The diagnostic value of PLND for PCa staging is acknowledged. however, there are still debate with regard to the survival benefit of extended PLND. Before the present study, there have been a variety of retrospective studies comparing the oncological outcomes of extended PLND versus standard PLND. In a recent systematic review, the comparison of 21 retrospective studies on no PLND versus any form of PLND revealed no significant difference in favor of PLND for biochemical recurrence, metastasis free survival or CSS16. 11 of 13 studies comparing extended PLND and standard PLND in terms of biochemical recurrence did not demonstrate significant difference. While two studies showed a benefit from extended PLND in specific subgroups: intermediate-risk patients (96% versus 90%, p = 0.017) and pN1 patients with < 15% of retrieved lymph nodes affected (43% versus 10%, p = 0.01)17,18.
One recent prospective randomized trial compared the oncological outcomes between extended PLND and standard PLND, finding extended PLND provides better pathological staging and better biochemical recurrence free survival only in ISUP grade groups 3–5. This study provided a high level evidence compared with previous studies. However, CSS data were not available because of short follow-up and limited sample size14. Another prospective randomized trial found that extended PLND had no significant association with lower biochemical recurrence rate. However, in this study, the differences in nodal count and the rate of positive nodes between extended and standard PLND were smaller than expected15.
Another multicenter retrospective study included large sample of intermediate risk and high risk prostate cancer patients with long follow up, but didn’t find significant difference on biochemical recurrence, metastasis free survival and CSS between patients with and without extended PLND12. Despite of the retrospective nature and possible selection bias, these results suggested the negative therapeutic value of extended PLND was not probably due to limited sample size and short follow up.
Abdollah et al and Preisser et at found more extensive PLND improves survival in patients with node-positive and node-negative prostate cancer6,10. However, on one hand, because we can’t obtain the lymph node status before surgery, these results couldn’t have guidance on clinical decision; On the other hand, according to Will Rogers phenomenon, the lymph node status is affected by the range of PLND. This reason may potentially affect these conclusions.
Most previously studies had negative results whether in retrospective or prospective studies. We assumed that the significant value of extended PLND is more likely in patients with higher risk of LN metastasis, so we used the SEER data to confirm the hypothesis. As most studies obtained negative results including intermediate and high risk patients, we only included the patients with high risk prostate cancer in our study. The SEER data is retrospective and with limited information available, so we established the prediction model according to patients’ characteristics in the database to accurately evaluate the LN metastasis risk. We also excluded patients received adjuvant radiotherapy in the database. This can eliminate the radiotherapy’s effect on survival, and better reflect the pure effect of PLND on survival; on the other hand, because PLND may also affect the prognosis by guiding adjuvant therapy (including radiotherapy), such exclusion criteria might exclude these effects on the survival. The SEER database didn’t include the data about the extent of PLND, but only the removed lymph node count. Therefore, as the previous study10,13, we used the RLNC as an indicator for the extent of PLND.
We established a prediction model for LN metastasis based on the preoperative information from patients with RLNC over 6. The area under receiver operating characteristic curve of our prediction model for training sample is 0.829. The predictive LNMR in each LNMR group was also similar to the proportion of LN metastasis. By using the subgroup analysis, we found more RLNC (RLNC > 11) could significantly improve CSS and OS in the subgroup of LNMR ≥ 30% but not significant in the subgroup of LNMR < 30%. And the interaction analysis showed statistical significance between LNMR and RLNC with regard to CSS. One previous study analyzed the SEER database and found that PLND at RP is associated with low cancer specific mortality and overall mortality in the setting of metastatic PCa 8. In our study, we found the survival benefit of extended PLND was more significant in patients with higher risk of lymph node metastasis (over 30%). In these patients, we speculate that there might also be potential micro-metastasis that is undetected. Another possible explanation is that all metastatic PCa is at very high risk of LN metastasis. The consistence of these results suggested that PLND might provide survival benefit in very advanced prostate cancer with more LN metastasis or distant metastasis. However, this inference requires further validation.
Taken together, our findings have important clinical implications. We identified a subgroup of D’Amico high risk PCa patients that benefit significantly from more RLNC in PLND. Such an indication will be valuable for future design of randomized clinical trial for high risk PCa. The present prospective clinical trials recruited all patients with intermediate risk and high risk patients, and the subgroup analysis only included one category, such as PSA value, Gleason score or clinical T stage14. Future prospective studies might use LNMR as an indicator for subgroup analysis.
Our study is not devoid of limitations. First, we arbitrarily used 6 and 11 as the cutoff value of analysis. Although the LN count is almost consistent with the standard and extended PLND in a prospective study, we couldn’t obtain the specific PLND range from the SEER database. Therefore, our results revealed the prognostic significance of PLNC, but not the extent of PLND. Second, we only included patients not receiving adjuvant radiotherapy, so the conclusion couldn’t be applied to patients receiving adjuvant radiotherapy. On the other hand, the impact of extended PLND could be evaluated more objectively in our study. Third, the data from SEER database is retrospectively obtained and has a high potential for bias due to selection of patients undergoing surgery. Fourth, the prediction model for LNMR was established based on patients with RLNC over 6, but the results might still underestimate the metastatic LN. Fifth, the LNMR subgroup was also arbitrarily selected, and the results showed more RLNC provided survival benefit when LNMR ≥ 30%, which required further validation. Last but not least, several important variables were unavailable in the SEER database, including American Society of Anesthesiologists score, comorbidity, adjuvant hormonal therapy and baseline hematological and biochemical blood values that might potentially predict survival in PCa.
The present retrospective study showed that more RLNC in PLND is associated with better CSS and OS when the LNMR is over 30%. Prospective randomized trials are necessary to determine the value of extended PLND in PCa patients with high LNMR.