Perineural invasion as an independent predictor of biochemical recurrence in prostate cancer following radical prostatectomy or radiotherapy: a systematic review and meta-analysis

According to the PRISMA guidelines [9], a systematic literature search of the PubMed, EMBASE, Chinese National Knowledge Infrastructure (CNKI) and Wan Fang databases was performed (up to May 2017). The search strategy used the following: (“prostate cancer” or “prostate AND neoplasms”) and (“radical prostatectomy” or “radiotherapy”) and (“perineural invasion”) and (“biochemical recurrence”). We also manually searched for potentially relevant studies from the references listed in the selected review articles. The language of the publications was limited to English and Chinese.

The inclusion criteria for the eligible studies were as follows: (1) all patients were diagnosed with histologically confirmed PCa, and PNI in RP specimens and biopsy specimens were assessed by pathologists; (2) all patients underwent RP or RT; (3) BCR after RP was defined as a detectable or rising PSA value after surgery that was ≥0.2 ng/ml with a second confirmation (American Urological Association [10]) ; BCR after RT was defined as a rise in PSA level of ≥2 ng/ml above the nadir (American Society for Radiation Oncology and Radiation Therapy Oncology Group in Phoenix [11]); (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 original articles; (5) the study was of a prospective or retrospective cohort design; (6) the articles were published in English or Chinese. The exclusion criteria were as follows: (1) letters, reviews, case reports, editorials and author responses; (2) non-human studies; (3) studies that did not analyze the outcome after PNI and BCR; (4) duplicate articles; (5) articles contained elements that were inconsistent with the inclusion criteria.

The data of the eligible studies were extracted independently by two investigators (Zhen-lei Zha and Wei Qu). Any discrepancies were resolved by discussion with a third reviewer (Hu Zhao). The following data were extracted from the included studies: first author, year of publication, country, recruitment period, sample size, patient’s age, preoperative PSA level, Gleason score, pathological stage, positive percentage of PNI, definition of BCR, follow-up time and the HR(95%CI) of PNI for BCR. When the study provided the results of both the multivariate and univariate outcomes, we chose the multivariate model. The quality of the eligible studies was evaluated according to the Newcastle-Ottawa scale (NOS) [12], which include 3 domains with 8 items. Studies with scores of 7 or more stars were considered high- quality studies.

All statistical analyses in this meta-analysis were performed by Stata 12.0 software (Stat Corp, College Station, TX, USA).The association between PNI and BCR outcome was presented as summary relative risk estimates (SRREs) and 95% CIs. Heterogeneity between studies was assessed using Q and I² statistics. P < 0.10 or I² > 50% was considered significant heterogeneity. A random effects model was used when obvious heterogeneity was observed, but 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 analyses were performed to examine potential sources of heterogeneity according to the adjusted parameters. Publication bias was assessed by funnel plots and was statistically determined by Begg’s tests; a p value < 0.05 was considered statistically significant.

The search and selection process for eligible studies is shown in Fig. 1. In all, 222 articles were initially identified. Among them, 73 duplicates were excluded. After the abstracts were screened, 93 articles were excluded for the following reasons: non-human studies, letters, case reports, reviews, and other obvious irrelevant studies. A further 37 articles were excluded after full-text review because the results did not reported PNI on the BCR. Finally, 19 retrospective cohort studies met our inclusion criteria and were included in the meta-analysis. Of these, 13 studies with 10,807patients were analyzed to investigate whether PNI acts as a predictive biomarker of BCR in PCa following RP. Six studies with 2,605 patients were evaluated to determine the relationship between PNI and the risk of BCR in PCa following RT.

The main characteristics of the included studies are shown in Tables 1 and 2. All articles included were published in English, except for one, which was published Chinese [13]. All studies were published between 2003 and 2017, and the median duration of follow-up varied from 18.4 to 108 months. Patients in these studies were all diagnosed with PCa and received RP (13 studies) or RT (6 studies). Of the 19studies, 9 originated in Asia, and 10 were conducted in the other regions (USA, Australia, Belgium, Canada). This meta-analysis was based on a total sample size of 13,412 patients, of which 4,197 patients were reported to have PNI. Regarding the GS, 8,306 patients presented with a GS ≥7. For quality evaluated by the NOS, all the studies were found to be of high quality.

The forest plots of the meta-analyses are shown in Fig. 2. A random effects model was applied because the heterogeneity was evident among these studies (p= 0.025, I²= 48.6%). The pooled HR indicated that the presence of PNI was associated with a higher risk of BCR in patients with PCa after RP (HR=1.23, 95% CI: 1.11, 1.36, p<0.001). According to the sensitivity analysis, the SRRE ranged from 1.18 (95% CI: 1.09, 1.29) to 1.26 (95% CI: 1.14, 1.38) (Fig. 4a). In the subgroup analyses, we found that the heterogeneity was decreased significantly in some models, such as those of geographical region (“other regions”) and, age <65 years. It should also be noted that; the results of the subgroup analyses were consistent with the primary findings (Table 3). Furthermore, no statistical evidence of publication bias was found as assessed by Begg’s tests (p = 0.124) ( Fig. 5a).

As shown in Fig. 3, the pooled HR from 6 studies indicated that PNI was an independent risk factor for BCA in PCa following RT (HR=1.22, 95% CI: 1.12, 1.34, p<0.001). Due to the lack of evidence of heterogeneity among the studies (p= 0.176, I² = 34.7%), a fixed effects model was applied. The SRRE for BCR ranged from1.20 (95% CI: 1.07, 1.34) to 1.27(95% CI: 1.15, 1.42) according to the sensitivity analysis (Fig. 4b). The results of the subgroup analysis showed that PNI in a sample size ≥ 500 cases was significantly associated with BCR (n=3, HR=1.20, 95% CI: 1.09, 1.31, p <0.001) (Table 3). Begg’s tests (p = 0.081) provided no evidence of substantial publication bias in these studies (Fig. 5b).