ABSTRACT
Pelvic lymph node dissection is an essential component of radical cystectomy (RC) for bladder cancer (BC), but the optimal extent of lymphadenectomy remains uncertain. We conducted a systematic review and meta‐analysis to compare oncologic and perioperative outcomes between extended and non‐extended lymphadenectomy during RC for BC. PubMed/MEDLINE, Embase, and ClinicalTrials. gov were searched up to October 2025 following PRISMA guidelines and PROSPERO registration. Randomized controlled trials (RCTs) and observational studies comparing extended versus non‐extended lymphadenectomy in adults undergoing RC were included. Outcomes included surgery duration, intraoperative blood loss, overall survival (OS), disease‐free survival (DFS), recurrence‐free survival (RFS), and cancer‐specific survival (CSS). Random‐effects meta‐analyses were performed, reporting hazard ratios (HRs) or mean differences (MDs) with 95% confidence intervals (CIs). Risk of bias was assessed using RoB 2.0 and ROBINS‐I, and certainty of evidence using GRADE. Fifteen studies including 5671 patients were analyzed, of which two were RCTs. Extended lymphadenectomy was associated with longer operative time (MD + 26.2 min) and improved DFS (HR: 1.47), but no significant benefit in OS or CSS. Non‐extended lymphadenectomy was associated with higher RFS (HR: 0.79). Heterogeneity was moderate to high, and certainty of evidence was very low for most outcomes and low for OS considering only RCTs. Extended lymphadenectomy during RC increases operative time and may improve DFS; however, the available evidence does not clearly support a consistent oncologic benefit.
Keywords: lymph node excision, pelvic lymph node dissection, radical cystectomy, survival analysis, urinary bladder neoplasms
1. Introduction
Bladder cancer (BC) is the seventh most commonly diagnosed malignancy in men worldwide and ranks tenth in the overall population. Incidence and mortality rates of BC vary across regions and are influenced by several factors, including the prevalence of risk factors—particularly smoking and occupational exposures—public health policies, early diagnosis strategies, and the accessibility and quality of available treatments [1].
For decades, the standard surgical treatment for patients with muscle‐invasive bladder cancer (MIBC) has been radical cystectomy (RC) combined with pelvic lymph node dissection. RC involves removing the bladder along with adjacent organs that may harbor tumors extending beyond the bladder. Pelvic lymphadenectomy is considered an essential component of RC and is strongly recommended by clinical guidelines, including those from the European Association of Urology (EAU) and the American Urological Association (AUA) [2, 3].
Several observational studies have suggested an association between more extensive pelvic lymphadenectomy and improved oncologic outcomes. Proposed explanations include more accurate pathologic staging and removal of occult nodal metastases. However, whether these associations reflect a true therapeutic benefit remains uncertain because observational studies are susceptible to selection bias and residual confounding [4, 5].
The LEA clinical trial evaluated the anatomical extent of lymphadenectomy but found no significant benefit of extended compared to limited lymphadenectomy in terms of recurrence‐free survival (RFS), overall survival (OS), or cancer‐specific survival (CSS). Similarly, the SWOG S1011 study, which compared standard and extended lymphadenectomy, also failed to demonstrate a survival benefit in disease‐free survival (DFS) [2, 6, 7].
However, interpretation of these findings is challenged by variations in the anatomical extent of lymphadenectomy across studies. In bladder cancer, standard pelvic lymph node dissection (PLND) generally includes the obturator, external iliac, and internal iliac nodal regions, extending from the circumflex iliac vein and Cloquet node distally to the common iliac bifurcation proximally, whereas extended PLND additionally encompasses the common iliac and presacral nodal packets up to the aortic bifurcation or the crossing of the ureter over the common iliac vessels [8, 9].
Although the importance of lymphadenectomy in the treatment of BC is well established, there is still a significant gap in the literature regarding the ideal extent of this procedure during RC. To date, no comprehensive meta‐analyses of randomized controlled trials (RCTs) and observational studies have clearly defined the comparative benefits of extended versus non‐extended lymph node retrieval. Given these discrepancies and the lack of a clear consensus regarding the oncological value of more extensive nodal dissection, we sought to compare oncologic outcomes between extended and non‐extended lymphadenectomy performed during RC in patients with BC through a systematic review of the literature.
2. Methods
2.1. Literature Search Strategy
This systematic review was conducted in full accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement [10], and was registered in the PROSPERO international database of prospectively registered systematic reviews on November 4, 2024 (CRD42024605952).
The research question was formulated using the PICOS (Patient, Intervention, Comparator, Outcome, Study design) framework as follows: Does extended lymphadenectomy provide better oncologic outcomes compared to non‐extended lymphadenectomy?
The search strategy used was: ((‘Bladder Tumors’) OR (‘Bladder Tumor’) OR (‘Tumor, Bladder’) OR (‘Tumors, Bladder’) OR (‘Neoplasms, Bladder’) OR (‘Urinary Bladder Cancer’) OR (‘Cancer, Urinary Bladder’) OR (‘Bladder Cancer’) OR (‘Bladder Cancers’) OR (‘Cancer, Bladder’) OR (‘Cancer of Bladder’) OR (‘Cancer of the Bladder’)) AND ((Lymphadenectomy) OR (Lymphadenectomies) OR (‘Lymph Node Dissection’)).
We searched the following databases up to October 2025: PubMed/MEDLINE, Embase, and ClinicalTrials. gov. We also reviewed the references of the included studies.
2.2. Study Screening, Selection and Extraction
We included RCTs, prospective and retrospective observational studies without language restrictions. Reviews, case reports, case series, letters to the editor, and editorials were excluded.
All records were screened by two independent reviewers. Duplicate records were removed, and studies were initially screened for title and abstract. Disagreements were solved through discussion with a third reviewer. Full texts were obtained for studies deemed potentially relevant during the title and abstract screening phase. Full texts were then screened using the same methodology Studies were included if they met the following criteria: prospective or retrospective design, reporting complete or partial data, and involving adult patients who underwent non‐extended or extended lymphadenectomy for BC.
For each eligible study, reviewers worked independently to extract data in duplicate with resolution of disagreements by discussion or adjudication by a third reviewer. The following variables were extracted from studies with complete or partial results: study duration and design, patient demographic and clinical characteristics, surgery‐related data, clinical and pathological staging, and oncologic outcomes.
2.3. Data Manipulation and Statistical Analysis
Extended and super‐extended templates were grouped together for the purposes of quantitative analysis, as were standard and limited templates. All extracted data were systematically organized in an Excel spreadsheet for detailed analysis. Meta‐analyses with a random‐effects model were performed for the following outcomes: number of lymph nodes removed, number of positive lymph nodes, lymph node density, operative time, DFS, CSS, RFS, and OS. For time‐to‐event outcomes, hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. For continuous variables, mean differences (MDs) and standard deviations (SDs) were used. Data presented as medians and interquartile ranges (IQRs) were converted to means and SDs. Ranges were converted to SDs. Both conversions used validated formulas [11, 12, 13].
Statistical heterogeneity was assessed using the I 2 statistic, with values > 75% indicating high heterogeneity, > 50% indicating moderate heterogeneity and < 30% suggesting low heterogeneity. All meta‐analyses were conducted using Review Manager (RevMan) version 5.4 (The Cochrane Collaboration).
2.4. Quality Assessment and Risk of Bias
The risk of bias for RCTs was assessed using the Cochrane Risk of Bias tool (RoB 2.0) [12], and for observational studies, the Risk Of Bias In Non‐randomised Studies ‐ of Interventions tool (ROBINS‐I) [14, 15] was used.
2.5. Certainty of Evidence (GRADE)
The certainty of evidence for each outcome was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach [16]. Evidence from RCTs was initially rated as high certainty and evidence from observational studies as low certainty, and then downgraded based on risk of bias, inconsistency, and imprecision, as applicable. Indirectness was assessed based on the alignment between study populations, interventions, comparators, and outcomes with the review question and was not considered serious for any outcome. Publication bias was not formally assessed because fewer than 10 studies were available for each outcome. A Summary of Findings table was generated to present the certainty of evidence for the main outcomes.
3. Results
3.1. Study Selection
We initially identified 6670 records. After removing 3624 duplicates, 3046 records were screened by title and abstract. Of these, 2910 did not meet inclusion criteria. The full texts of the remaining 136 records were assessed for eligibility, leading to the inclusion of 15 studies in the final analysis. Among the included studies, two were RCTs, one was a prospective cohort, and twelve were retrospective cohorts. The PRISMA flow diagram summarizing the search and selection processes are shown in Figure 1.
Figure 1.
Prisma flow diagram.
3.2. Baseline Characteristics of Included Studies
We included 15 studies with both retrospective and prospective designs, including two RCTs. A total of 5671 participants were included. Of these, 2607 underwent extended lymphadenectomy and 3064 underwent non‐extended lymphadenectomy, with 19% patients with positive nodes in both groups (509 and 610, respectively). Regarding tumoral staging, most patients had pT3/pT4 disease (n = 2487, 43.8%). Baseline characteristics are summarized in Table 1. Staging, surgical and follow‐up characteristics are shown in Table 2.
Table 1.
Baseline characteristics.
| Author, year | Country | Study design | Comparisons | Participants | Age (years) | Male | |||
|---|---|---|---|---|---|---|---|---|---|
| Extended | Non extended | Extended | Non extended | Extended | Non extended | ||||
| Poulsen et al. [22] | Denmark | Retrospective | Extended X Limited | 126 | 68 | 58.2 (10.6) | 57.7 (9.3) | 102 (80.9%) | 55 (80.9%) |
| Finelli et al. [32] | USA | Retrospective | Extended X Limited | 11 | 11 | — | — | — | — |
| Dhar et al. [24] | Switzerland and USA | Retrospective | Extended X Limited | 322 | 336 | 64.5 (9.6) | 59.8 (9.0) | 251 (78.0%) | 265 (79.0%) |
| Holmer et al. [28] | Sweden | Retrospective | Extended X Limited | 101 | 69 | 65.3 (7.4) | 63.5 (8.5) | 83 (82.2%) | 56 (81.2%) |
| Abol‐Enein et al. [18] | Egypt | Prospective | Extended X Standard | 200 | 200 | 55.0 (8.96) | 50.5 (8.96) | 162 (81%) | 155 (77.5%) |
| Dharaskar et al. [23] | India | Retrospective | Extended X Standard | 27 | 51 | — | — | 23 (85.2%) | 47 (92.1%) |
| Simone et al. [27] | Italy | Retrospective | Extended X Standard | 349 | 584 | 65.4 (8.7) | 66.9 (9.2) | 309 (88.5%) | 502 (86%) |
| Jensen et al. [21] | Denmark | Retrospective | Extended X Limited | 265 | 204 | 61.8 (9.0) | 61.25 (8.2) | 208 (78.4%) | 156 (76.6%) |
| Brunocilla et al. [20] | Italy | Retrospective | Extended X Standard and Limited | 39 | 191 | 68.3 (8.3) | 234 (83.0%) | ||
| Abdi et al. [17] | Canada | Retrospective | Extended X Standard | 105 | 105 | 68.4 (9.0) | 68.7 (10.3) | 78 (74.3%) | 84 (80%) |
| Xuehereti et al. [25] | China | Retrospective | Extended X Standard | 91 | 48 | 64.6 (11.7) | 117 (84.2%) | ||
| Gschwend et al. [6] | Germany | RCT | Extended X Limited | 198 | 203 | 66.7 (11.2) | 67.3 (9.0) | 151 (76%) | 163 (80%) |
| Deimling et al. [26] | Austria | Retrospective | Extended X Standard | 255 | 255 | 66.0 (9.7) | 71.0 (10.4) | 410 (73%) | 303 (74%) |
| Lerner et al. [7] | USA | RCT | Extended X Standard | 292 | 300 | 66.8 (9.6) | 66.0 (9.1) | 236 (81%) | 234 (78%) |
| Al Nader et al. [19] | Germany | Retrospective | Extended X Limited | 203 | 439 | 65.8 (10.6) | 67.0 (10.3) | 165 (81.3%) | 355 (80.9%) |
Table 2.
Staging, surgical and follow‐up characteristics.
| Author, year | pN + | pT stage | Lymph nodes removed | Positive lymph nodes | Follow‐up (months) | Neoadjuvant or adjuvant therapy | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Extended | Non extended | Extended | Non extended | Extended | Non extended | Extended | Non extended | Extended | Non extended | Extended | Non extended | |
| Poulsen et al. [22] | 36 (28.6%) | 15 (22.1%) |
pT0‐pTa: 9 (7.1%) pTis 17 (13.5%) pT1: 16 (12,7%) pT2: 13 (10.3%) pT3a: 17 (13.5%) pT3b: 45 (35.7%) pT4a: 5 (4%) pT4b: 2 (1.6%) |
pT0‐pTa: 4 (5.9%) pTis 4 (5.9%) pT1: 17 (25%) pT2: 9 (13.2%) pT3a: 11 (16.2%) pT3b: 20 (29.4%) pT4a: 1 (1.5%) pT4b: 1 (1.5%) |
31.5 (11.24) | 15.75 (5.3) | — | — | 26.82 (10.33) | 54.75 (17.71) | CT after recurrence | |
| Finelli et al. [32] | 3 (27%) | 3 (27%) |
pT1: 5 (45.4%) pT2: 4 (36.3%) pT3: 2 (18.1%) pT4: 0 |
pT1: 4 (36.3%) pT2: 1 (9.0%) pT3: 5 (45.4%) pT4:1 (9.0%) |
19.5 (7.53) | 5.5 (4.4) | — | — | 11.0 (10.99) | 66% of the patients with positive lymph nodes underwent adjuvant CT | ||
| Dhar et al. [24] | 84 (26%) | 44 (13%) |
pT2: 150 (46.5%) pT3: 172 (53.4%) |
pT2: 200 (59.5%) pT3: 136 (40.5%) |
24.25 (5.71) | 14.25 (5) | 7.75 (4.33) | 2 (0.69) | — | — | No other therapies | |
| Holmer et al. [28] | 38 (37.6%) | 12 (17.4%) |
pT0: 0 (0.0%) pTa: 5 (5.4%) pTis: 7 (7.5%) pT1: 10 (10.8%) pT2: 23 (24.7%) pT3: 40 (43%) pT4a: 8 (8.6%) |
pT0: 10 (14.5%) pTa: 2 (2.9%) pTis: 8 (11.6%) pT1: 7 (10.1%) pT2: 19 (27.5%) pT3: 16 (23.2%) pT4a: 7 (10.1%) |
38.25 (12.6) | 13.25 (7.4) | — | — | 39.75 (11.4) | 92.75 (12.9) | Adjuvant CT: 16 (15.8%) | Adjuvant CT: 9 (13%) |
| Abol‐Enein et al. [18] | 48 (24%) | 48 (24%) |
pT1/Tis: 23 (11.6%) pT2: 47 (23.6%) ≥ pT3:129 (64.8%) |
pT1/Tis: 29 (14.5%) pT2: 32 (16%) ≥ pT3: 139 (69.5%) |
49 (14) | 16 (5.97) | — | — | 50.2 (51.34) | No other therapies | ||
| Dharaskar et al. [23] | 7 (25.9%) | 13 (25.5%) |
pTa/pT1: 5 (18.5%) pT2: 13 (48.1%) pT3: 6 (22.2%) pT4: 1 (3.7%) |
pTa/pT1: 7 (13.7%) pT2: 23 (45%) pT3: 16 (31.3%) pT4: 3 (5.8%) |
14.59 (5.4) | 8.25 (6.35) | 0.52 (1.0) | 0.57 (1.45) | 12.25 (9.26) | 21.32 (12.06) | No other therapies | |
| Simone et al. [27] | 107 (30.7%) | 187 (32%) |
pT0/pTa/pTis/pT1: 94 (26.9%) pT2: 98 (28.1%) pT3: 108 (31%) pT4: 49 (14%) |
pT0/pTa/pTis/pT1: 140 (24%) pT2: 131 (22.5%) pT3: 235 (40.2%) pT4: 78 (13.3%) |
32.7 (14.9) | 16.6 (11.8) | — | — | — | — |
Adjuvant CT: 38 (10.9%) Adjuvant RT: 3 (0.8%) |
Adjuvant CT: 63 (10.8%) Adjuvant RT: 5 (0.8%) |
| Jensen et al. [21] | 61 (23%) | 43 (21%) |
pTa/pTis: 9 (3%) pT1: 49 (18%) pT2: 102 (38%) pT3: 78 (29%) pT4: 27 (10%) |
pTa/pTis: 2 (1%) pT1: 28 (14%) pT2: 82 (40%) pT3: 74 (36%) pT4: 18 (9%) |
23 (10.2) | 6 (2.7) | — | — | 49.5 (10.6) | 113.75 (10.4) | No other therapies | |
| Brunocilla et al. [20] | — | — |
pT0: 41 (14.5%) pT1: 41 (14.5%) pT2: 65 (23.0%) pT3: 87 (30.9%) pT4 (48 (17.0%) |
pT0: 41 (14.5%) pT1: 41 (14.5%) pT2: 65 (23.0%) pT3: 87 (30.9%) pT4 (48 (17.0%) |
23.5 (6.5) | 13.12 (6.3) | 1.4 (3.7) | 0.94 (2.32) | 59.2 (44.3) |
CT: 30.5% RT: 1.5% CT/RT: 1.5% |
||
| Abdi et al. [17] | 28 (26.7) | 26 (24.8) |
pT0/pTis/pTa/pT1 53 (50.4%) pT2 8 (7.6%) pT3 28 (26.6%) pT4 16 (15.2%) |
pT0/pTis/pTa/pT1 47 (44.8%) pT2 8 (7.6%) pT3 32 (30.5%) pT4 18 (17.1%) |
21 (12.03) | 9 (4.51) | 0.33 (0.75) | 0.33 (0.75) | 19.2 (19.8) | 18 (22.6) | Neoadjuvant CT: 30 (28.6%) | Neoadjuvant CT: 20 (19.1%) |
| Xuehereti et al. [25] | 33 (36.3%) | 9 (18.8%) | — | — | 20.3 (3.8) | 10.6 (3.1) | 0.6 (1.3) | 0.3 (1) | — | — | — | — |
| Gschwend et al. [6] | 44 (22%) | 56 (28%) |
pT1: 31 (16%) pT2: 88 (44%) pT3: 63 (32%) pT4: 16 (8.1%) |
pT1:24 (12%) pT2: 81 (40%) pT3: 68 (34%) pT4: 30 (15%) |
33.33 (18.67) | 19 (10.45) | — | — | — | — | Adjuvant CT: 28 (14%) | Adjuvant CT: 30 (15%) |
| Deimling et al. [26] | 131 (51.3%) | 161 (63.1%) |
< pT2: 87 (34%) pT2: 61 (24%) ≥ pT3: 107 (42%) |
< pT2: 106 (42%) pT2: 55 (22%) ≥ pT3: 94 (37%) |
24 (12.67) | 15.5 (10.44) | 1 (2.24) | 1 (1.49) | 31.33 (28.2) | Adjuvant CT: 35 (14%) | Adjuvant CT: 36 (14%) | |
| Lerner et al. [7] | 75 (26%) | 71 (24%) |
pT0: 59 (20%) pTis/pTa/pT1: 49 (17%) pT2: 54 (18%) pT3 or pT4: 55 (19%) |
pT0:61 (20%) pTis/pTa/pT1: 55 (18%) pT2: 52 (17%) pT3/pT4: 61(20%) |
46.75 (13.83) | 28.75 (9.6) | 10 (5.95) | 4.75 (2.62) | 73.2 (median) | Neoadjuvant CT: 166 (57%) | Neoadjuvant CT: 170 (57%) | |
| Al Nader et al. [19] | 53 (26.1%) | 122 (27.8%) |
pT0/NMIBC: 49 (24.1%) pT2: 51 (25.1%) pT3: 79 (38.9%) pT4: 24 (11.8%) |
pT0/NMIBC: 106 (24.1%) pT2: 122 (27.8%) pT3: 135 (30.8%) pT4: 76 (17.3%) |
24 (16.69) | 8.33 (5.21) | 4.33 (5.97) | 2.33 (2.33) | 56 (52.27) | 42.67 (30.49) |
Perioperative CT: 49 (24.1%) |
Perioperative CT: 64 (14.6%) |
Most included studies enrolled exclusively patients with urothelial carcinoma. However, several studies also included patients with variant histologies, including squamous cell carcinoma, adenocarcinoma, or urothelial carcinoma with variant differentiation, namely Abdi et al. [17], Abol‐Enein et al. [18], Al‐Nader et al. [19], Brunocilla et al. [20], Finelli et al. [21]), Jensen et al. [21], Lerner et al. [7], and Poulsen et al. [22]. Detailed histological characteristics of each study are provided in Table S1.
3.3. Lymphadenectomy Definitions
Considerable variability was observed in the anatomical definitions of lymphadenectomy across the included studies. Although standard pelvic lymph node dissection (PLND) is generally defined as encompassing the obturator, external iliac, and internal iliac nodal regions up to the common iliac bifurcation, and extended PLND additionally includes the common iliac and presacral nodal packets up to the aortic bifurcation or the crossing of the ureter over the common iliac vessels, several studies employed alternative templates. In some cohorts, the extent of dissection classified as standard or limited differed from contemporary definitions, whereas the boundaries of extended lymphadenectomy also varied substantially. For example, Finelli et al. extended the dissection cranially to the aortic bifurcation and distal aorta, corresponding more closely to a super‐extended template than to the currently accepted definition of extended PLND. Similar variations were identified across other studies, reflecting the absence of uniform anatomical templates during the study periods. To improve transparency and facilitate interpretation of the pooled analyses, the specific anatomical boundaries adopted in each study have been summarized in Table S2.
3.4. Surgical Outcomes
All 15 studies assessed the number of lymph nodes removed, with a higher count in the extended group [MD: 15.04 (95% CI: 11.91–18.18, p < 0.001)]. Heterogeneity was considered to be high (I 2 = 98%, p < 0.001). Results of the meta analysis of removed lymph nodes are shown in Figure S1.
The number of positive lymph nodes was assessed by eight studies [7, 17, 19, 20, 23, 24, 25, 26] with a total of 3059 participants (Supplementary Figure 2). There were more positive lymph nodes in the extended group, but with no statistically significant difference [MD: 1.71 (95% CI: 0.21–3.21, p = 0.03)]. Studies were highly heterogeneous (I 2 = 99%, p < 0.001).
Four studies evaluated lymph node density [17, 23, 26, 27] (Figure S3), which was lower in the extended group [MD: −4.08 (95% CI : −7.20 – −0.96, p = 0.01)]. Heterogeneity was high (I 2 = 86%, p < 0.001).
Surgery duration was assessed by four studies [7, 19, 21, 25] (Figure S4). Surgical time increased by a mean of 26 min with the extended technique [MD: 26.19 (95% CI: 12.16–40.21, p = 0.0003)]. Heterogeneity was high (I 2: 81%, p = 0.001).
Intraoperative blood loss was reported in four studies [7, 17, 19, 25] (Figure S5). Patients treated with the extended technique showed a higher mean blood loss (mL) compared with those undergoing the non‐extended approach, but the difference was not statistically significant [MD: 100.67 (95% CI: −6.49 – 207.83, p = 0.07)]. Heterogeneity across studies was high (I 2: 94%, p < 0.001).
3.5. Oncologic Outcomes
Five studies assessed OS [6, 7, 17, 21, 26], including a total of 2,182 participants (Table S3). Extended lymphadenectomy was not associated with OS [HR: 0.82 (95% CI: 0.64–1.05, p = 0.12)]. Heterogeneity was moderate (I 2: 65%, p = 0.02) (Figure 2a).
Figure 2.
Meta analysis of the association between lymphadenectomy type and survival outcomes: (a) Overall survival; (b) Disease‐free survival; (c) Recurrence‐free survival; (d) Cancer‐specific survival.
When the analysis was restricted to randomized controlled trials, OS was evaluated in two studies [6, 7], comprising 993 patients in total (Supplementary Figure 6). No significant difference in OS was observed comparing the lymphadenectomy approaches [HR: 0.95 (95% CI: 0.66–1.37, p = 0.78)]. Between‐study heterogeneity was moderate (I 2: 70%, p = 0.07).
Three studies assessed DFS [7, 15, 25], including a total of 1,925 participants (Figure 2b). Extended lymphadenectomy was associated with a higher DFS when compared to non‐extended lymphadenectomy [HR: 1.47 (95% CI: 1.27–1.71, p < 0.001)]. Studies were highly heterogeneous (I 2: 82%, p = 0.004).
Four studies assessed RFS [6, 14, 20, 24], including a total of 1590 participants (Figure 2c). Non‐extended lymphadenectomy was associated with higher RFS when compared to extended lymphadenectomy, [HR: 0.79 (95% CI: 0.63–0.99, p = 0.04)]. Studies showed moderate heterogeneity (I 2: 70%, p = 0.02).
Lastly, CSS was assessed by four studies [6, 21, 27, 28], including a total of 1973 participants (Figure 2d). Extended lymphadenectomy was not associated with CSS [HR: 0.93 (95% CI: 0.52–1.61, p = 0.800)]. Studies were highly heterogeneous (I 2 = 88%, p < 0.001).
3.6. Quality Assessment and Certainty of Evidence of the Included Studies
In the observational cohort analysis, four studies showed a critical risk of bias. Dharaskar et al. [23] showed critical risk of bias due to confounding, participant selection, intervention classification, and outcome assessment. Dhar et al. [24] also had a critical risk of bias in participant selection and outcome measurement. Jensen et al. [21] presented critical risk of bias related to confounding, missing data, and selection of the reported outcomes. Brunocilla et al. [20] showed critical risk of bias from confounding, outcome measurement, and selection of the reported outcomes. The remaining nine studies showed a “moderate” risk of bias (Figure S7).
In the RCTs analysis, Lerner et al. [7] presented a moderate risk of bias, due to outcome measurement. Gschwend et al. [6] showed a high risk, primarily from randomization process and outcome measurement issues (Figure S8).
The certainty of evidence was rated as very low for OS, DFS, RFS, CSS, surgery duration, and blood loss, mainly due to serious risk of bias, substantial heterogeneity, and imprecision. In the RCT‐only analysis, the certainty of evidence for OS was rated as low. The Summary of Findings table is provided in Table 3.
Table 3.
Summary of findings.
| Outcome | No. of studies (participants) | Effect estimate | Heterogeneity | Certainty of evidence (GRADE) | Rationale |
|---|---|---|---|---|---|
| Surgery duration | 4 (851) | MD + 26.19 min (95% CI 12.16–40.21) | I 2 = 81% | ⊕◯◯◯ Very low | Downgraded for serious risk of bias (predominance of observational studies with critical/moderate risk of bias) and inconsistency (substantial heterogeneity). |
| Intraoperative blood loss | 4 (691) | MD + 100.67 mL (95% CI: −6.49–207.83) | I 2 = 94% | ⊕◯◯◯ Very low | Downgraded for serious risk of bias (predominance of observational studies with moderate risk of bias), inconsistency (substantial heterogeneity), and imprecision (CI crosses the line of no effect). |
| Overall survival (OS) | 5 (2182) | HR: 0.82 (95% CI: 0.64–1.05) | I 2 = 65% | ⊕◯◯◯ Very low | Downgraded for serious risk of bias (predominance of observational studies with critical/moderate risk of bias and one RCT with high risk of bias), inconsistency (moderate heterogeneity), and imprecision (CI crosses the line of no effect). |
| Overall survival (OS) RCTs only | 2 (993) | HR: 0.95 (95% CI: 0.66–1.37) | I 2 = 70% | ⊕⊕◯◯ Low | Downgraded for serious risk of bias (one trial with high risk of bias), inconsistency (moderate heterogeneity), and imprecision (wide CI crossing the line of no effect). |
| Disease‐free survival (DFS) | 3 (1925) | HR: 1.47 (95% CI: 1.27–1.71) | I2 = 82% | ⊕◯◯◯ Very low | Downgraded for serious risk of bias (observational studies with moderate risk of bias) and inconsistency (substantial heterogeneity). |
| Recurrence‐free survival (RFS) | 4 (1590) | HR: 0.79 (95% CI: 0.63–0.99) | I 2 = 70% | ⊕◯◯◯ Very low | Downgraded for serious risk of bias (observational studies with critical/moderate risk of bias and one trial with high risk of bias), inconsistency (moderate heterogeneity), and imprecision (upper CI close to the line of no effect). |
| Cancer‐specific survival (CSS) | 4 (1973) | HR: 0.93 (95% CI: 0.52–1.61) | I 2 = 88% | ⊕◯◯◯ Very low | Downgraded for serious risk of bias (observational studies with critical/moderate risk of bias and one trial with high risk of bias), inconsistency (substantial heterogeneity), and imprecision (very wide CI crossing the line of no effect). |
4. Discussion
In this systematic review and meta‐analysis comparing extended versus non‐extended lymphadenectomy during RC for BC, we included data from two RCTs, one prospective cohort, and 12 retrospective studies. To our knowledge, this is the largest review in the topic, including 15 studies with 5671 participants, of which 993 are from RCTs. Extended lymphadenectomy was associated with longer surgical time and improved DFS, but did not result in better CSS or OS. The non‐extended technique was associated with higher RFS.
Previous meta‐analyses evaluating the extent of lymphadenectomy during radical cystectomy have yielded conflicting findings. Wang et al. [29], based predominantly on observational studies, reported improved recurrence‐free and disease‐free survival with extended lymphadenectomy, although no overall survival benefit was observed. More recently, Ślusarczyk et al. [30] restricted their analysis to the two available randomized controlled trials comparing extended and standard lymphadenectomy and found no improvement in recurrence‐free or overall survival, while reporting increased perioperative morbidity associated with extended dissection. These reviews addressed specific aspects of lymphadenectomy extent but were limited either by reliance on observational data or by the inclusion of only randomized comparisons between standard and extended templates. By incorporating both contemporary randomized and observational evidence, as well as studies evaluating limited, standard, and extended dissections, the present study provides the largest and most comprehensive synthesis currently available, encompassing multiple lymphadenectomy strategies and oncologic outcomes across a broader spectrum of clinical scenarios.
One possible explanation for our findings is that non‐extended lymphadenectomy already covers the main lymph nodes of the bladder, including the obturator, internal iliac, external iliac, and common iliac drainage. Removing additional nodes beyond these areas may not provide further oncologic benefit, while inevitably prolonging operative time and exposing patients to higher morbidity. This could explain why extended procedures increase retrieved lymph nodes but do not translate into improved survival outcomes.
The observed improvement in DFS with extended lymphadenectomy should be interpreted with caution, as well as the increased RFS with the standard LND. Only one of the three studies contributing to this outcome was a RCT, and this trial did not demonstrate a significant difference between extended and non‐extended lymphadenectomy. The remaining evidence was derived from observational studies, several of which were judged to have moderate to critical risk of bias. It is plausible that residual confounding and selection bias may have contributed to an overestimation of the effect size, rendering the pooled result statistically significant despite the lack of confirmation in randomized evidence.
Most of the patients in the included studies were node‐negative, who are the least likely to benefit from extended lymphadenectomy. In our review, only 19% of participants had positive lymph nodes, which limits the ability to generalize the results to that subgroup. Abol‐Enein et al. [18] examined this issue: only 96 patients (24%) had lymph node metastases, but when analyses were restricted to node‐positive patients, those who received extended lymphadenectomy had better 5‐year DFS (48.0% vs. 28.2%, p = 0.029) compared to those who received standard lymphadenectomy.
The presence of histological variants is clinically relevant, as they may influence tumor behavior and response to treatment. Only a few studies specifically addressed this issue, which means that current results should be interpreted with caution in this subgroup. This limitation is consistent with previous evidence showing that patients with pure histologic variants have poor survival outcomes compared to those with conventional urothelial carcinoma [31]. In our review, only Abdi et al. [17], Al‐Nader et al. [19], Lerner et al. [7], Finelli et al. [32] and Jensen et al [21] reported on variant histologies.
Neoadjuvant therapy, either with chemotherapy or immunotherapy, is considered the gold standard for the management of MIBC. However, the use of neoadjuvant treatment remains heterogeneous, with no universally standardized protocols, leading to wide variability in its adoption, ranging from 14% to 57% of the patients in our study. These differences need to be taken into account when interpreting our results.
Furthermore, the lack of an overall survival benefit in patients with nodal disease beyond the standard pelvic template may reflect the presence of occult micrometastatic dissemination. In this setting, involvement of common iliac or more proximal lymph nodes may represent a marker of systemic disease rather than a purely locoregional process. Consequently, although extended lymphadenectomy may improve staging and regional disease control, its impact on overall survival is likely limited once disease extends beyond the scope of surgical cure. This concept is particularly relevant in the era of modern systemic therapies, such as enfortumab vedotin plus pembrolizumab, which have demonstrated substantial survival benefits in advanced urothelial carcinoma [33].
Another consideration is that many included studies were conducted before the widespread adoption of cisplatin‐based neoadjuvant chemotherapy, which is currently considered the standard of care for eligible patients with muscle‐invasive bladder cancer. Consequently, the use of systemic therapy varied substantially across studies, potentially affecting oncologic outcomes and limiting the generalizability of some findings to contemporary practice.
Another important source of heterogeneity relates to surgical quality assurance and adherence to lymphadenectomy templates. Only the SWOG S1011 trial [7] reported a formal quality‐control process, requiring operative photographic documentation and central review to verify compliance with the assigned lymphadenectomy template. In contrast, most observational studies did not describe objective measures to validate the anatomical extent of dissection. Although some studies attempted to reduce variability by having procedures performed by the same surgeons or within specialized centers, surgeon‐specific differences in the interpretation and execution of lymphadenectomy templates may have persisted. Consequently, variations in surgical technique and adherence to predefined anatomical boundaries may have influenced both lymph node yield and oncologic outcomes across studies.
Future research should focus on identifying patient subgroups who may benefit from extended lymphadenectomy, such as those with clinically positive nodes or aggressive tumor features. High‐quality prospective studies are needed to evaluate not only oncologic outcomes but also functional results, quality of life, and cost‐effectiveness. Standardizing the anatomical definition of lymphadenectomy templates is also crucial to ensure comparability between studies. Additionally, emerging biomarkers such as circulating tumor DNA (ctDNA) may help refine preoperative risk stratification and identify patients at higher risk of occult nodal or micrometastatic disease. Although ctDNA‐guided decisions regarding lymphadenectomy extent remain investigational, this approach represents a promising avenue for future research and treatment individualization [34, 35].
Several limitations should be acknowledged when interpreting our findings. Most of the available evidence originated from retrospective observational studies and retrospective cohorts, with only two randomized controlled trials included, increasing the risk of selection bias and residual confounding. Furthermore, although lymphadenectomy templates are generally defined according to established anatomical boundaries, considerable variability existed in their implementation across studies. Procedures described under the same nomenclature were not always anatomically equivalent, introducing an important source of clinical heterogeneity. Additional variability arose from differences in complication reporting systems, pathological processing of surgical specimens, and the limited use of quality‐control measures to verify adherence to the intended dissection template. Surgeon experience and expertise were also inconsistently reported and rarely standardized, potentially influencing both lymph node yield and oncologic outcomes. These factors likely contributed to the low‐to‐very‐low certainty of evidence observed across outcomes and should be considered when interpreting the results of the present analysis.
5. Conclusions
Extended lymphadenectomy was associated with improved DFS and a longer operative time, with a mean increase of 26 min. The non‐extended technique was associated with higher RFS. There was no statistically significant difference between groups in CSS or OS. Extended lymphadenectomy may play a role in patients with known locally advanced and/or lymph node disease in the preoperative setting. Future studies should compare groups that are more likely to benefit from extended lymphadenectomy, such as patients with positive lymph nodes.
6. Synopsis
This systematic review and meta‐analysis evaluated the impact of extended versus non‐extended lymphadenectomy during radical cystectomy for bladder cancer, including 15 studies and 5671 patients. Extended lymphadenectomy was associated with improved disease‐free survival and longer operative time, but did not improve cancer‐specific or overall survival. These findings suggest that while extended lymphadenectomy may enhance regional disease control, its routine use should be balanced against increased surgical complexity and the lack of demonstrated survival benefit.
Supporting information
Supporting File
Acknowledgements
The authors Maria Fernanda Dias Azevedo and Pedro Henrique Souza Brito contributed equally to this manuscript as first authors.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supporting File
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.