BCR). Defined as a detectable prostate-specific antigen (PSA) level following RP in the absence of clinical progression, BCR is the most common pattern of disease relapse [4]. Patients with BCR have a considerably worse prognosis, often develop metastasis, and can die of the disease [3, 4]. Therefore, identifying prognostic predictors of BCR after RP to assist clinicians in predicting outcomes for decision making is required.

Numerous nomograms including pathological tumour stage [5], Gleason’s score [6], seminal vesicle invasion [7], and lymphatic invasion [8] have been developed to predict subsequent risk of BCR after RP. Unfortunately, because the collective prognostic value of these factors is unsatisfactory, better biomarkers are urgently needed. Positive surgical margin (PSM) is defined as the histological presence of cancer cells at the inked margin on the RP specimen [9]. Although PSM is frequently reported in radical prostatectomy series, their clinical relevance remains uncertain despite extensive investigation. A number of studies have demonstrated an association between PSM and BCR [5, 10, 11], while others have observed insignificant or even contrary correlations [12–14].

Previously, Yossepowitch [15] systematically reviewed related studies on PSM reporting survival of surgical treatment for patients with PCa. These studies suggested that PSM in PCa should be considered an adverse oncological outcome. Nevertheless, a meta-analysis was not performed because of low-quality evidence and potential risks of bias. A meta-analysis utilises statistical methods to contrast and combine results from multiple studies, increasing the statistical power and reproducibility compared with individual studies [16]. Hence, to obtain the most conclusive results, we conducted a meta-analysis with high-quality retrospective cohort studies to assess the prognostic value of PSM in BCR.

Methods

Literature search

This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search of the literature in PubMed, EMBASE, and Wan Fang databases up to November 2017 was performed using a combined text and MeSH heading search strategy with the following terms: (“prostate cancer” or “prostate AND neoplasms”) and (“radical prostatectomy”) and (“positive surgical margin”) and (“biochemical recurrence” OR “biochemical failure”). In addition, reference lists in the recent reviews, meta-analysis, and included articles were manually searched to identify related articles. The language of the publications was limited to English and Chinese.

Inclusion and exclusion criteria

We defined the inclusion and exclusion criteria for study selection at the initiation of the search. The following inclusion criteria were used: (1) included definitive diagnosis of PCa and PSM assessed by pathologists; (2) all patients underwent RP treatment; (3) BCR after RP was defined; (4) the risk of BCR was estimated as hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) or the risk could be calculated from the reported data; and (5) published in English or Chinese. The following exclusion criteria were used: (1) letters, reviews, case reports, editorials, and author responses; (2) non-human studies; (3) studies that did not analyse the outcome after PSM and BCR; (4) studies with duplicated patient populations that had been reported in previous publications; or (5) articles contained elements that were inconsistent with the inclusion criteria.

Data extraction and quality assessment

Two investigators (Zhenlei Zha and Hu Zhao) independently extracted the data from all eligible publications. Any differences among evaluators were resolved by discussion with a third investigator (BinWu). The following data were extracted from the included studies using a standardised data collection protocol (Table 1, Table 2): first author’s name, year of publication, country, recruitment period, sample size, patient’s age, preoperative PSA level, Gleason score, pathological stage, positive percentage of PSM and BCR, definition of BCR, follow-up time, and the HRs (95% CIs) of PSM in univariate or multivariate Cox analyses for BCR. The quality of the eligible studies was evaluated according to the Newcastle–Ottawa Scale (NOS), which include three domains (selection of the study population, comparability of the groups, ascertainment of the outcome). We identified articles of “high quality” as those with NOS scores of 6–9, whereas scores of 0–5 were considered to indicate poor quality.

Table 1.

Primary characteristics of the included studies

Author Year Country No. of patients Recruitment period Age
(years)		 p-PSA
(ng/ml)		 Follow-up (months) Surgical approach
Wettstein et al. [35] 2017 Switzerland 371 2008–2015 Median (range)
63 (41–78)		 Median (range)
6.79 (0.43–81.4)		 Median (range)
28 (1–64)		 NA
Xun et al. [6] 2017 China 172 2003–2014 Median (IQR)
68 (62–72)		 Median (IQR)
16.1 (10.9–28.3)		 Median (IQR)
46.4 (33.4–62.4)		 NA
Meyer et al. [36] 2017 Germany 903 1992–2005 Median (IQR)
63 (59–66)		 Median (IQR)
6.4 (4.6–9.0)		 Median (IQR)
133 (97–157)		 NA
Gandaglia et al. [37] 2017 Multi-centred 94 2011–2015 Median (IQR)
64.3 (57.1–68.9)		 Median (IQR)
9.7 (5.1–17.5)		 Median (IQR)
23.5 (18.7–27.3)		 Robot-assisted RP
Shangguan et al. [33] 2016 China 172 2003–2014 Median (range)
68 (62–72)		 Median (range)
16.1 (10.9–28.3)		 Median (IQR)
46.4 (33.4–62.4)		 Open and laparoscopic RP
Zhang et al. [34] 2016 China 168 2006–2011 Median (range)
69 (53–85)		 Median (range)
13.31 (4.59–36.12)		 Median (range)
68 (7–98)		 Laparoscopic RP
Simon et al. [12] 2016 Multi-centres 411 2001–2013 Mean ± SD
61 ± 6.1		 NA Median
63		 NA
Sevcenco et al. [38] 2016 Multi-centres 7205 2000–2011 Median (IQR)
61 (57–66)		 Median (IQR)
6 (4–9)		 Median (IQR)
27 (19–48)		 NA
Pagano et al. [20] 2016 USA 180 1990–2011 Median (range)
63.7 (58.8–67.6)		 Median (range)
9.1 (6.3–17.1)		 Median (range)
26.7 (8.8–66)		 NA
Moschini et al. [39] 2016 USA 1011 1987–2012 NA Median
12.0		 Median
211.2		 NA
Mortezavi et al. [40] 2016 Switzerland 100 1999–2007 Mean ± SD
63.5 ± 6.5		 Mean ± SD
9.6 ± 8.3		 Median (range)
126 (60–176)		 Laparoscopic RP
Mao et al. [41] 2016 China 106 2008–2009 Mean (range)
68.1 (48–83)		 Mean (range)
25.1 (3.1–104.3)		 Median (range)
69 (8–84)		 Laparoscopic RP
Whalen et al. [29] 2015 USA 609 2005–2011 Mean ± SD
61.2 ± 7.3		 Mean ± SD
6.8 ± 6.3		 Median (range)
20.5 (1–80)		 NA
Song et al. [42] 2015 Korea 2137 1988–2011 Median (IQR)
67 (63–71)		 Median (IQR)
6.9 (4.7–11.2)		 Mean (range)
39.4 (8–1834)		 NA
Reeves et al. [43] 2015 Australia 1479 2005–2012 Median
62		 NA Median
14		 NA
Hashimoto et al. [5] 2015 Japan 837 2006–2013 Median (range)
65 (39–78)		 Median (range)
6.9 (3–47.4)		 Median (range)
20.5 (1.3–91.3)		 Robot-assisted RP
Alvin et al. [44] 2015 Singapore 725 2003–2013 Median (range)
62 (37–79)		 Median (range)
7.9 (0.79–72.9)		 Mean (range)
28.5 (6–116)		 Robot-assisted RP
Touijer et al. [13] 2014 USA 369 1988–2010 Median (IQR)
62 (57–66)		 Median (IQR)
8 (5–15)		 Median
48		 NA
Ritch et al. [45] 2014 USA 979 2003–2009 Median
62		 NA Median
47		 Open and robot-assisted RP
Kang et al. [21] 2014 Korea 3034 2004–2011 Mean ± SD
65.9 ± 6.6		 Mean ± SD
11.6 ± 12.2		 Median
47		 NA
Fairey et al. [14] 2014 USA 229 1987–2008 Median (range)
65 (41–83)		 NA Median (range)
174 (2.4–253.2)		 NA
Turker et al. [46] 2013 Turkey 331 1993–2009 Mean ± SD
62.79 ± 6.4		 Mean ± SD
11.1 ± 10.5		 Mean ± SD
29.7 ± 33.2		 NA
Sammon et al. [10] 2013 USA 794 1993–2010 Mean ± SD
63.4 ± 8.1		 Mean ± SD
5.6 ± 3.6		 Median (IQR)
26.4(12.2–54.6)		 NA
Chen et al. [30] 2013 China 152 2004–2011 NA NA Median (range)
48 (12–87)		 Laparoscopic RP
Sooriakumaran et al. [11] 2012 Sweden 944 2002–2006 Median (IQR)
62.2 (58.2–65.8)		 Median (IQR)
6.4(4.8–9.0)		 Median (IQR)
75.6(67.2–86.4)		 Robot-assisted RP
Lu et al. [31] 2012 China 894 1993–1999 Median (IQR)
62 (57–66)		 Median (IQR)
6.0 (4.5–8.6)		 Median (IQR)
9.9 (6.1–11.3)		 NA
Iremashvili et al. [47] 2012 USA 1444 2003–2010 Mean (range)
61.3 (56–66.3)		 Mean (range)
5.7 (4.5–8.0)		 Median (range)
43.2 (3–216)		 Open and robot-assisted RP
Connolly et al. [48] 2012 Australia 160 1988–1997 Mean ± SD
63.1 ± 6.3		 Median (IQR)
9.95 (6.0–21.4)		 Median (IQR)
26.2 (5.5–37.3)		 Robot-assisted RP
Busch et al. [49] 2012 Germany 1845 1999–2007 Mean ± SD
62.0 ± 5.9		 Median (range)
26.3 (17.0–42.1)		 Median (range)
56 (0–35)		 Laparoscopic RP
Berge et al. [50] 2012 Norway 577 2002–2008 Mean (range)
61.5 (42–76)		 Mean (range)
8.4 (0.3–31)		 Median (range)
36 (3–72)		 Laparoscopic RP
Lee et al. [51] 2011 Korea 1000 2003–2009 Median (range)
66 (37–82)		 Median (range)
7.8 (0.1–261.8)		 Mean
39.4		 NA
Alenda et al. [23] 2011 France 1248 1998–2008 Mean (range)
63 (44–78)		 Mean (range)
10.9 (0.9–134)		 Median
23.4		 NA
Fukuhara et al. [52] 2010 Japan 364 2000–2009 Median (range)
66 (52–78)		 Median (range)
8.1 (1.7–77.7)		 Median (range)
33 (10–109)		 NA
Cho et al. [53] 2010 Korea 171 2005–2009 Mean (range)
64.4 (49–80)		 NA Mean (range)
23.3 (2–51)		 NA
Alkhateeb et al. [26] 2010 Canada 1268 1992–2008 Mean ± SD
62.0 ± 6.6		 Median (range)
6.2 (0.1–65.9)		 Mean (range)
78.1 (3–192)		 NA
Jeon et al. [54] 2009 Korea 237 1995–2004 Mean (range)
64.5 (44–86)		 Mean (range)
11.5 (0.2–98)		 Median (range)
21.6 (2–88)		 NA
Schroeck et al. [55] 2008 USA 3194 1988–2007 Median (IQR)
62.6(57.2–67.9)		 Median (IQR)
6.3(4.5–9.6)		 Median
31.2		 NA
Pavlovich et al. [56] 2008 USA 508 2001–2005 Mean ± SD
57.6 ± 6.7		 Mean (range)
6.0 (0.3–27)		 Median (range)
12 (2–52)		 Laparoscopic RP
Hong et al. [57] 2008 Korea 372 2003–2007 Mean (range)
64.2 (37–72)		 Mean (range)
8.7 (0.2–104.2)		 NA NA
Cheng et al. [8] 2005 Indiana 504 1990–1998 Mean (range)
62 (34–80)		 NA Mean (range)
44 (1.5–144)		 NA
Shariat et al. [58] 2004 USA 630 1994–2002 Median (range)
60.9 (40–75)		 Mean (range)
6.1 (0.1–99)		 Median (range)
21.4 (1–101.3)		 NA
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p-PSA preoperative prostate-specific antigen, SD standard deviation, IQR interquartile range, NA data not applicable

Table 2.

Tumour characteristics of the included studies

Author Specimen
GS ≦ 7/˃ 7		 Staging system T stage
1–2/3–4		 SM+/ SM− No. of BCR (%) Definition of BCR
Wettstein et al. [35] 292 /79 WHO/ISUP 2016 263/108 133/238 49 (13.2%) Rising and verified PSA levels > 0.1 ng/ml
Xun et al. [6] 131/41 TNM 2002 NA 62/110 80 (46.5%) The date of the first PSA elevated to 0.2 ng/ml
Meyer et al. [36] 879/24 TNM 2002 903/0 37/206 137(15.2%) PSA level of ≧ 0.2 ng/ml and rising after RP
Gandaglia et al. [37] 55/39 TNM 2002 22/72 30/64 24 (25.5%) Two consecutive increases in PSA ≧ 0.2 ng/ml
Shangguan et al. [33] 131/41 NA NA 62/110 NA Two consecutive increases in PSA ≧ 0.2 ng/ml
Zhang et al. [34] 136/32 TNM 2012 NA 30/138 NA First PSA elevated to 0.2 ng/ml
Simon et al. [12] 368/43 NA NA 353/58 70 (17%) Single PSA concentration of > 0.2, two concentrations at 0.2 ng/ml
Sevcenco et al. [38] 6645/560 TNM 2009 NA 6137/1074 798 (11.1%) Two consecutive increases in PSA ≧ 0.2 ng/ml
Pagano et al. [20] 90/90 TNM 2002 NA 74/106 120 (66.5%) Two postoperative PSA values of ≧ 0.2 ng/ml
Moschini et al. [39] 647/364 NA 355/657 566/445 697 (69%) PSA 0.4 ng/ml or greater
Mortezavi et al. [40] 86/14 NA 79/21 25/75 12 (12%) Two consecutive increases in PSA ≧ 0.2 ng/ml
Mao et al. [41] 78/28 TNM 2002 63/43 20/86 31 (29.2%) Two consecutive increases in PSA ≧ 0.2 ng/ml
Whalen et al. [29] 516/93 TNM 1997 435/174 483/126 73 (12%) Two consecutive increases in PSA ≧ 0.2 ng/ml
Song et al. [42] 1722/415 NA 1899/248 2132/13,433 466 (21.8%) Greater than 0.2 ng/ml
Reeves et al. [43] 1306/142 NA 1042/454 390/1089 238 (20.5%) Greater than 0.2 ng/ml
Hashimoto et al. [5] 634/373 WHO 2004 677/160 243/594 102 (12.2%) Two consecutive increases in PSA ≧ 0.2 ng/ml
Alvin et al. [44] 663/58 TNM 2010 497/228 311/414 104 (14%) Two consecutive increases in PSA ≧ 0.2 ng/ml
Touijer et al. [13] 184/185 TNM 2010 46/323 138/231 201 (54%) PSA ≧ 0.1 ng/ml with confirmatory rise
Ritch et al. [45] 783/196 TNM 2002 955/24 335/644 317 (32.4%) Greater than 0.2 ng/ml
Kang et al. [21] 2575/459 TNM 2009 NA 974/2060 NA A serum PSA value of 0.4 ng/ml or greater after RP
Fairey et al. [14] 133/96 TNM 2002 0/229 105/124 83 (36.2%) Detectable PSA (ng/ml) followed by two consecutive confirmatory (1988–1994: PSA ≧ 0.3; 1995–2005: PSA ≧ 0.05; 2006–present: PSA ≧ 0.03)
Turker et al. [46] 167/164 TNM 1994 NA 80/251 70 (21%) Higher than 0.2 ng/ml on 2 separate measurements 1 month apart
Sammon et al. [10] 760/34 AJCC 2002 592/202 162/632 107 (13.5%) Two consecutive increases in PSA ≧ 0.2 ng/ml
Chen et al. [30] 109/43 NA 0/152 27/125 80 (52.6%) Two consecutive increases in PSA ≧ 0.2 ng/ml
Sooriakumaran et al. [11] 900/44 NA 651/230 194/704 135 (15.2%) Greater than 0.2 ng/ml
Lu et al. [31] 796/98 TNM 2010 703/191 250/644 277 (31%) PSA ≧ 0.1 ng/ml with confirmatory rise
Iremashvili et al. [47] 1286/258 NA NA 479/965 210 (15%) Greater than 0.2 ng/ml
Connolly et al. [48] 95/65 NA 65/95 60/100 88 (55%) Greater than 0.2 ng/ml
Busch et al. [49] 1538/307 NA 1802/9 537/1308 450 (24.4%) PSA ≧ 0.1 ng/ml with confirmatory rise
Berge et al. [50] 553/24 TNM 2002 441/136 168/409 91 (16%) Two consecutive increases in PSA ≧ 0.2 ng/ml
Lee et al. [51] 236/764 NA NA 337/663 99 (9.9%) Two consecutive increases in PSA ≧ 0.2 ng/ml
Alenda et al. [23] 1248/0 NA NA 400/843 176 (16.9%) PSA > 0.2 ng/mL
Fukuhara et al. [52] 332/32 TNM 2002 275/89 157/207 66 (18.1%) Two consecutive increases in PSA ≧ 0.2 ng/ml
Cho et al. [53] 153/14 TNM 2002 126/45 58/109 15 (8.8%) A serum PSA value of 0.4 ng/ml or greater after RP
Alkhateeb et al. [26] 1159/109 NA 853/415 264/1004 NA A serum PSA value of 0.4 ng/ml or greater after RP
Jeon et al. [54] 190/45 TNM 2002 145/92 86/151 67 (28.3%) Two consecutive increases in PSA ≧ 0.2 ng/ml
Schroeck et al. [55] 2855/359 NA 1991/1166 982/2212 706 (25.7%) Greater than 0.2 ng/ml
Pavlovich et al. [56] 494/14 TNM 2002 416/92 69/439 102 (20%) Two consecutive increases in PSA ≧ 0.2 ng/ml
Hong et al. [57] 361/11 TNM 2002 371/0 46/326 NA First value greater than 0.2 ng/ml
Cheng et al. [8] 410/94 TNM 1997 348/156 174/330 157 (21.2%) Two consecutive increases in PSA ≧ 0.1 ng/ml
Shariat et al. [58] 565/65 TNM 1997 NA 179/451 80 (12.7%) First value greater than 0.2 ng/ml
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GS Gleason score, SM+/SM surgical margin positive/surgical margin negative, BCR biochemical recurrence, NA data not applicable

Statistical analyses

All statistical analyses in this meta-analysis were performed by Stata 12.0 software (Stat Corp, College Station, TX, USA). The association between PSM and BCR outcome was presented as summary relative risk estimates (SRREs) and 95% CIs. Heterogeneity between studies was calculated by the chi-square-based Q test and I2. A value of p < 0.10 or I2 > 50% was considered as statistically significant heterogeneity. A random-effects model was used if heterogeneity was significant, and otherwise, a fixed-effects model was used. Sensitivity analysis was used to estimate the reliability of the pooled results via the sequential omission of each study. Subgroup analysis was performed to check whether the pooled HR was influenced by the region, publication year, mean age, sample size, mean preoperative PSA (p-PSA), median follow-up, and the cut-off value for BCR. To assess the stability of the combined HR, sensitivity analysis was performed by removing individual studies from the meta-analysis. Publication bias was assessed by funnel plots and was statistically determined by Egger’s linear regression. Statistical significance was defined as a two-tailed value of p < 0.05, except for the heterogeneity tests.

Results

Literature search and study characteristics

The full process of the systematic literature review is shown in Fig. 1. In accordance with the PRISMA search strategy, 1048 relevant studies were initially identified. After carefully reading each article, 780 studies were excluded for the following reasons: duplicates, letters, or reviews; or contained no evaluated margin status and focus on BCR. After the remaining studies (n = 268) were reviewed, additional studies were excluded because certain cohorts were studied more than once or relevant data were lacking. Forty-one high-quality retrospective studies comprising 37,928 patients (94–3294 per study) were ultimately included in the meta-analysis.

Fig. 1.

Fig. 1

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Flow diagram of the study selection process for this meta-analysis

The primary characteristics of the included studies are summarised in Table 1. All studies were published between 2004 and 2017. Of these, 19 studies were conducted in an Asian country, and 12 were conducted in North America; the rest were conducted in Europe (7) or in multiple countries (3). The median follow-up period of the studies ranged from 14 to 174 months. All included studies were published in English, except for two that were in Chinese. Of all of the studies, 8 used laparoscopic RP, 7 used robot-assisted RP, and 3 used open RP. BCR was defined using different cut-off values (0.1 ng/ml, 0.2 ng/ml, 0.4 ng/ml) among the included studies, and the incidence of BCR after RP ranged from 8.8 to 66.5% according to the reported values (Table 2). NOS [17] was applied to assess the quality of the included studies, and the results showed that all of the studies were of high quality with an NOS score ≥ 7. (Additional file 1: Table S1).

Meta-analysis

The forest plots of the meta-analysis in our study demonstrated that PSM was associated with poorer BCR in RP patients by univariate analysis (random-effects model, pooled HR = 1.56; 95% CI 1.46, 1.66; p < 0.001; Fig. 2) and multivariate analysis (random-effects model, pooled HR = 1.35; 95% CI 1.27, 1.43; p < 0.001; Fig. 3). Given the large heterogeneity between the studies, subgroup analyses were performed by region, publication year, mean age, sample size, mean preoperative PSA (p-PSA), median follow-up, and the cut-off value for BCR. Although no significant modifiers accounting for the inter-study heterogeneity were detected, the results of subgroup analyses were consistent with the primary findings (Table 3).

Fig. 2.

Fig. 2

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Forest plots of the association between PSM and BCR risk in the stratification analysis by univariate mode

Fig. 3.

Fig. 3

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Forest plots of the association between PSM and BCR risk in the stratification analysis by multivariate mode

Table 3.

Overall analyses and subgroup analyses for the included studies

Analysis specification No. of studies Study heterogeneity Effects model Pooled HR (95% CI) p value
I2 (%) p heterogeneity
Univariate analysis (BCR)
 Overall 25 70.9 < 0.001 Random 1.56 (1.46,1.66) < 0.001
 Geographical region
  Asia 12 72.1 < 0.001 Random 1.61 (1.43,182) < 0.001
  Europe and North America 12 70.8 < 0.001 Random 1.50 (1.37,1.65) < 0.001
 Date of publication
  ≥ 2014 13 81.8 < 0.001 Random 1.52 (1.36,1.70) < 0.001
  < 2014 12 18.5 0.262 Fixed 1.61 (1.52,1.71) < 0.001
 Mean age (years)
  ≥ 64 9 84 < 0.001 Random 1.62 (1.34,1.97) < 0.001
  < 64 15 55.6 0.005 Random 1.54 (1.45,1.64) < 0.001
 Sample size (cases)
  ≥ 500 10 40.1 0.09 Random 1.61 (1.52,1.70) < 0.001
  < 500 15 76.9 < 0.001 Random 1.51 (1.33,1.71) < 0.001
 Mean p-PSA (ng/ml)
  ≥ 10 7 81 < 0.001 Random 1.65 (1.38,1.97) < 0.001
  < 10 14 58.5 0.003 Random 1.59 (1.48,1.71) < 0.001
 Median follow-up
  ≥ 36 months 11 77.1 < 0.001 Random 1.49 (1.33,1.67) < 0.001
  < 36 months 14 59.8 0.002 Random 1.61 (1.49,1.74) < 0.001
 BCR (ng/ml)
  Cutoff value 0.1 4 0 0.775 Fixed 1.61 (1.49,1.72) < 0.001
  Cutoff value 0.2 20 72 < 0.001 Random 1.58 (1.46,1.70) < 0.001
  Cutoff value 0.4 1 – – – – –
Multivariate analysis (BCR)
 Overall 32 79.2 < 0.001 Random 1.35 (1.27,1.43) < 0.001
 Geographical region
  Asia 14 67 < 0.001 Random 1.42 (1.29,1.55) < 0.001
  Europe and North America 15 84.7 < 0.001 Random 1.31 (1.19,1.43) < 0.001
  Multi-centred 3 71.9 0.029 Random 1.33 (1.00,1.78) 0.053
 Date of publication
  ≥ 2014 16 82.9 < 0.001 Random 1.27 (1.17,1.39) < 0.001
  < 2014 16 67.2 < 0.001 Random 1.44 (1.32,1.56) < 0.001
 Mean age (years)
  ≥ 64 8 62.5 0.009 Random 1.56 (1.32,1.85) < 0.001
  < 64 22 81.5 < 0.001 Random 1.33 (1.24,1.43) < 0.001
 Sample size (cases)
  ≥ 500 18 77.1 < 0.001 Random 1.40 (1.32,1.49) < 0.001
  < 500 14 76.8 < 0.001 Random 1.28 (1.12,1.47) < 0.001
 Mean p-PSA (ng/ml)
  ≥ 10 7 80.8 < 0.001 Random 1.36 (1.22,1.57) < 0.001
  < 10 19 79 < 0.001 Random 1.35 (1.24,1.48) < 0.001
 Median follow-up
  ≥ 36 months 16 79.6 < 0.001 Random 1.36 (1.24,1.46) < 0.001
  < 36 months 15 79.8 < 0.001 Random 1.34 (1.21,1.47) < 0.001
 BCR (ng/ml)
  Cutoff value 0.1 5 87.7 < 0.001 Random 1.22 (1.01,1.48) 0.044
  Cutoff value 0.2 23 71.3 < 0.001 Random 1.39 (1.30,1.48) < 0.001
  Cutoff value 0.4 4 82.2 0.001 Random 1.34 (1.15,1.57) < 0.001
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The sensitivity analysis and publication bias

With a sensitivity analysis, the overall significance did not change when any single study was omitted. The summary relative risk estimate (SRRE) for BCR ranged from 1.52 (95% CI, 1.44–1.62) to 1.58 (95% CI, 148–1.68) (Fig. 4a) in univariate analysis and 1.34 (95% CI, 1.26–1.42) to 1.37 (95% CI, 1.29–1.45) (Fig. 4b) in multivariate analysis. These results indicated that the findings were reliable and robust. To test for publication bias, Egger’s linear regression was performed. No significant publication bias was detected between these studies regarding HR of BCR in univariate analysis (p-Begg = 0.971; Fig. 5a) and multivariate analysis (p-Begg = 0.401; Fig. 5b), respectively.

Fig. 4.

Fig. 4

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Sensitivity analysis of the association between PSM and BCR risk in PCa patients. a Univariate analysis mode. b Multivariate analysis mode

Fig. 5.

Fig. 5

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Funnel plots and Begg’s tests for the evaluation of potential publication bias. a Univariate analysis mode. b Multivariate analysis mode

Discussion

With the increased public awareness and wide use of PSA-based screening, the number of patients diagnosed with PCa annually has been increasing [6]. Because RP provides superior cancer control and functional outcomes, this surgery has become a standard first-line treatment for eligible patients [18]. However, despite various advances in surgical technology, BCR has been reported in approximately 25–35% patients after RP and even more patients with intermediate–high risk [19]. Because BCR reportedly leads to distant metastasis and cancer death [20], it is necessary for men with BCR to undergo salvage radiation or hormonal therapy [11]. Therefore, identifying modifiable factors that affect the progression of BCR may help physicians in the selection of patients who are more likely to benefit from adjuvant multimodal therapy.

A number of nomograms have been developed to predict BCR after RP using either preoperative or postoperative variables [21]. Several clinical and pathologic factors have been included in these models, most of which cannot be altered by the treating physician (preoperative PSA [22], pathological T stage [5], pathological Gleason score [23]). The D’Amico risk stratification scheme [20] and Cancer of the Prostate Risk Assessment (CAPRA) score [24] have also been adopted in the urological community to predict the probability of BCR. Although these nomograms have been internationally validated, unfortunately, only a small number of them have predicted the probability of 5-year BCR with more than 70% accuracy [25]. Thus, efforts to improve existing outcome prediction tools for PCa are always encouraged.

PSM is a frequent situation encountered after radical prostatectomy (RP) for localised PCa with an occurrence ranging from 6 to 41% [9, 26, 27]. The incidence of PSM depends on various factors, including tumour biology, patient characteristics, pathological assessment method, and surgical technique [28]. We reported an overall PSM rate of 45.7% (17,339/37,928), which was slightly higher than other large series. Because the goal of surgical procedures is the complete removal of the tumour, the presence of PSM after RP is considered to be an adverse outcome associated with failure of the surgery to cure the PCa. However, the effects of PSM on clinical outcomes and the risk of BCR are still unclear. Several studies concluded that a PSM is an independent factor of BCR in patients with PCa after RP [11, 29–31]. However, not all patients with PSM show recurrence according to other studies [27, 28, 32]. Moreover, several reports showed that the effect of PSMs on prognosis depends on certain clinical and pathological features of the disease [26].

To the best of our knowledge, this study is the most up-to-date and informative meta-analysis on the association between PSM and BCR risk. The results obtained in our meta-analysis are in line with the previous systematic review by Yossepowitch et al. In addition, our study presented a series of advancements in comparison with previous studies. First, we included more eligible studies with high quality. The search by Yossepowitch et al. included studies up to 2013. However, our search included 21 additional studies published from 2014 to 2017, thereby improving the evaluation on the effect and enabling more subgroup analyses. In addition, the studies retrieved for our analysis were not limited to English; two Chinese articles [33, 34] also met the criteria for inclusion. Similar to Yossepowitch et al., we identified a significant relationship between PSM and BCR in RP. However, we also found that the pooled result of PSM had a large heterogeneity in both univariate (I2 = 70.9%) and multivariate (I2 = 79.2%) analyses. Even though the cut-offs varied among the included studies (0.1 ng/ml, 0.2 ng/ml, 0.4 ng/ml), the subgroup analyses achieved results similar to both univariate and multivariate analyses (Table 3). Meanwhile, the sensitivity analysis of our study revealed that the omission of each study did not have a significant impact on the merged value of HR.

However, several limitations of this study should be considered. First and foremost, all included studies were retrospective; therefore, the data extracted from those studies may have led to potential inherent bias. Second, the criteria to determine the presence of PSM in the pathological specimen were inconsistent in the included studies, which may have potentially contributed to heterogeneity. Thus, rigorous morphological criteria should be established to standardise the diagnosis of PSM. Third, substantial heterogeneity was observed in the meta-analysis, and although we used the random-effects model according to heterogeneity, it still existed in our studies. Moreover, from the subgroup analyses, we believed that the heterogeneity was caused by differences in factors such as patient and tumour characteristics. Finally, studies with negative results tend to be unsubmitted or unpublished; grey literature was not included, meaning that language bias may have been present in this study.

Conclusions

In conclusion, this meta-analysis demonstrates that PSM has a detrimental effect on BCR risk in patients with PCa after RP and could therefore be considered to be an independent prognostic factor of BCR. Due to PSM’s excellent feasibility and low cost, this method should be more widely employed for BCR risk stratification and BCR prediction in patients with PCa. Given the inherent limitations of retrospective studies, further research is warranted, preferably with a longer follow-up period, to elucidate the potential role of PSM in influencing BCR risk.

Additional file

Additional file 1: (21KB, docx)

Table S1. Quality assessment of cohort studies included in this meta-analysis. (DOCX 20 kb)

Availability of data and materials

All data generated or analysed during this study are included in this published article (and its supplementary information files).

Authors’ contributions

LZ and BW contributed to the conceptualization. ZZ, HZ, and BW contributed to the literature search. YJ and YJ contributed to the data analysis. ZZ, HZ, and YJ contributed to the writing of the original draft. LZ contributed to the writing and review and editing. All authors read and approved the final manuscript

Ethics approval and consent to participate

Not applicable.

Consent for publication

I give my consent for information about my relative circle to be published in the World Journal of Surgical Oncology (WJSO-D-18-00097R1, Lijin Zhang). I understand that the information will be published without my relative’s (circle as appropriate) name attached, but that full anonymity cannot be guaranteed. I understand that the text and any pictures or videos published in the article will be freely available on the internet and may be seen by the general public. The pictures, videos, and text may also appear on other websites or in print, may be translated into other languages, or used for commercial purposes. I have been offered the opportunity to read the manuscript.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Footnotes

Zhenlei Zha, Hu Zhao and Yuefang Jiang contributed equally to this work.

Electronic supplementary material

The online version of this article (10.1186/s12957-018-1433-3) contains supplementary material, which is available to authorized users.

Contributor Information

Lijin Zhang, Email: stzlj913729553@163.com.

Bin Wu, Email: jyrmyywb@163.com.

Zhenlei Zha, Email: zhazhenl@sohu.com.

Hu Zhao, Email: phdzhaoh@sina.com.

Yuefang Jiang, Email: 1957jiangyf@sina.com.

Jun Yuan, Email: 6.1229231679@qq.com.

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Associated Data

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Additional file 1: (21KB, docx)

Table S1. Quality assessment of cohort studies included in this meta-analysis. (DOCX 20 kb)

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