This study analysed the relationship between lymph node yield and risk of cancer recurrence in men undergoing RP, stratified by pre-operative likelihood of nodal involvement. We found no difference in risk of BCR with increased nodal yield at RP in low-risk men (Briganti risk < 5%), however in high-risk men (Briganti risk ≥5%) there was a modest benefit in terms of reduced BCR risk at a median of 8-years follow-up, on multivariate analysis.

The present study adds incremental value to the existing evidence base, due to several strengths of the study which overcome many of the limitations of previous studies including a large sample size, long term follow-up (median 80 months), groups stratified to high-risk and low-risk according to the gold standard for prediction of LNI (Briganti nomogram risk), analysis of lymph node yield as a continuous and categorical variable as opposed to a theoretical standard PLND and ePLND template with multivariate analysis to adjust for confounding factors. The analysis of lymph node yield may represent a better surrogate for extent of PLND then theoretical templates and thus improve evaluation of the therapeutic benefit of PLND. Further, the data was collected from a prospectively maintained database with detailed baseline and follow-up data as compared to analysis performed using population wide registries such as the SEER or BAUS database.

Previous studies and meta-analyses have reported conflicting results regarding the oncologic benefit of performing PLND, but the weight of evidence is consistent with the findings from our study, demonstrating a consistent lack of benefit in low-risk men and conflicting evidence regarding a weak benefit for ePLND in high-risk men [10, 12, 13, 16,17,18,19,20]. For example, in the recent RCT by Lestingi et al., there was no benefit to extended vs. limited PLND in the overall population, but in the subgroup with ISUP grade 3–5 disease, extended PLND had a significantly better BCR free survival (HR 0.33, 95% CI 0.14–0.74, interaction p = 0.007). This finding was hypothesis-generating rather than definitive (due to small sub-group sample size) but is nevertheless consistent with the results of the present study, wherein only the high-risk sub-group appear to benefit from increased lymph node yield.

In the current multivariate analysis, clinical factors including PSA, ECE, surgical margin and positive nodes were independently associated with BCR. Increased lymph node yield was associated with reduced risk of BCR on multivariate analysis only in the high-risk subgroup, but not in the overall cohort or the low-risk subgroup. A retrospective multi-variate analysis of 9,742 patients from 4 institutions with Briganti risk > 5% by Preisser et al. showed that PSA, surgical margins, grade and pathological stage were independent predictors of BCR, however ePLND with a median yield of 14 nodes (vs. no PLND) was not a predictor of BCR, metastasis or PCa-death [12]. However, this study was limited by a short median follow-up of 33.5 months and did not assess whether higher vs. lower lymph node yield influenced BCR. In a systematic review of 66 studies, Fossati et al. demonstrated no significant benefit for PLND against no PLND in terms of BCR, metastasis free survival or cancer specific survival. However, many of the studies were limited by lack of multivariate analysis, failure to stratify into lower- vs. higher risk groups, short median follow-up, and small sample size.

Our finding that increased nodal yield reduced BCR risk, is supported by other studies. A meta-analysis of 6 studies involving 5,554 patients who underwent PLND demonstrated that increased lymph node yield with ePLND had a significant benefit in terms of BCR-free survival (HR 0.62, 95%CI 0.36–0.87)[21]. Choo et al., in a meta-analysis of 9 studies reported that there was a significant difference in BCR for ePLND vs. limited PLND, thus demonstrating the potential oncological benefit of increased lymph node yield (HR 0.71, 95% CI 0.56–0.90; p = 0.005) [18].

If ePLND does ‘truly’ confer a very weak oncologic benefit in high-risk Pca, as in the present study (i.e. a slight reduction in BCR-risk at 8-years, with no difference in mestastasis or mortality), then this marginal benefit must be weighed against the cost and morbidity of ePLND. A recent metanalysis of the peri-operative outcomes found that overall, 14.1% of patients experienced at least one postoperative complication secondary to PLND [9]. Further, the pooled meta-analysis demonstrated that RP + standard PLND had significantly decreased risk of intra-operative and post-operative complications when compared to ePLND. Therefore, ePLND also confers a significant cost and resource burden on the healthcare system, given it adds up to 60–75 min to overall procedure duration and causes increased complications. Thus, there is an urgent need for an adequately powered, non-inferiority RCT of ePLND vs. no PLND in men undergoing RP for high risk Pca, combining a long-term PCa-survival primary endpoint with secondary oncologic, morbidity, QOL and cost endpoints, and ideally incorporating pre-operative PSMA-PET/CT (to guide ePLND beyond the template if positive, but not to guide selection for ePLND).

This study has limitations. The main limitation is its retrospective and non-randomised design. Whilst RCTs provide the ideal level of evidence to guide practice, those published to date have failed to resolve the therapeutic dilemma regarding the benefit of ePLND in high-risk men. Further trials of ePLND vs. no PLND in high-risk PCa with long-term follow-up are being planned or underway,[22] but will not report final outcomes for more than a decade.

A further limitation of our study is that only 12.8% of men who theoretically underwent an ePLND had ≥ 10 nodes removed as is seen in Table 3, which is fewer than expected. This may at least partially explain our modest (although still statistically significant) reduction in BCr in the high-risk group.

Furthermore, 68Ga-prostate-specific membrane antigen (PSMA) PET/CT has been shown to improve accuracy over conventional CT for staging of pelvic nodal disease in patients with high-risk prostate cancer [23], although PSMA-PET has limited sensitivity ≤ 50% for micrometastases < 4 mm [24, 25]. Given it is this sub-group of men with 1–2 micro-metastases who may in fact be most likely to achieve prolonged BCR-free survival from ePLND, using PSMA-PET-CT to guide selection for ePLND may result in avoidance of PLND in those men who are most likely to benefit from PLND. Conversely, men with positive PSMA-PET/CT for nodal disease are more likely to harbour distant micro metastatic disease and therefore receive reduced oncological benefit from PLND despite its morbidity. Thus, PSMA-PET should not be used to guide selection for PLND outside of RCTs. The benefit of PSMA-PET may be via combination with novel intra-operative PLND techniques such as PSMA-Tc radio-guided targeted PLND, PSMA-PET may augment the sensitivity of PLND via localising nodes outside a surgeon’s standard template (e.g. pre-sacral, meso-rectal, etc.), thus optimising the oncologic benefit of PLND, as seen in preliminary results from the DETECT trial at our institution [26, 27].