Oncological safety of intrafascial nerve-sparing radical prostatectomy compared with conventional process: a pooled review and meta-regression analysis based on available studies

Radical prostatectomy is recommended as an effective treatment for clinically localized prostate cancer [1, 2], and used to cure patients with low/intermediate risk of disease [3]. Based on the updated anatomy understandings, the approaches to preserve peri-prostatic nerves have undergone many modifications from the conventional nerve-sparing surgery [4]. Intrafascial technique was a kind of refinements, characterized by developing a dissection plane medially/internally to the prostatic fascia, in order to maximally preserve peri-prostatic nerves and to enhance the post-surgical recovery of continence and potency. This technique is now applied worldwide in combination with different surgical approaches and procedures [5, 6].

Controversy about the intrafascial nerve-sparing technique has persisted since its introduction [7]. Most doubts were concentrated at its oncological safety, considering the necessity of removing all fascial coverings of the prostatic surface in resecting a tumor. It is generally recognized that the greater extent of structures spared, the higher is the risk of residual tumor; therefore, some surgeons would be concerned that intrafascial dissection would compromise its oncological safety and incur a risk of a higher rate of positive surgical margins (PSMs) [8].

There were obvious variations regarding the oncological results reported by different surgeons, which may be influenced by factors such as surgeon characteristics, surgical procedures, patient inclusion criteria, and outcome assessment methods. The purpose of this study was to critically summarize existing clinical trials and provide a detailed and comprehensive assessment of the oncological findings of intrafascial prostatectomy to guide urologists in selecting the appropriate technique.

This review was performed according to the Preferred Reporting Items of Systematic Reviews and Meta-analysis (PRISMA) statement. A total of 117 records were retrieved after electronic search strategy, which ultimately included 21 studies [6, 11‐30]. Figure 1 present the PRISMA flowchart of literature searches and Table 3 provided detailed characteristics of the included studies. Among the 21 studies included, 15 were controlled studies and 6 were surgical series. Eight trials paralleling conventional interfascial technique as controlled groups were included for comparative meta-analysis. Additional file 1: Table S1 showed the risk of bias in individual studies.

In this study we conducted a systematic review and pooled analysis of oncological outcomes following intrafascial nerve-sparing prostatectomy. In 2012, a detailed and in-depth systematic review summarizing all surgical series of RALP between 2008 to 2011 was reported by Novara et al. [31], wherein they indicated that the prevalence of PSM after RALP was, on average, 15% in all-stage disease and 9% in pathologically localized cancer; PSM rates were similar following RARP, RRP, and LRP. The authors proposed an average PSM rate of 15 and 10% could be expected for all-stage and pT2 cancers after RALP, respectively. In this present meta-analysis, we found that the pooled PSM rate in the intrafascial group was, overall, 14.2% in all stages of prostate cancer and 9.7% in pT2 disease regardless of surgery types, which seemed to match the results of previous review. Comparative analysis revealed no significant difference in PSM rate between the intra- and inter-fascial groups, which was consistent with a previous meta-analysis [32]. From this point of view, oncological outcomes of intrafascial technique seemed acceptable, or at least not worse than with conventional approach. However, a hasty conclusion of the oncological safety of this technique should be avoided, as there are additional issues worthy of critical appraisal.

Extracapsular extension of carcinoma could lead to higher PSM rate of radical prostatectomy compared with that associated with a localized tumor. The mean percentage of pT2 cancer in the intrafascial studies included in our present review was 84.5% (range: 58.6–98.1%), which is significantly higher than that in the 17 surgical series included in Novara’s review [31] (t-test of independent samples: mean difference = − 7.91569, t = − 2.618, p = .014); this meant, surgeons selected more patients with localized disease to perform intrafascial approach, but only comparable total PSM rates were gained. Moreover, according to the guidelines of the European Association of Urology, radical prostatectomy could be extended for indications such as patients with intermediate-risk, localized prostate cancer with clinical stage T2b–T2c, Gleason score = 7, or PSA 10–20 ng/ml [3]. However, our review found that most surgeons applied more rigorous selection criteria against generally recommended indications for radical prostatectomy. For example, the VIP team in 2005 reported a notably low PSM rate with a robot-assisted surgical system wherein only 1 case of positive margin was detected from among 46 patients who underwent intrafascial RALRP [27]. With regard to their selection criteria, only patients with clinical T1c stage cancer combined with a Gleason score ≤ 6 and preoperative PSA ≤10 were selected for the adoption of the intrafascial technique. Therefore, the currently acceptable low PSM rate following intrafascial prostatectomy could be attributed to more stringent patient selection and, subsequently, a higher proportion of localized disease; however, the oncological safety of this technique could not be confirmed. If intrafascial dissection is carried out among patients with a high risk of extracapsular invasion, the result may be unsatisfactory. For example, in 2006, Curto et al. reported a contemporary laparoscopic surgical series wherein a surgical team experienced in over 2800 LRP performed intrafascial prostatectomies in patients with organ-confined prostate cancer (including 3 cases of cT3a disease) without other selection restrictions such as PSA level or Gleason score, for control of preoperative oncological risk. Subsequently, the percentage of pT2 cancer was only 58.6% and the overall PSM rate in all-stage tumors was as high as 30.7% (127/413) [11].

SSOS had four components, by which we used to evaluate the patients’ selection criteria for intrafascial prostatectomy of the included studies. We performed in-depth regression analysis setting total PSM rates as dependent variable by including each section and excluding each section from SSOS (see Additional file 5: Table S2). The result showed that section 1 (clinical T stage) was the most influential factor, as only section 1 could significantly affect PSM rates and when excluding section 1, the regression model became insignificant. Thus surgeons should make clinical T stage a priority when using SSOS as an indication.

A histological study by the VIP team indicated that 2/30 anterolateral zones of the prostate specimen after the Veil technique revealed capsular incision, compared with 0/40 for the standard technique [33]. In pathologically localized disease, the tumor does not invade beyond the limit of the prostatic capsule; thus, only intracapsular incision will lead to positive margins. Theoretically, intrafascial dissection should increase risk of capsular incision compared with the interfascial technique and, subsequently, with a localized tumor situated close to the capsule or having large volume, is likely to lead to PSM. This can be inferred from Curto’s surgical series [11], wherein investigators found a higher PSM rate, especially for pT2c tumors, as compared with the previous largest series; however, this difference was not present for other pathological stages.

For comparative analysis, we only included parallel-group studies including conventional interfascial nerve-sparing prostatectomy as the control. Several studies compared the outcomes of intrafascial prostatectomy with that of wide dissection or non-nerve-sparing prostatectomy, but as reported in some of these studies, wider preservation of the NVBs may be associated with a higher risk of PSM [34, 35]. Thus, for these studies, the oncological results could be confounded by the nerve-sparing technique, and, therefore, we did not include these studies in the comparative analysis. In our meta-analysis comparing intra- and inter-fascial groups, we stratified studies according to patient selection balance; however, the overall pooled result demonstrated there was no significant difference for PSM rate in all pathological stages of disease. Notably, in the study by Khoder et al. [12], patients were selected to undergo intrafascial prostatectomy only if biopsy Gleason scores were ≤ 6 and PSA ≤10 ng/mL with low tumor size; patients with relatively higher Gleason scores and PSA levels were allocated to the interfascial group, and this was considered as selection imbalance. These researchers ultimately reported that PSM rates for pT2 stage and all pathological stages were lower in the intrafascial group compared with the interfascial group; however, this advantage was not reported for pT3 cancer. From the subgroup results in our comparative analysis, a significantly lower PSM rate was identified in favor of the intrafascial technique in pT2 and all-stage disease for pooled studies with non-balanced selection criteria. All of these non-balanced studies applied additional more stringent patient selection criteria for the intrafascial technique, as compared with patient selection for the interfascial group. With regard to subgroup analysis of balanced studies, pooled results revealed a higher PSM rate, although statistically non-significant, with the intrafascial technique for pT2 and all-stage cancers. The variance between subgroups of balanced and non-balanced studies reconfirmed the crucial role of patient selection in controlling the PSM rate. In pT3 cancer, a higher PSM rate, although statistically non-significant, was detected for the interfascial group and may be attributable to insufficient sample size.

The PSM rate is known to be associated with surgeon-related characteristics, with surgical experience being the most important factor. Surgeons experienced in high-volume resections could decrease the PSM rate [36, 37]. A study evaluating the learning curve of radical prostatectomy indicated that increasing surgical experience was associated with substantial reductions in cancer recurrence: however, for LRP, the learning curve was slower than for RRP [38]. The relatively high PSM rate for LRP reported by Choi et al. in 2012 can be attributed to the learning curve [18]. In fact, the authors emphasized that, in the first 30 cases, the PSM rate was 51.7%, and then subsequently decreased to 9.5%. However, there are no published studies reporting an evaluation of PSM with the learning curve of the intrafascial technique.

Regarding on the dissection plane during procedure, surgeons supplied several technical variations, including VIP technique and Leipzig technique. We included all the intrafascial surgeries in this pooled study regardless of the variable techniques. Most authors described their dissection technique in the original manuscripts, but ignored pathological evaluation of the specimen regarding whether the utilized surgical technique was intra or interfacial nerve sparing. Thus we can only judge the classification depending on the authors’ description. As the PSM rates were affected by the dissection plane, the quality of the original trials may confound our conclusion and this is a major limitation when we included these trials in our pooled analysis.

In the present review, no obvious evidence indicative of preserving technique, including D-fascia preservation, puboprostatic ligament sparing, or selective/no ligation of DVC, was detected in conjunction with increased PSM rate. In a retrospective controlled study reported by Hoshi et al. in 2013 [15], the authors reconfirmed that the DVC preserving technique would not increase the PSM rate, as compared with the conventional intrafascial technique. Further, we could not conclusively determine any significant differences among the 3 surgical types of RRP, LRP, and RALRP from our pooled results. Overlapping results could be identified from the studies of Asimakopoulos and Greco. Asimakopoulos et al. conducted a randomized comparison between LRP and RALRP and found no statistically significant differences for the PSM rate [21]. In the study of Greco et al. comparing RRP with LRP, results demonstrated that both surgical types had similar PSM rates [24]. In terms of our regression model, age was another relevant predictor of the PSM rate, demonstrating that older patients had higher PSM rates for pT3 and all-stage cancers.

In summary, intrafascial technique resulted in a total PSM rate of 14.2% for all-stage cancer and 9.7% in pT2 disease. With stringent case selection and conducted by experienced surgeons, intrafascial prostatectomy could offer an acceptable or, at least, equivalent PSM rate compared with the conventional interfascial approach. Current patient selection criteria are more stringent than those indicated for radical prostatectomy by guidelines, and we proposed SSOS as an indication of intrafascial prostatectomy. Preoperative SSOS should be more than 7 points to obtain an acceptable postoperative PSM rate of 15% on average.