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More Extensive Pelvic Lymph Node Dissection Improves Survival in Patients with Node-positive Prostate Cancer

European Urology

Comment from Henk van der Poel: Removing more than 14 nodes improved cancer specific survival at 10 years after prostatectomy by more than 15% in this retrospective series.

Abstract

Background

The role of extended pelvic lymph node dissection (ePLND) in treating prostate cancer (PCa) patients with lymph node invasion (LNI) remains controversial.

Objective

The relationship between the number of removed lymph nodes (RLNs) and cancer-specific mortality (CSM) was tested in patients with LNI.

Design, setting, and participants

We examined data of 315 pN1 PCa patients treated with radical prostatectomy (RP) and anatomically ePLND between 2000 and 2012 at one tertiary care centre. All patients received adjuvant hormonal therapy with or without adjuvant radiotherapy (aRT).

Outcome measurements and statistical analysis

Univariable and multivariable Cox regression analyses tested the relationship between RLN number and CSM rate, after adjusting to all available covariates. Survival estimates were based on the multivariable model; patients were stratified according to RLN number using points of maximum separation.

Results and limitations

The average number of RLNs was 20.8 (median: 19; interquartile range: 14–25). Mean and median follow-up were 63.1 and 54 mo, respectively. At 10-yr, the CSM-free survival rate was 74.7%, 85.9%, 92.4%, 96.0%, and 97.9% for patients with 8, 17, 26, 36, and 45 RLNs, respectively. By multivariable analyses, the number of RLNs independently predicted lower CSM rate (hazard ratio [HR]: 0.93; p = 0.02). Other predictors of CSM were Gleason score 8–10 (HR: 3.3), number of positive nodes (HR: 1.2), and aRT treatment (HR: 0.26; all p ≤ 0.006). The study is limited by its retrospective nature.

Conclusions

In PCa patients with LNI, the removal of a higher number of LNs during RP was associated with improvement in cancer-specific survival rate. This implies that ePLND should be considered in all patients with a significant preoperative risk of harbouring LNI.

Patient summary

We found that removing more lymph nodes during prostate cancer surgery can significantly improve cancer-specific survival in patients with lymph node invasion.

Take Home Message

The removal of a higher number of lymph nodes during radical prostatectomy in patients with node-positive prostate cancer appears to be associated with improvement in the cancer-specific survival rate. This implies that extensive pelvic lymph node dissection should be considered in all patients with a significant preoperative risk of harbouring a lymph node invasion.

Keywords: Neoplasm recurrence, Prostatic neoplasms/pathology, Prostatic neoplasms/surgery, Prostatic neoplasms/mortality, Lymph node invasion, Lymph node dissection.

1. Introduction

Radical prostatectomy (RP) is one of the most commonly used treatments for patients with prostate cancer (PCa) [1] and [2]. However, the benefit of an extended pelvic lymph node dissection (ePLND) is still debated. It is generally accepted that whenever a PLND is indicated, this should be anatomically extended [3] . Such an extensive approach represents the only accurate staging procedure for lymph node invasion (LNI) in PCa [4] . However, the therapeutic impact of this ePLND (if any) is still unclear [5], [6], [7], [8], [9], [10], [11], [12], and [13].

Results of a recent randomised clinical trial suggested that ePLND could significantly decrease the risk of biochemical recurrence (BCR) after RP in patients with intermediate- or high-risk tumours [6] . However, although BCR risk reduction is an important finding, it does not necessarily translate into better survival. In contrast, several observational reports failed to demonstrate any beneficial impact of ePLND on BCR and/or survival [5], [9], and [13]. There may be two main reasons for this result: (1) use of limited and nonhomogeneous PLND, which might have artificially undermined the role of PLND, and (2) selection of patients at lower risk of dying from PCa. These points are key, since any therapeutic benefit associated with surgical treatments of PCa should be tested using a proper surgical approach (ie, ePLND) in a properly selected population (ie, patients at higher risk of dying from the disease).

To address this issue, we tested the relationship between the number of removed lymph nodes (RLNs) and cancer-specific mortality (CSM) in pN1 patients treated with RP and ePLND.

2. Materials and methods

We evaluated the data of 315 M0 pN1 PCa patients treated with RP and ePLND between 2000 and 2012 at one tertiary care centre. Patients were staged preoperatively with pelvic/abdominal computerised tomography or abdominal ultrasound, bone scan, and chest x-ray. Seven surgeons performed RP using a standardised retropubic technique. EPLNDs consisted of excision of fibrofatty tissue along the external iliac vein, the distal limit being the deep circumflex vein and the femoral canal. Proximally, ePLND was performed up to and including the bifurcation of the common iliac artery. Furthermore, all fibrofatty tissue within the obturator fossa was removed to completely skeletonise the obturator nerve. The lateral limit consisted of the pelvic sidewall, and the medial dissection limit was defined by perivesical fat. In all the patients included in our cohort, LNs along the internal iliac vessels were dissected. In some cases, LNs located in the presacral and common iliac areas were also removed.

Postoperatively, all patients received adjuvant hormonal therapy (aHT), which was intended to be lifelong. However, given the retrospective nature of the cohort, it is uncertain whether patients discontinued treatment after a period of androgen-deprivation therapy. Additionally, 147 (46.7%) patients received aRT. ART was administered based on the clinical judgment of each treating physician according to patient and cancer characteristics. Radiation therapy consisted of localised radiation delivered to the prostate and to the seminal vesicle bed with pelvic LN irradiation (whole pelvis radiotherapy). Details of the aRT technique used have been previously published [14] . Adjuvant treatments (both aHT and aRT) were initiated within 90 d from RP. The institutional review board approved the study.

2.1. Variable definition

All patients included in this study had complete clinical and pathology data, which consisted of age at surgery, prostate-specific antigen (PSA) value, D’Amico risk group (low- vs intermediate- vs high-risk) [15] , pathologic Gleason score (2–7 vs 8–10), pathologic tumour stage (pT2 vs pT3a vs pT3b vs pT4), surgical margin status (negative vs positive), number of removed LNs (RLNs), number of positive lymph nodes, aRT status (no aRT vs aRT), and year of surgery.

2.2. Statistical analyses

Descriptive statistics of categorical variables focused on frequencies and proportions. Means, medians, and interquartile ranges (IQR) were reported for continuously coded variables. Chi-square and Mann-Whitney tests were used to compare the statistical significance of differences in proportions and medians, respectively.

Univariable and multivariable Cox regression analyses were used to test the relationship between the number of RLNs and CSM rate, after adjusting for all available covariates. Estimated survival curves were plotted based on the multivariable model results. Survival curves were stratified according to the number of RLNs, using the points of maximum separation, as described by Harrell [16] . The number of RLNs was then dichotomised according to the most informative cut-off predicting CSM. This was obtained applying the chi-square test for every possible cut-off value and choosing the lowest p value. Survival curves were then stratified according to the most informative cut-off for the number of RLNs. Finally, predicted 10-yr survival according to the number of RLNs was plotted for the entire cohort, and after stratification according to Gleason score and aRT status.

All statistical analyses were performed using the R statistical package system (R Foundation for Statistical Computing, Vienna, Austria), with a two-sided significance level set at p < 0.05.

3. Results

3.1. Baseline patient characteristics

Clinical and pathologic demographics of the cohort, stratified by adjuvant treatment status are reported in Table 1 . The average PSA value was 24.2 ng/ml (median: 11.2 ng/ml; IQR: 6.9–24.4 ng/ml). Most of the patients included in the study were affected by high-risk disease at diagnosis (60%). Most patients harboured a pT3b disease (66%), and had a pathologic Gleason score 8–10 (57%). Average number of RLNs and positive LNs was 20.8 (median: 19; IQR: 14–25) and 3.3 (median: 2.0; IQR: 1–3), respectively. For all examined variables, there were no statistically significant differences between patients treated with aRT versus without aRT (all p ≥ 0.07).

Table 1 Descriptive statistics for the cohort of 315 patients with nonmetastatic lymph node–positive prostate cancer, treated with radical prostatectomy and pelvic lymph node dissection between 2000 and 2012 at one tertiary care centre *

  Entire cohort

(n = 315; 100%)
No adjuvant radiotherapy

(n = 168; 53.3%)
Adjuvant radiotherapy

(n = 147; 46.7%)
p value
Age, yr
 Mean 65.3 65.9 64.6 0.1
 Median 66 66 65  
 IQR 60–71 60–71 60–70  
PSA, ng/ml
 Mean 24.2 28.1 21.2 0.1
 Median 11.2 11.4 11  
 IQR 6.9–24.0 7.4–26.5 6.7–22.5  
Risk group
 Low risk 29 (9.2) 17 (10.1) 12 (8.2) 0.8
 Intermediate risk 97 (30.8) 52 (31.0) 45 (30.6)  
 High risk 189 (60.0) 99 (58.9) 90 (61.2)  
Removed lymph nodes
 Mean 20.8 21.4 20.2 0.3
 Median 19 20 19  
 IQR 14–25 14-26 13-26  
Positive lymph nodes
 Mean 3.3 3.5 3.2 0.6
 Median 2 1.5 2  
 IQR 1–3 1–3 1–3  
Gleason score
 2–7 136 (43.2) 81 (48.2) 55 (37.4) 0.07
 8–10 179 (56.8) 87 (51.8) 92 (62.6)  
Pathologic stage
 pT2 21 (6.7) 13 (7.7) 8 (5.4) 0.7
 pT3a 66 (21) 32 (19) 34 (23.1)  
 pT3b 207 (65.7) 112 (66.7) 95 (64.6)  
 pT4 21 (6.7) 11 (6.5) 10 (6.8)  
Surgical margins
 Negative 134 (42.5) 71 (42.3) 63 (42.9) 0.9
 Positive 181 (57.5) 97 (57.7) 84 (57.1)  
Year of surgery
 Mean 2006.3 2005.9 2006.6 0.1
 Median 2007 2007 2007  
 IQR 2006–2010 2005–2010 2006–2009  

* Data were stratified according to adjuvant treatment status: no adjuvant radiotherapy versus adjuvant radiotherapy.

IQR = interquartile range.

3.2. Cox regression analyses and survival estimates

At univariable analyses, Gleason score 8–10 (hazard ratio [HR]: 2.9), pT4 (HR: 6.7), aRT treatment (HR: 0.40), and the number of positive LNs (HR: 1.1) were the only predictors of CSM rate (all p ≤ 0.02) ( Table 2 ). At multivariable analyses, Gleason score 8–10 (HR: 3.3) and a higher number of positive LNs (HR: 1.2) were independently associated with higher CSM rate (all p ≤ 0.006) ( Table 2 ). Conversely, aRT treatment (HR: 0.26) and a higher number of RLNs (HR: 0.93) were independent predictors of a lower CSM rate (all p ≤ 0.02) ( Table 2 ).

Table 2 Univariable and multivariable Cox regression analyses predicting cancer-specific mortality in 315 pN1 prostate cancer patients treated with radical prostatectomy, extended pelvic lymph node dissection, and adjuvant treatments

  Univariable analysis Multivariable analysis
  HR (95% CI) p value HR (95% CI) p value
Age, yr 1.00 (0.95–1.05) 0.8 1.00 (0.95–1.05) 0.9
PSA, ng/ml 1.00 (1–1.01) 0.1 1.00 (0.99–1.01) 0.4
Gleason score
 2–7 1.00 (Ref.) 1.00 (Ref.)
 8–10 2.99 (1.37–6.49) 0.006 3.31 (1.41–7.75) 0.006
Pathologic stage
 pT2 1.00 (Ref.) 1.00 (Ref.)
 pT3a 0.66 (0.12–3.63) 0.6 0.55 (0.09–3.2) 0.5
 pT3b 0.91 (0.21–3.96) 0.9 0.57 (0.12–2.72) 0.4
 pT4 6.74 (1.44–31.51) 0.01 3.53 (0.6–20.93) 0.1
Surgical margins
 Negative 1.00 (Ref.) 1.00 (Ref.)
 Positive 1.76 (0.85–3.63) 0.1 0.92 (0.4–2.13) 0.8
Adjuvant radiotherapy
 No 1.00 (Ref.) 1.00 (Ref.)
 Yes 0.4 (0.19–0.86) 0.02 0.26 (0.11–0.63) 0.003
Removed lymph nodes 1.03 (1–1.07) 0.05 0.93 (0.88–0.99) 0.02
Positive lymph nodes 1.12 (1.07–1.17) <0.001 1.16 (1.09–1.24) <0.001
Year of surgery 0.96 (0.88–1.05) 0.4 0.93 (0.84–1.02) 0.1

CI = confidence interval; HR = hazard ratio; Ref. = reference.

Survival estimates were calculated based on the multivariable model. Mean and median follow-up periods were 63.1 and 54 mo, respectively. Patients were stratified according to the number of RLNs, using the points of maximum separation ( Fig. 1 a). At 10 yr, the CSM-free survival rate was 74.7%, 85.9%, 92.4%, 96.0%, and 97.9% for patients with 8, 17, 26, 36, and 45 nodes removed, respectively (p = 0.02). The most informative cut-off for the number of RLNs was 14. At 10 yr, the CSM-free survival rates were significantly higher for patients with ≥ 14 RLNs compared to their counterparts with <14 RLNs (p = 0.04) ( Fig. 1 b).

gr1

Fig. 1 Kaplan-Meier survival estimates based on multivariable analysis, depicting cancer-specific survival rate in 315 pN1 prostate cancer patients treated with surgery and adjuvant treatment. Patients were stratified according to (a) the total number of lymph nodes removed and (b) the most informative cut-off for the association between the number of nodes removed and cancer-specific survival.

Figure 2 a presents the predicted 10-yr CSM-free rate for the entire cohort by the number of RLNs. The predicted CSM-free rate increased consistently with rising number of RLNs, from 79.1% for patients with 10 RLNs to 97.0% for patients with 40 RLNs. Similar trends were observed when patients were stratified according to Gleason score and aRT status ( Fig. 2 b and 2c).

gr2

Fig. 2 The multivariable analysis 10-yr cancer-specific survival rate predicted (a) by the total number of lymph nodes removed for the entire cohort, (b) after stratification according to Gleason score, and (c) by adjuvant radiotherapy (aRT) status.

4. Discussion

There is a continuing debate and uncertainty regarding the role of ePLND in PCa patients treated with RP [5], [6], [7], [8], and [9]. This might be attributed to a drop in the utilisation rate of ePLND, even in patients with intermediate- or high-risk tumours. This trend was further accentuated by the introduction of minimally invasive approaches, where the performance of an ePLND might be more challenging and time consuming [17] . However, omitting ePLND might translate into less favourable cancer control outcomes and have a detrimental impact on patient outcomes [6] . To verify this hypothesis, we tested the relationship between the number of RLNs and CSM risk after RP in patients with LNI.

We made several findings. First, at univariable analysis, a direct positive relationship was evident between the number of RLNs and the CSM rate. Specifically, a higher number of RLNs was associated with a higher CSM rate (HR: 1.03), with a borderline statistical significance level (p = 0.05). However, after adjusting for all available confounders, the relationship between the number of RLNs and CSM rate flipped. Specifically, the removal of more LNs was associated with lower CSM rate (HR: 0.93; p = 0.02). The controversy between the results of univariable and multivariable analyses might be explained as follows: Frequently, patients with more aggressive tumours are offered a more extended PLND. This might result in a selection bias, where patients with the higher number of RLNs are those that harbour the more aggressive tumours. Consequently, it might seem that removing more LNs is associated with less favourable survival (as in the case of our univariable analysis), simply because of the selection bias at baseline. However, multivariable analysis was able to correct the baseline selection bias, and demonstrated that removing more LNs is associated with a more favourable CSM rate. Nevertheless, such a confounding association might not be properly assessed in other cohorts where patients have not routinely received an ePLND.

Second, our survival estimates, based on multivariable analysis, showed that the beneficial impact of ePLND on CSM might not appear before 20–30 mo of follow-up ( Fig. 1 a and 1b). This implies that a long follow-up is necessary to test the impact of ePLND on survival. This is another factor that might have limited the reliability of previous reports. Third, factors other than the number of RLNs appear to have an impact on CSM rate in patients with LNI. Specifically, patients with a higher grade and higher number of positive LNs, and those not receiving aRT, appear to have less favourable CSM rate.

In a previous report, Joslyn et al. [7] analysed data of 13 020 PCa patients treated initially with RP between 1988 and 1991, within the Surveillance, Epidemiology, and End Results database. Authors found that removing four or more LNs was associated with a more favourable survival rate in both node-negative and node-positive patients. However, these observations originated from historic patients that were treated in the early PSA era. In another report, Masterson et al. [8] examined the data of 4611 PCa patients treated with RP, and found that the number of RLNs was not associated with the risk of disease recurrence. However, when selecting only pN0 patients, a higher number of RLNs removed was significantly related to a lower BCR risk. Additionally, Bivalacqua et al. [11] have shown patients undergoing an ePLND had better oncologic outcomes at 10-yr follow-up compared to their counterparts receiving a limited PLND. Conversely, other authors found the number of RLNs was not associated with BCR and/or survival, even in high-risk patients [5], [9], [12], and [13] It is noteworthy that most of the reports focused exclusively on pN0 patients. This might have resulted in a selection bias (Will Rogers phenomenon), where pN0 patients with higher number of RLNs are better staged and, thus, are more likely to be really free from LNI. Conversely, pN0 patients with lower number of RLNs are less probable to be accurately staged, and might actually harbour an overlooked LNI. The less favourable survival rates observed in these individuals might largely be attributable to this. Although such an effect may have also have partly influenced our results, we tried to minimise it by focusing only on pN1 patients homogenously treated with an ePLND. Specifically, one of the strengths of our study is that it was based on men with LNI receiving adequate extent of PLND. Given the heterogeneous natural history of PCa, it is likely that a well-performed ePLND, as well as any surgical treatment for PCa [18] and [19], exerts its maximal effect on those who are at higher risk of dying from PCa. Selecting individuals who are exposed to higher cancer-specific risk and lower risk of competing causes of death may thus maximise the effect of this extensive surgical approach.

Our study has several clinical implications. Our findings showed that a more extensive PLND offers better cancer control outcomes in patients with LNI. It is noteworthy that the risk for LNI in contemporary PCa patients is still significant [20] and [21], and that accurate preoperative staging with imaging of these individuals is not possible [4] . Consequently, an ePLND in these men is mandatory to achieve reliable staging and to improve survival of those with LNI.

Moreover, our results emphasise that it is necessary to be cautious in interpreting data that originate from cohorts where patients are not homogenously treated with an ePLND and/or without long follow-up. Such data might artificially undermine the benefits of ePLND. However, our results cannot answer the clinically relevant question regarding the optimal anatomic extent of ePLND in patients with LNI. Certainly, all these patients should receive an anatomic dissection of all lymphatic tissue in the obturator fossa, as well as along the external and internal iliac vessels. This should be invariably performed in all patients whenever a PLND is indicated [3] . In addition, our results seem to support not only a meticulous and careful dissection of all these areas, but also of the presacral and common iliac areas in patients with adverse PCa characteristics, as previously recommended [22] and [23]. However, such an approach can be only suggested, but not fully supported, by our results. Indeed, while our study shows an association between the number of LNs removed and patient survival, the lack of data regarding the exact anatomic scheme of LND in each patient prevents us from giving a clear recommendation about this subject.

Finally, our results showed that patients with LNI might benefit from maximising local disease control with aRT. This corroborates our previous findings [24], [25], and [26] and implies that not all patients with LNI necessarily harbour a metastatic disease. Indeed, patients with few positive LNs showed excellent cancer-specific survival rates after adjusting for postoperative treatments [12] and [27]. In this study, we report the first single-institution series supporting the role of more extensive PLND, regardless of the extent of nodal invasion.

Our study is not devoid of limitations. First, our results were derived from retrospective, observational data. Therefore, our findings should be considered in the context of retrospective, observational evidence and warrant prospective, randomised validation. Despite that an anatomically ePLND was routinely offered to all RP patients in our institution, a fluctuation in the number of RLNs was observed. Indeed, the RLNs ranged between 4 and 83. This might be derived from individual variability related to patient characteristics, which is inevitable, especially in such a large cohort. Moreover, many unobserved confounders, such as surgical [28] , pathologic expertise, and/or imperceptible changes over time might have affected the LN count [29] . Likewise, at surgeon discretion, a more extended PLND that involved presacral and/or common iliac LNs was performed in some patients. These unobserved confounders might explain, at least partially, the variability in the LN count over the study period. In this context, we would like to highlight that the range of RLNs observed in our series is in line with what has been reported by other esteemed authors in large cohorts of patients treated with RP and anatomically defined ePLND [11], [29], [30], [31], and [32]. However, such variability allowed us to test the effect between the number of RLNs and patient survival, since it is likely that some patients received even more meticulous PLND and a more careful dissection of pelvic lymphatic tissue, based on the judgment and expertise of different treating physicians. Second, a pathology review was not performed. Despite the variability in surgical technique and pathology reports, which might have introduced potential biases, our data benefited from a high expertise and standardised protocols, given the tertiary care centre nature of our institute. Overall, seven experienced surgeons (>150 cases each at the time of study initiation) performed RP and ePLND. Moreover, four pathologists examined the pathology specimens over the study period. Although all of them applied a standardised protocol for nodal evaluation [33] , we cannot exclude that a possible heterogeneity in nodal count may have introduced, given the retrospective nature of our study. Third, data regarding complication rate were not available. Fourth, all patients included in the analyses received aHT. Consequently, our observations might not be applicable in patients with positive LNs and who received no aHT. Moreover, the use of aRT was administered based on the clinical judgment of each treating physician according to patient and cancer characteristics. Although this might have introduced a potential bias, it should be highlighted that multivariable analysis and stratified analysis corroborate the beneficial impact of an ePLND, regardless of the adjuvant treatment status.

5. Conclusions

Our results showed that in PCa patients with LNI, the removal of a higher number of LNs during RP was associated with an improvement in cancer-specific survival rate. Particularly, the most informative cut-off for the number of RLNs was 14. This implies that an ePLND should be considered in all patients with a significant preoperative risk of harbouring an LNI.


Author contributions: Alberto Briganti had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Abdollah, Suardi, Briganti.

Acquisition of data: Gandaglia, Nini, Moschini.

Analysis and interpretation of data: Abdollah, Sun, Gandaglia, Capitano.

Drafting of the manuscript: Abdollah, Briganti.

Critical revision of the manuscript for important intellectual content: Briganti, Salonia, Karakiewicz, Shariat, Montorsi.

Statistical analysis: Abdollah, Sun, Capitano, Gandaglia.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Briganti, Saloni, Karakiewicz, Shariat, Montorsi.

Other (specify): None.

Financial disclosures: Alberto Briganti certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None

Funding/Support and role of the sponsor: None.

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Footnotes

a Division of Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy

b Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Centre, Montreal, Quebec, Canada

c Department of Urology, Medical University of Vienna, Vienna, Austria

lowast Corresponding author. Department of Urology, Urological Research Institute, San Raffaele Hospital, University Vita-Salute, Via Olgettina, 60, Milan 20132, Italy. Tel. +39 02 2643 7790; Fax: +39 02 2643 7298.