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The Impact of the Extent of Lymphadenectomy on Oncologic Outcomes in Patients Undergoing Radical Cystectomy for Bladder Cancer: A Systematic Review

European Urology

Abstract

Context

Controversy exists regarding the therapeutic value of lymphadenectomy (LND) in patients undergoing radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC).

Objective

To systematically review the relevant literature assessing the impact of LND on oncologic and perioperative outcomes in patients undergoing RC for MIBC.

Evidence acquisition

Medline, Medline In-Process, Embase, the Cochrane Central Register of Controlled Trials, and the Latin American and Caribbean Center on Health Sciences Information (LILACS) were searched up to December 2013. Comparative studies reporting on no LND, limited LND (L-LND), standard LND (S-LND), extended LND (E-LND), superextended LND (SE-LND), and oncologic and perioperative outcomes were included. Risk-of-bias and confounding assessments were performed.

Evidence synthesis

Twenty-three studies reporting on 19 793 patients were included. All but one study were retrospective. Planned meta-analyses were not possible because of study heterogeneity; therefore, data were synthesized narratively. There were high risks of bias and confounding across most studies as well as extreme heterogeneity in the definition of the anatomic boundaries of LND templates. All seven studies comparing LND with no LND favored LND in terms of better oncologic outcomes. Seven of 14 studies comparing (super)extended LND with L-LND or S-LND reported a beneficial outcome for (super)extended LND in at least a subset of patients. No difference in outcome was reported in two studies comparing E-LND and S-LND. The comparative harms of different extents of LND remain unclear.

Conclusions

Although the quality of the data was poor, the available evidence indicates that any kind of LND is advantageous over no LND. Similarly, E-LND appears to be superior to lesser degrees of dissection, while SE-LND offered no additional benefits. It is hoped that data from ongoing randomized clinical trials will clarify remaining uncertainties.

Patient summary

The current literature suggests that removal of lymph nodes in bladder cancer surgery is beneficial and might result in better outcomes in terms of prolonging survival; however, the quality of the available studies is poor, and high-quality studies are needed.

Take Home Message

Current evidence suggests that extended lymphadenectomy might be superior to lesser degrees of dissection in terms of oncologic outcomes with comparable perioperative morbidity. High-quality data from randomized clinical trials are needed to draw a firm conclusion.

Keywords: Bladder neoplasms, Radical cystectomy, Lymphadenectomy, Lymph node dissection, Standard, extended, or superextended dissection, Oncologic outcomes.

1. Introduction

Lymphadenectomy (LND) combined with radical cystectomy (RC) is considered the standard of care for patients with muscle-invasive bladder cancer (MIBC). Up to 25% of patients harbor lymph node (LN) metastases at the time of RC, and the staging role of LND is unequivocal. In 1982, Skinner [1] was the first to report long-term survival in LN-positive patients undergoing RC and LND without systemic treatment. The therapeutic value of LND, however, remains a topic of continuous debate. While the results of two ongoing randomized clinical trials (RCTs) evaluating the impact of different LND templates on survival are awaited, the current evidence base remains uncertain with regard to the true benefits and harms of LND. In this study we systematically reviewed the available literature to evaluate the impact of the extent of LND on survival and perioperative outcomes in patients undergoing RC for MIBC.

2. Evidence acquisition

2.1. Search strategy

The review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement and principles outlined in the Cochrane Handbook for Systematic Reviews of Interventions[2] and [3]. Highly sensitive electronic searches were conducted to identify all reports of RCTs or nonrandomized comparative studies (NRCSs) assessing LND in patients undergoing RC for MIBC. The searches were not limited by language or publication date. The databases searched were Medline (1946 to December 2013), Medline In-Process (December 20, 2013), Embase (1974 to December 2013), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 8, 2013), and the Latin American and Caribbean Center on Health Sciences Information (LILACS; December 2013). The database search was complemented by additional sources, including the reference lists of included studies, which were hand searched, and additional reports identified by an expert panel (European Association of Urology [EAU] Working Group on MIBC). Ongoing trials were identified at ClinicalTrials.gov. The full search strategy is presented in Supplement 1.

Two reviewers independently screened titles and abstracts of all citations identified by the search strategies. Full-text copies of all potentially relevant reports were obtained and independently assessed by the reviewers to determine whether they met the predefined inclusion criteria. Any disagreements were resolved by consensus or arbitration by a third person. A data extraction form was developed specifically for this assessment to collect information on study design, characteristics of participants, characteristics of interventions, and outcome measures.

2.2. Inclusion and exclusion criteria

The inclusion criterion was comparative studies only, and these studies included RCTs, prospective NRCSs, prospective observational studies with a comparator arm, and retrospective comparative studies. Registry or database studies were also eligible if the analysis was clearly structured as a comparison between control and intervention groups. Studies with no comparator group (eg, single-arm case series), noneffectiveness studies (eg, nomogram studies), reviews, and studies with <10 patients in each arm were excluded.

The study population was limited to patients with localized muscle-invasive urothelial or squamous cell carcinoma of the bladder (cT2–4 N0M0). Studies including predominantly patients with variant histology other than squamous cell carcinoma were excluded because of low incidence and the potentially different biologic behavior of these cancers. Clinical staging was preferred, but if it was not reported, staging based on RC specimen was accepted. Studies with mixed populations (eg, cTa, cTis, cT1) were retained for consideration for inclusion if there were no studies that included patients with MIBC exclusively. Studies including patients who underwent neoadjuvant or adjuvant treatment were also retained.

The types of interventions included LND undertaken during RC for bladder cancer (BCa). Because of the expected heterogeneity in defining the extent of LND across studies, the extent of LND was determined a priori based on discussion in an expert panel (EAU Working Group on MIBC) and was categorized as follows: (1) limited LND (L-LND): LND confined to the obturator and/or perivesical fossa only; (2) standard LND (S-LND): LND performed up to the common iliac arteries; (3) extended LND (E-LND): LND performed up to the proximal boundary of the crossing of the common iliac vessels with the ureters or the aortic bifurcation, with or without the presacral LNs; and (4) superextended LND (SE-LND): LND performed up to the proximal boundary of the inferior mesenteric artery. The primary outcome was overall survival (OS); secondary outcomes included recurrence-free survival (RFS), disease-free survival (DFS), progression-free survival, cancer-specific survival, and perioperative outcomes (eg, operative time, blood loss, lymphocele).

2.3. Assessment of risks of bias

Two reviewers independently assessed the risk of bias (RoB) of individual studies. Any disagreement was resolved by discussion or reference to a third reviewer. The standard Cochrane Collaboration RoB tool [4] was used to assess the RoB in RCTs, while for NRCSs, the RoB tool recommended by the Cochrane Non-Randomised Studies Methods Group was used [5] and [6]. In addition, for NRCSs, the main confounders were identified a priori based on a study by Palmer et al. [7] . In this study, a survey among BCa experts was performed to identify and rank potential confounding variables and defining thresholds for imbalance for these variables. The main confounders identified are summarized in Figure 1 . Each confounder was assessed according to whether it had been considered by the authors, whether the confounder was balanced across the groups, and the degree to which adjustment had been made for the confounder [7] . The risk of confounding bias was considered to be high if the confounder was not described/considered, was imbalanced among the groups, or was not adjusted for in the statistical analysis. Review Manager 5.2 was used to present these results ( Fig. 1 ) [8] .

gr1

Fig. 1 Risk-of-bias assessment using the Cochrane risk-of-bias tool. ASA = American Society of Anesthesiologists. fx1 = High risk of bias. fx2 = Low risk of bias; the variable was either balanced between the groups (assessed as no or small imbalance) or was adjusted for in the analysis. fx3 = Unclear risk of bias.

2.4. Data analysis

A narrative synthesis was performed [9] . Descriptive statistics were used to summarize baseline characteristics data. For continuous outcomes, data were summarized using mean (plus or minus standard deviation, if available) and median (plus or minus interquartile range, if available); for categorical outcomes, data were summarized using proportions. For summarizing outcome data, categorical outcomes were presented as proportions at 5- and 10-yr time points following surgery based on crude point estimates as reported by authors, with level of significance set at 5%. Outcomes at other time points were narratively described. For time-to-event data reported by authors using univariable or multivariable Cox regression analysis, data were summarized as hazard ratios and 95% confidence intervals.

3. Evidence synthesis

3.1. Quantity of evidence identified and characteristics of included studies

A total of 1897 abstracts were identified by the search ( Fig. 2 ). Of these abstracts, 38 were selected for full-text screening. One additional study was identified through reference searching. After full-text screening, 23 studies met the inclusion criteria [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], and [32]. Seven studies were reported only in the form of conference meeting abstracts, while 16 studies were reported in full-text papers. With one exception, all studies were retrospective comparative studies. Sixteen studies were single-center studies, of which eight studies used a historical cohort as the control group, and seven studies were multicenter studies.

gr2

Fig. 2 Flow diagram of studies identified, excluded, and included.

3.2. Risk-of-bias and confounding assessment of included studies

RoB and confounding assessment for each of the individual studies was performed, and the results are presented in Figure 1 . Because of the retrospective design in 22 of 23 studies, there was high or unclear RoB across all domains. The issue of confounding was also poorly addressed by the majority of studies, as it was unclear in most studies if any of the confounding factors had been considered, either prospectively or retrospectively through statistical adjustment.

3.3. Results of comparisons of interventions

3.3.1. No lymph node dissection versus lymph node dissection
3.3.1.1. Study characteristics

A total of seven studies comparing LND with no LND were identified, including a total of 13 833 patients ( Table 1 a) [10], [11], [12], [13], [14], [15], and [16]. The intervention differed among the studies and included any LND [10], [14], and [15], L-LND [13] , S-LND [11], [12], and [16], E-LND [16] , or SE-LND [16] .

Table 1 (a) Descriptive outcomes and (b) oncologic outcomes in patients undergoing no lymphadenectomy (LND) versus any LND

A.
  LE Type of LND Number of patients Follow-up duration (IQR/range) pN+, no. (%) pT stage, no. (%) Neoadjuvant or adjuvant therapy, no. (%)
    C I C I C I C I C I C I
Liu et al., 2011 [10] 3 No LND Any 334 1606 NR N/A NR NR NR
Isaka et al., 1985 [11] 4 No LND Standard 15 80 40 mo (range: 5-143) 40 mo (range: 2-110) N/A 9 (11) ≤pT2: 10 (67)

>pT2: 5 (33)
≤pT2: 55 (69)

>pT2: 25 (31)
NR Neoadjuvant rad: 58 (72)
Miyakawa et al., 1985 [12] 4 No LND Standard 45 65* NR N/A NR ≤cT2: 6 (13)

>cT2: 24 (53)

cTx: 15 (33)
≤cT2: 26 (37)

>cT2: 38 (54) cTx: 6 (9)
NR
Yuasa et al., 1988 [13] 4 No LND Limited 8 22 Minimum 1 yr N/A NR NR NR
Abdollah et al., 2012 [14] 3 No LND Any 2789 8394 NR N/A 2182 (26) ≤pT2: 1787 (64) >pT2: 1002 (36) ≤pT2: 4157 (49)

>pT2: 4237 (51)
NR
Zhang et al., 2013 [15] 4 No LND Any 24 63 NR N/A NR NR NR
Brunocilla et al., 2013 [16] 3 No or limited LND Standard 116--> 19 No LND--> 97 L-LND 94 Mean: 59.2 mo (range 1-171) 26 (22) 28 (30) NR Excluded
    No or limited

LND
Extended/superextended 116--> 19 No LND--> 97 L-LND 62--> 39 E-LND--> 23 SE-LND Mean: 59.2 mo (range 1-171) 26 (22) 19 (31) NR Excluded
B.
  LND comparator OS (%) RFS/DFS (%) CSS/DSS (%) Multivariable Cox regression analysis
    5 yr 10 yr 5 yr 10 yr 5 yr 10 yr HR 95% CI p value
Liu et al. [10] No LND NR NR NR NR NR NR NR NR NR
  Any LND NR NR NR NR NR NR NR NR NR
Isaka et al. [11] No LND 25.0 NR NR NR NR NR NR NR NR
  Standard 64.0, p < 0.05 NR NR NR NR NR NR NR NR
Miyakawa et al. [12] No LND 35.0 NR NR NR NR NR NR NR NR
  Standard 66.0, p < 0.05 NR NR NR NR NR NR NR NR
Yuasa et al. [13] No LND 50.0 NR NR NR NR NR NR NR NR
  Limited 67.8, p < 0.01 NR NR NR NR NR NR NR NR
Abdollah et al. [14] No LND ±41 * 27.2 * NR NR ±58 52.5 Cancer-specific mortality **

All patients, 1.33

pTa–pTis, 2.09

pT1, 1.60

pT2, 1.68

pT3, 1.15

pT4, 1.11


1.24–1.44

1.16–3.79

1.18–2.17

1.47–1.91

1.01–1.33

0.96–1.28


<0.01

<0.05

<0.05

<0.01

NS

NS
  Any LND ±47, p < 0.01 * 34.1, p < 0.01 * NR NR ±61, p < 0.01 57.5, p < 0.01 1.00 (reference)
Zhang et al. [15] No LND NR NR NR NR NR NR NR NR NR
  Any LND NR NR NR NR NR NR NR NR NR
Brunocilla et al. [16] No/limited NR NR NR NR ±50 ±35 1.00 (reference)
  1. Standard NR NR NR NR ±60, p = 0.010 ±75, p = 0.010 CSS

Total cohort, 0.99
0.55–1.35 0.49
  2. Extended/superextended NR NR NR NR ±78, p = 0.010 ±75, p = 0.010 CSS

Total cohort, 0.46
0.37–0.89 0.036

* Overall mortality.

** Adjusting for age, gender, race tumor grade, and year of cystectomy.

* 70 patients were included of whom 65 patients underwent no LND.

C = control group; E-LND = extended LND; I = intervention group; IQR = interquartile range; LE = level of evidence; L-LND = limited LND; LND = lymphadenectomy; N/A = not applicable; NR = not reported; rad = radiotherapy; S-LND = standard LND; SE-LND = superextended LND.

More details are available in the full table online.

CI = confidence interval; CSS = cancer-specific survival; DFS = disease-free survival; DSS = disease-specific survival; HR = hazard ratio; LND = lymphadenectomy; NR = not reported; NS = not significant; OS = overall survival; RFS = recurrence-free survival.

The ± symbol indicates that the Kaplan-Meier curve was used to estimate the percentage.

3.3.1.2. Oncologic outcomes

Table 1 b summarizes the oncologic outcomes comparing no LND versus any LND. All studies reported a benefit for LND in at least one oncologic outcome. Liu et al. [10] did not report any numerical data but stated that LND was associated with improved OS and DFS in pT1 patients only compared with no LND.

3.3.1.3. Perioperative outcomes

No studies reported on perioperative outcomes.

3.3.2. Limited lymph node dissection versus standard lymph node dissection

No studies were identified for comparison of limited LN dissection and standard LN dissection.

3.3.3. Limited lymph node dissection versus (super)extended lymph node dissection
3.3.3.1. Study characteristics

Five studies addressed this question involving a total of 1 394 patients ( Table 2 a) [17], [18], [19], [20], and [21]. Brossner et al. [21] focused on perioperative outcomes. Bostrom et al. [19] compared L-LND with E-LND; however, an unknown number of patients in the E-LND group underwent SE-LND, and >50% of patients in the L-LND group did not undergo LND at all.

Table 2 (a) Descriptive outcomes and (b) oncologic outcomes in patients undergoing limited lymphadenectomy (LND) versus (super)extended LND

A.
  LE Type of LND Number of patients Follow-up duration (IQR/range) pN+, no. (%) pT stage, no. (%) Neoadjuvant or adjuvant therapy
    C I C I C I C I C I C I
Hori et al., 2013 [17] 4 Limited Extended 53 47 NR 10 (19) 14 (30) NR NR
Holmer et al., 2009 [18] 4 Limited Extended 69 101 Median: 94 mo (range: 61–122) Median: 38 mo (range: 13–70) 12 (17) 38 (38) ≤pT2: 46 (67) >pT2: 23 (33) ≤pT2: 53 (52) >pT2: 48 (48) Neoadj: Excluded Adj chemo: 13% vs 16%
Bostrom et al., 2011 [19] 4 Limited Extended or superextended 563 NR NR (7) NR (26) NR Neoadj: Excluded Adj chemo: 1% vs 21%
Jensen et al., 2012 [20] 4 Limited Standard, extended or superextended 204--> 202 L-LND--> 2 no LND 265--> 170 SE-LND--> 46 E-LND--> 49 S-LND Median: 113 mo (range: 86–143) Median: 45 mo (range: 24–84) 43 (21) 61 (23) ≤pT2: 112 (55) >pT2: 92 (45) ≤pT2: 160 (60) >pT2: 105 (40) Excluded
Brossner et al., 2004 [21] 3 Limited Superextended 46 46 30 d 10 (22) 18 (39) ≤pT3a: 24 (52) pT3b–pT4: 22 (48) ≤pT3a 28 (61) pT3b–pT4b 18 (39) NR
B.
  LND comparator OS (%) RFS/DFS (%) CSS/DSS (%) Multivariable Cox regression analysis
    5 yr 10 yr 5 yr 10 yr 5 yr 10 yr HR 95% CI p value
Hori et al. [17] Limited 61 NR NR NR 73 NR NR NR NR
  Extended 47, p = 0.65 NR NR NR 50, p = 0.27 NR NR NR NR
Holmer et al. [18] Limited NR NR ±66 ±65 ±66 No cases 1.00 (reference)
  Extended NR NR ±75, p = 0.27 No cases, p = 0.27 ±73, p = 0.45 No cases Disease-specific mortality *

All patients, 0.81

≤pT2, 0.80

>pT2, 0.54

RFS *

All patients, 0.73

≤pT2, 0.88

>pT2, 0.42
0.44–1.47

0.28–2.32

0.26–1.14

0.41–1.30

0.34–2.30

0.20–0.88
0.48

0.68

0.10



0.28

0.79

0.022
Bostrom et al. [19] Limited NR NR NR NR NR NR 1.00 (reference) - -
  Extended or superextended NR NR NR NR NR NR DSS

All patients, 0.53
0.31–0.93 0.026
Jensen et al. [20] Limited All patients: 55

≤pT2: 77

>pT2: 43

LN negative: 66

LN positive: 12
NR All patients: 62

≤pT2: 83

>pT2: 54

LN negative: 75

LN positive: 8
NR All patients: 67

≤pT2: 88

>pT2: 62

LN negative: 80

LN positive: 14
NR 1.00 (reference) - -
  Standard, extended, or superextended All patients: 67, p < 0.05

≤pT2: 77, NS

>pT2: 71, p < 0.05

LN negative: 75, NS

LN positive: 38, p < 0.05
NR All patients: 64, NS

≤pT2: 80, NS

>pT2: 61, NS

LN negative: 74, NS

LN positive: 29, p < 0.05
NR All patients: 72, p < 0.05

≤pT2: 88, NS

>pT2: 62, p < 0.05

LN negative: 80, NS

LN positive: 14, p < 0.05
NR RFS

All patients, 0.90

DSS

All patients, 0.71

OS

All patients, 0.60
0.65–1.24

0.50–1.01

0.45–0.81
0.51

0.06

 < 0.01
Brossner et al. [21] Limited NR NR NR NR NR NR NR NR NR
  Superextended NR NR NR NR NR NR NR NR NR

* Adjusting for sex, age, and adjuvant chemotherapy.

C = control group; E-LND = extended LND; I = intervention group; IQR = interquartile range; LE = Level of evidence; LN = lymph node; LND = lymphadenectomy; L-LND = limited LND; NR = not reported; S-LND = standard LND; SE-LND = superextended LND.

More details are available in the full table online.

CI = confidence interval; CSS = cancer-specific survival; DFS = disease-free survival; DSS = disease-specific survival; HR = hazard ratio; LN = lymph node; LND = lymphadenectomy; NR = not reported; NS = not significant; OS = overall survival; RFS = recurrence-free survival.

The ± symbol indicates that the Kaplan-Meier curve was used to estimate the percentage.

3.3.3.2. Oncologic outcomes

Table 2 b summarizes the oncologic outcomes comparing L-LND with E/SE-LND. Of the five studies included, three studies reported improvement of at least one oncologic outcome for E/SE-LND [18], [19], and [20]. Brossner et al. [21] did not report oncologic outcomes, while Hori et al. [17] found no statistically significant difference in oncologic outcomes for L-LND and E-LND performing univariable analysis.

3.3.3.3. Perioperative outcomes

Jensen et al. [20] reported no prolonged operative time for E-LND compared with L-LND (mean: 306 vs 302 min; p = 0.92). Brossner et al. [21] , however, reported prolonged operative time for SE-LND compared with L-LND (median: 330 vs 277 min; p < 0.01). This study reported no differences in number of blood units transfused (1.15 vs 0.38, respectively; p = 0.37), lymphoceles (none in both groups), 30-d complication rate (11% vs 9%, respectively; p = 0.28), or 30-d mortality (three vs one event, respectively; p = 0.57) [21] .

3.3.4. Standard lymph node dissection versus (super)extended lymph node dissection
3.3.4.1. Study characteristics

Nine studies were identified involving 3104 patients ( Table 3 a) [22], [23], [24], [25], [26], [27], [28], [29], and [30]. Four studies used data from the Cleveland Clinic [22], [23], [25], and [28]. Abd El-Latif et al. [23] differed from their previous study [22] by extending the study period by 2 yr (2004–2010 vs 2006–2010). One study specifically looked at the outcomes of laparoscopic LND [25] .

Table 3 (a) Descriptive outcomes and (b) oncologic outcomes in patients undergoing standard lymphadenectomy (LND) versus (super)extended LND

A.
  LE Type of LND Number of patients Follow-up duration (IQR/range) pN+, no. (%) pT stage, no. (%) Neoadjuvant or adjuvant therapy
    C I C I C I C I C I C I
Abd-El-Latif et al., 2011 [22] 3 Standard Extended or superextended 122 199 Median: 24 mo (IQR 12–36) Excluded NR Neoadj: 17 (5%) Adj: NR
Abd-El-Latif et al., 2012 [23] 3 Standard Extended or superextended 183 240 Median: 24 mo NR NR NR
Dharaskar et al., 2011 [24] 4 Standard (a. en bloc; b. LN packets) Extended 51 27 a. Median: 24 mo (range: 0–49) b. Median: 14 mo (range: 0–43) Median: 6 mo (range: 0–37) 13 (26) 7 (26) ≤pT2: 32 (63) >pT2: 19 (37) ≤pT2: 20 (74) >pT2:

7 (26)
NR
Finelli et al., 2004 [25] 3 Standard Extended 11 11 Mean: 11 mo (range: 2–43) 3 (27) 3 (27) ≤pT2: 5 (45) >pT2: 6 (55) ≤pT2: 9 (82) >pT2:

2 (18)
Neoadj: NR Adj chemo: 2 (9%)
Poulsen et al., 1998 [26] 4 Standard Extended 68 126 Median: 5.14 yr (range: 0.17–7.94) Median: 1.96 yr (range: 0.29–4.73) 15 (22) 35 (28) ≤pT2: 34 (50) >pT2: 33 (49) pTx: 1 (1) ≤pT2: 55 (43) >pT2: 69 (55)

pTx: 2 (2)
Excluded
Simone et al., 2012 [27] 3 Standard Extended 584 349 NR 187 (32) 107 (31) ≤pT2: 271 (46)

>pT2: 313 (54)
≤pT2: 192 (55) >pT2: 157 (45) Neoadj: Excluded Adj chemo: 101 (11%)

Adj rad: 8 (0.8%)
Dhar et al., 2008 [28] 3 Standard Extended 336 322 For RFS: 25 mo (range: 1.1–166) For OS: 36 mo (range: 1.1–166) For RFS: 40 mo (range: 1–229)

For OS: 51 mo (range: 1–229)
44 (13) 83 (26) ≤pT2: 200 (60)

>pT2: 136 (40)
≤pT2: 150 (47.0) >pT2: 172 (53.0) Neoadj: Excluded Adj: NR
Abol-Enein et al., 2011 [29] 3 Standard Superextended 200 200 50.2 mo (IQR: 69.0) for patients alive at last follow–up 48 (24) 48 (24) ≤pT2: 61 (31) >pT2: 139 (70) ≤ pT2: 70 (35) >pT2: 129 (65) 0
Wang, 2013 [30] 3 Standard Extended 42 33 NR NR NR Excluded
B.
  LND comparator OS (%) RFS/DFS (%) CSS/DSS (%) Multivariable Cox regression analysis
    5 yr 10 yr 5 yr 10 yr 5 yr 10 yr HR 95% CI p value
Abd El-Latif et al. [22] Standard NR NR NR NR NR NR 1.00 (reference) - -
  Extended or superextended NR NR NR NR NR NR OS

All patients, 2.50

CSS

All patients, 2.00

RFS

All patients, 2.60


0.98–6.5



0.4–11.1



0.7–9.9


NR



NR



NR
Abd El-Latif et al. [23] Standard ±58 NR NR NR NR NR NR NR NR
  Extended or superextended ±40, p = 0.14 NR NR NR NR NR NR NR NR
Dharaskar et al. [24] Standard No cases No cases NR NR NR NR NR NR NR
  Extended No cases No cases NR NR NR NR NR NR NR
Finelli et al. [25] Standard NR NR NR NR NR NR NR NR NR
  Extended NR NR NR NR NR NR NR NR NR
Poulsen et al. [26] Standard NR NR All patients: 56

≤pT3: ** 85

>pT3: 27

pN0: 71

pN+: 7
NR NR NR NR NR NR
  Extended NR NR All patients: 62, p = 0.33

≤pT3: ** 64, p < 0.02

>pT3: 39, p = 0.87

pN0: 90, p < 0.02

pN+: 24, p = 0.15
NR NR NR NR NR NR
Simone et al. [27] Standard NR NR 42.6 NR 50.9 NR 1.00 (reference)
  Extended NR NR 63.1, p < 0.01 NR 68.8, p < 0.01 NR DFS

All patients, 0.51 *

pT2, 0.41

pT3, 0.55

PT4, 0.33

pN0, 0.63

pN1, 0.19

pN2, 0.40

CSS

All patients, 0.56 *

pT2, 0.40

pT3, 0.65

PT4, 0.33

pN0, 0.54

pN1, 0.15

pN2, 0.45


0.40–0.65

0.22-0.78

0.40–0.77

0.20–0.55

0.4– 0.91

0.08–0.49

0.24–0.67



0.42–0.73

0.19–0.83

0.44–0.94

0.19–0.58

0.30–0.95

0.05–0.41

0.25–0.80


<0.01

0.004

0.001

<0.001

0.011

<0.001

<0.001



<0.01

0.011

0.019

<0.001

0.034

<0.001

<0.001
Dhar et al. [28] Standard pT2N0: 68

pT2N0–2: 64

pT3N0: 26

pT3N0–2: 22
NR pT2N0: 67

pT2N0–2: 63

pT3N0: 23

pT3N0–2: 19
NR NR NR NR NR NR
  Extended pT2N0: 66, p = 0.12

pT2N0–2: 61, p = 0.10

pT3N0: 46, p = 0.002

pT3N0–2: 42, p = 0.002
NR pT2N0: 77, p = 0.12

pT2N0–2: 71, p = 0.22

pT3N0: 57, p < 0.0001

pT3N0–2: 49, p < 0.0001
NR NR NR NR NR NR
Abol-Enein et al. [29] Standard NR NR All patients: 54.7

LN−: 66.2

LN+: 28.2
NR NR NR DFS, 1.45 *** 1.06–1.99 0.02
  Superextended NR NR All patients: 66.6, p = 0.04

LN−: 72.3, p = 0.24

LN+: 48.0, p = 0.029
NR NR NR 1.00 (ref) - -
Wang [30] Standard NR NR NR NR 59.0 NR NR NR NR
  Extended NR NR NR NR 77.0, p = 0.08 NR NR NR NR

* HR was recalculated using the same reference group (standard LND) as in the subgroup analysis.

** ≤pT3a indicated organ-confined disease in this study.

*** Adjusting for pT stage, pN stage, age, gender, tumor grade, and histology.

Adj = adjuvant; C = control group; chemo = chemotherapy; I = intervention group; IQR = interquartile range; LE = level of evidence; LN = lymph node; LND = lymphadenectomy; neoadj = neoadjuvant; NR = not reported; OS = overall survival; rad = radiotherapy; RFS = recurrence-free survival.

More details are available in the full table online.

CI = confidence interval; CSS = cancer-specific survival; DFS = disease-free survival; DSS = disease-specific survival; HR = hazard ratio; LN = lymph node; LND = lymphadenectomy; NR = not reported; OS = overall survival; RFS = recurrence-free survival.

The ± symbol indicates that the Kaplan-Meier curve was used to estimate the percentage.

3.3.4.2. Oncologic outcomes

Table 3 b summarizes the oncologic outcomes of S-LND compared with E/SE-LND, and contradicting results were reported. Four studies noted no difference in oncologic outcomes between S-LND and E-LND [22], [23], [24], and [30], although only one study reported on data from multivariable analysis [22] . Three studies reported a benefit for E-LND, and one study reported a benefit for SE-LND for at least one oncologic outcome. Subgroup analysis in these studies revealed no consistent subgroup that benefited most from E-LND. For example, Poulsen et al. [26] reported an RFS benefit for E-LND in patients with organ-confined disease, while Dhar et al. [28] found an RFS benefit only for patients with >pT2 disease.

3.3.4.3. Perioperative outcomes

Poulsen et al. [26] reported a lymphocele rate of 1.6% for E-LND and 1.5% for S-LND. One patient in the E-LND group (0.8%) died perioperatively from complications unrelated to LND. Finelli et al. [25] , performing laparoscopic LND, reported an estimated increase in operative time, from 30 to 45 min for S-LND to 90 min for E-LND (no p value reported).

3.3.5. Extended lymph node dissection versus superextended lymph node dissection
3.3.5.1. Study characteristics

Two multi-institutional studies, involving 1462 patients, were included ( Table 4 a) [31] and [32].

Table 4 (a) Descriptive outcomes and (b) oncologic outcomes in patients undergoing extended lymphadenectomy (LND) versus superextended LND

A.
  LE Type of LND Number of patients Follow-up duration (IQR/range) pN+, no. (%) pT stage, no. (%) Neoadjuvant therapy Adjuvant therapy, no. (%)
    C I C I C I C I C I C I C I
Simone et al., 2012 [31] 3 Extended Superextended 503 NR NR NR Excluded Excluded
Zehnder et al., 2011 [32] 3 Extended Superextended 405 554 Median: 9.9 yr (range: 0–22.3) Median: 10.9 yr (range: 0–24.1) 114 (28) 195 (35) pT2: 169 (42) pT3: 236 (58) pT2: 253 (46) pT3: 301 (54) Excluded Excluded Chemo: 46 (11) Chemo: 195 (35)
B.
  LND comparator OS (%) RFS/DFS (%) CSS/DSS (%) Multivariable Cox regression analysis
    5 yr 10 yr 5 yr 10 yr 5 yr 10 yr HR 95% CI p value
Simone et al. [31] Extended NR NR ±59 NR NR NR NR NR NR
  Superextended NR NR ±64, p = 0.41 NR NR NR NR NR NR
Zehnder et al. [32] Extended ±54 ±42 ±61 ±59 NR NR NR NR NR
  Superextended ±50, p = 0.45 ±40, p = 0.45 ±61, p = 0.75 ±59, p = 0.75 NR NR NR NR NR

C = control group; chemo = chemotherapy; I = intervention group; IQR = interquartile range; LE = level of evidence; LN = lymph node; LND = lymphadenectomy; NR = not reported.

More details are available in the full table online.

CI = confidence interval; CSS = cancer-specific survival; DFS = disease-free survival; DSS = disease-specific survival; HR = hazard ratio; LND = lymphadenectomy; NR = not reported; OS = overall survival; RFS = recurrence-free survival.

The prefix ± indicates that the Kaplan-Meier curve was used to estimate the percentage.

3.3.5.2. Oncologic outcomes

Table 4 b summarizes the oncologic outcomes comparing E-LND with SE-LND. Both studies reported no statistically significant difference in survival outcomes between E-LND and SE-LND, irrespective of tumor stage or nodal status.

3.3.5.3. Perioperative outcomes

No studies reporting on perioperative outcomes were identified.

3.4. Discussion

3.4.1. Principal findings

To the best of our knowledge, this study represents the most robust literature review focusing on the impact of the anatomic extent of LND on post-RC oncologic and perioperative outcomes. The findings of this study suggest that in terms of oncologic outcomes, any extent of LND is better than no LND for patients undergoing RC for MIBC. Additionally, E-LND might improve oncologic outcomes compared with lesser degrees of dissection, although extending the dissection beyond E-LND is unlikely to yield any further benefits. With respect to perioperative outcomes, a secondary outcome of this study, SE-LND resulted in increased operative time compared with less extended LND templates but does not appear to substantially increase postoperative morbidity.

3.4.2. Clinical implications of our study findings

The data in this study support the routine performance of LND in patients undergoing RC. Whether the reported beneficial oncologic outcomes are a result of stage migration (the so-called Will Rogers phenomenon), represent a true therapeutic benefit of LND, or a combination of both remains uncertain. There is, however, a clear staging role of LND, as supported by LN mapping studies [33] and [34]. Thus, in spite of the lack of RCTs, the current evidence base is sufficiently convincing to recommend LND for patients undergoing RC for MIBC.

While L-LND may contribute to disease staging, performing LND outside the true pelvis (ie, S-LND or more extended LND) should be considered a potential therapeutic intervention, as skip nodal lesions are rare and therefore unlikely to contribute to disease staging [33] and [34]. To date, however, questions remain about the potential therapeutic value of LND and what extent of LND is the most effective. Based on the current data, consisting of retrospective studies with a significant RoB and confounding, the evidence base is not strong enough to provide firm recommendations regarding the most optimal extent of LND. Conversely, these studies are currently the best available evidence and fairly consistently report an oncologic benefit for E-LND compared with less extended LND templates. In addition, E-LND appears not to increase perioperative morbidity. Collectively, there is accumulating evidence that E-LND may be beneficial for patients undergoing RC for MIBC, and can be therefore recommended for patients undergoing RC for MIBC.

3.4.3. How does this systematic review compare with other recent reviews?

To our knowledge, two systematic reviews on the importance of LND in BCa have been published [35] and [36]. Fan et al. [36] performed a systematic review and meta-analysis of studies comparing E-LND and nonextended LND and its impact on RFS. The authors concluded that E-LND was associated with improved RFS compared with nonextended LND. Subgroup analysis revealed that patients with ≥pT3 BCa, independent of LN status, benefit from E-LND. Tilki et al. [35] performed a systematic review only and concluded that the extent of LND may influence DFS after RC, independent of LN status and pT stage.

The outcomes of our present study are in line with these reviews. However, there are important methodological differences that deserve discussion. Tilki et al. [35] included studies using the LN count as a surrogate for the extent of LND. Although an association between LN count, the extent of LND, or even post-RC outcomes has been suggested [37], [38], and [39], using the LN count as a surrogate for the extent of LND has limitations, as acknowledged by the authors. Differences in surgical technique, sample processing, and pathologic assessment greatly influence the LN count and consequently affect reproducibility [37], [40], and [41]. The LN count cannot adequately be determined intraoperatively, whereas surgeons can adhere to anatomic templates, making studies comparing LND templates more clinically relevant. For these reasons, only studies describing anatomic templates for the extent of LND were included in our review. In addition, although Tilki et al. [35] described some studies comparing LND templates (references 26, 28, 29, and 32 in Tilki et al.), an additional 19 studies were included in this study, providing a more comprehensive overview of studies comparing different LND templates.

The attempt by Fan et al. [36] to perform a meta-analysis is noteworthy, but the results of this study should be interpreted with caution. Aside from the low-quality studies included in the analysis with its associated bias, differences in the definition of the extent of LND were not adjusted for in this study. Reflecting the lack of consensus on what constitutes an L-LND, S-LND, E-LND, or SE-LND, there was significant heterogeneity in the definition regarding the extent of LND across studies. To illustrate, Abol-Enein et al. [29] and Dhar et al. [28] were both classified as E-LND studies, although the proximal boundaries were the inferior mesenteric artery and crossing of the ureter with the common iliac vessels, respectively. For this reason, we chose to define the LND templates a priori and, if necessary, reclassify accordingly if sufficiently large numbers of studies did not match our chosen definitions. Although the definitions chosen for each of the LND templates may not be universally accepted by all clinicians, their use at least allows for a certain degree of standardization, which enables a comparison of outcomes among different LND templates.

3.4.4. Strengths and limitations of the review

The strength of the current study is the comprehensive literature review that evaluates the impact of the extent of LND on post-RC outcomes using a robust and transparent methodological approach based on Cochrane Review principles and that incorporates the assessment of RoB and confounding, which are essential in any review involving nonrandomized studies. The search strategy was complemented by additional sources for potentially important articles, which included an expert panel (EAU Working Group on MIBC). The review was limited to comparative studies to maintain at least moderate levels of evidence. Throughout the entire review process, peer review was obtained from the expert panel, which represents a reference group of international experts. This approach ensured a comprehensive review of the literature while maintaining methodological rigor and enabled the authors to put into clinical context the relevance and implication of the review findings.

The major limitation of the review is the quality of included studies; except for one prospective study, all studies were retrospective, nonstandardized, comparative studies with high risks of bias and confounding. In particular, selection bias may have affected clinical outcomes (eg, cases with apparent nodal disease intraoperatively in which no LND was performed or less extended LND than anticipated was performed). This review highlights the lack of high-quality and reliable evidence concerning the benefits and harms of LND during RC in terms of oncologic and perioperative outcomes. The results, however, are supported by the fact that these studies are fairly consistent in reporting an oncologic benefit. Currently, two phase 3 RCTs evaluating the impact of different LND templates on survival—one in Germany and one initiated by SWOG (S1011)—are ongoing. The final results of these studies may provide a more definitive answer to some aspects of this important clinical question. Standardization of the LND templates and surgeon expertise, however, are of critical importance for the success of these trials.

4. Conclusions

This systematic review set out to determine the evidence base in regard to the comparative effectiveness of LND in patients undergoing RC for MIBC in terms of oncologic benefits and perioperative outcomes. The findings reveal a lack of randomized studies and an evidence base derived mainly from retrospective studies with significant risks of bias and confounding. Nevertheless, the data indicate that any form of LND produces more favorable oncologic outcomes compared with no LND. There was no evidence that LND results in increased perioperative adverse events compared with no LND. In terms of how different extents of LND influence outcomes, the findings indicate that E-LND might be superior to lesser degrees of dissection from an oncologic perspective; however, further extending the dissection (eg, SE-LND) is not beneficial. The results of ongoing RCTs, it is hoped, will clarify the remaining uncertainties regarding the role of LND during RC for MIBC.


Author contributions: Harman M. Bruins 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: Bruins, Veskimae, Hernandez, Imamura, Dahm, Lam, N’Dow, Witjes.

Acquisition of data: Bruins, Veskimae, Hernandez, Imamura.

Analysis and interpretation of data: Bruins, Veskimae, Hernandez, Imamura, Lam, Witjes.

Drafting of the manuscript: Bruins, Veskimae, Hernandez, Imamura, Stewart, Lam.

Critical revision of the manuscript for important intellectual content: Dahm, Neuberger, Lam, N’Dow, van der Heijden, Compérat, Cowan, De Santis, Gakis, Lebret, Ribal, Sherif, Witjes.

Statistical analysis: Bruins, Lam, Dahm.

Obtaining funding: None.

Administrative, technical, or material support: Stewart, Lam.

Supervision: Lam, Dahm, Witjes.

Other (specify): None.

Financial disclosures: Harman M. Bruins 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: The conflict of interest statements of all members of the EAU Muscle Invasive Bladder Cancer Guideline panel and EAU Guidelines Office can be found at http://www.uroweb.org/guidelines/eau-guidelines-board-and-working-panels/?id=58&gid=39 . All coauthors who are not members of the panels (Bruins, Veskimae, Hernandez, Imamura, Neuberger, Dahm, Stewart) do not have any conflicts of interest.

Funding/Support and role of the sponsor: None.

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Footnotes

a Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands

b Department of Urology, Tampere University Hospital, Tampere, Finland

c Department of Urology, Hospital Universitario Fundación Alcorcón, Madrid, Spain

d Academic Urology Unit, University of Aberdeen, Scotland, UK

e Department of Urology, University of Florida, Gainesville, FL, USA

f Malcom Randall Veterans Affairs Medical Center, Gainesville, FL, USA

g Department of Pathology, Groupe Hospitalier Pitié—Salpêtrière, Paris, France

h Department of Radiology, Queen Alexandra Hospital, Portsmouth, UK

i 3rd Medical Department/LBI-ACR VIEnna—LBCTO and ACR-ITR VIEnna, Kaiser Franz Josef Spital, Vienna, Austria

j Department of Urology, Eberhard-Karls University, Tübingen, Germany

k Department of Urology, Foch Hospital, Suresnes, France

l Department of Urology, Hospital Clinic, University of Barcelona, Barcelona, Spain

m Department of Surgical and Perioperative Science, Umeå University, Umeå, Sweden

lowast Corresponding author. Radboud University Medical Centre, Department of Urology, Geert Grooteplein Zuid 10 (659), P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Tel. +31 24 361 37 35; Fax: +31 24 354 10 31.