Perioperative outcomes using template mapping after radical cystectomy and extended lymph node dissection

Abstract

Background

To evaluate oncologic and perioperative outcomes of extended pelvic lymph node dissection (PLND) during robot-assisted radical cystectomy (RARC) based on the location of lymph node positivity (LN⁺).

Methods

We reviewed a tertiary center database of patients with bladder cancer who underwent extended PLND during RARC from 2004 to 2020. Patients were assigned to a standard (sPLN⁺) or extended (ePLN⁺) cohort based on LN⁺ location. ePLN⁺ patients were LN⁺ in one or more of the following: common iliac, presacral, aortic bifurcation, or paracaval packets. The Kaplan-Meier method estimated recurrence-free survival (RFS) and overall survival (OS). Perioperative 90-day complications were identified using the Clavien-Dindo system.

Results

Ninety patients were included; 43 (48%) were sPLN^+, and 47 (52%) were ePLN⁺. The median follow-up for sPLN⁺ and ePLN⁺ patients was 14.9 and 20.0 months, respectively. ePLN⁺ patients were older than sPLN⁺ patients (median age 75 vs. 68 years, p = 0.019). There were more ≤ cT1 LN⁺ patients in the sPLN⁺ cohort compared to the ePLN⁺ cohort (26% vs. 9%, p = 0.037). We recorded no differences in 90-day mortality or in RFS or OS between baseline and 12-year follow-up between groups (all, p > 0.05). Overall, the grade II or higher complication rate was 71%, with similar rates for the sPLN⁺ and ePLN⁺ (77% vs. 66%, p = 0.26) cohorts.

Conclusion

Location of LN⁺ does not affect oncologic outcomes in patients who underwent extended PLND. This underscores the lack of a notable therapeutic benefit beyond the standard dissection template.

Clinical trial number

Not applicable.

Introduction

Bladder cancer is the fourth most common malignancy in the United States [1]. It is estimated that in 2024, 83,000 patients were diagnosed with bladder cancer, and approximately 16,840 died from this disease [1]. Radical cystectomy with pelvic lymph node dissection (PLND) remains the gold standard for the treatment of muscle-invasive bladder cancer (MIBC) and selected patients with high-risk non-muscle invasive bladder cancer (NMIBC) [2]. Advances in recent years have led to the adoption of robot-assisted radical cystectomy (RARC). Catto et al. demonstrated a statistically significant benefit of RARC with a higher median number of days alive after surgery, lower rate of thromboembolic events, lower rate of wound complications, and improved overall quality of life compared to open radical cystectomy [3]. Up to 25% of patients with disease who undergo surgery will be found to be node-positive. Thus, PLND is crucial in determining the need for adjuvant chemotherapy and overall prognosis [4,5,6]. Standard PLND includes removing lymph nodes (LNs) from the obturator, external, and internal iliac regions [6,7,8]. Extended PLND consists in removing LNs from the deep obturator, common iliac, presacral, paracaval, interaortovacal, and para-aortal regions besides the standard template-related regions.

However, the therapeutic role of the extent of PLND remains controversial. Leissner et al. showed that more extensive PLND (≥ 16 nodes) was significantly associated with tumor-free survival at 5-years in patients with pT1, T2, and T3 tumors [7]. Abol-Enein et al. performed a non-randomized prospective trial to evaluate oncologic outcomes in 400 patients undergoing standard (n = 200) and extended (n = 200) PLND. The authors reported a significantly improved 5-year disease-free survival in patients undergoing extended PLND compared with patients undergoing standard PLND (48.0% vs. 28.2%; p = 0.029) [8]. Conversely, Gschwend et al. performed the first randomized phase III trial to investigate the therapeutic role of extended PLND vs. standard PLND. This study failed to show the superiority of the extended approach over the standard approach regarding recurrence-free survival (RFS) (5-year RFS 65% vs. 59%; HR = 0.84 [95% CI 0.58–1.22]; p = 0.36), cancer-specific survival (CSS) (5-year CSS 76% vs. 65%; HR = 0.70 [95% CI 0.46 – 1.07]; p = 0.10), and overall survival (OS) (5-year OS 59% vs. 50%; HR = 0.78; [95% CI 0.57–1.07]; p = 0.12) [9]. The SWOG S1011 trial recently randomized patients with localized MIBC who underwent radical cystectomy to extended PLND (n = 292) and standard PLND (n = 300). The authors did not find improved 5-year disease-free survival (56% vs. 60%, p = 0.45) or OS (59% vs. 63%) among patients undergoing extended lymphadenectomy compared to the standard approach, and recorded higher perioperative morbidity and mortality for patients undergoing extended lymphadenectomy [10, 11].

Consequently, in the post-SWOG S1011 era, evaluating the real-world outcomes of the extent of PLND is paramount, particularly considering the recent level I evidence reporting equivocal overall and disease-free survival between patients undergoing extended vs. standard dissection [12, 13]. We aimed to evaluate the oncologic and perioperative outcomes of a standardized set of patients undergoing RARC and extended PLND based on template-based LN positivity.

Methods

Patient population

We retrospectively reviewed an institutional review board (IRB)-approved (IRB#05148) database of 562 patients who underwent RARC with extended PLND and extracorporeal urinary diversion. We included patients with high-risk NMIBC and MIBC. Baseline characteristics included age at surgery, sex, race, ethnicity, body mass index (BMI), American Society of Anesthesiologists (ASA) score, operative time, length of hospital stay, clinical stage, neoadjuvant chemotherapy status, radiotherapy status, and variant histology. Patients were consecutively treated at a single tertiary referral cancer center between February 2004 and October 2020. RARC and PLND were completed as described previously [12]. All patients underwent an extended template PLND, and pathologic node positive (pN⁺) patients were identified. Patients whose procedures were converted to open surgery (n = 3), who showed only perivesical LN positivity (n = 5), or who underwent palliative RARC (n = 2) were excluded.

LN mapping

Patients had separate packets sent from the obturator, node of Cloquet, internal iliac, external iliac, common iliac, presacral, aortic bifurcation, and paracaval LNs to precisely identify the location of LN disease. Patients were assigned to either standard template pelvic LN positivity (sPLN⁺) or extended template pelvic LN positivity (ePLN⁺) cohorts based on the location of LN positivity. Patients in the ePLN⁺ cohort had LN positivity in one or more of the following packets: common iliac, presacral, aortic bifurcation, or paracaval LNs. Patients in the sPLN⁺ cohort had LN positivity in one or more of the following packets: external iliac, internal iliac, obturator, or node of Cloquet.

Disease recurrence, morbidity, and mortality

Local recurrence was defined as radiographic or biopsy-proven evidence of disease recurrence within the pelvis. Distant recurrence was defined as radiographic or biopsy-proven evidence of disease recurrence outside the pelvis. Perioperative 90-day complications were first categorized and then graded using the Clavien-Dindo classification system. Meaningful complications were measured as grade II or higher (≥ grade II) events [14]. Perioperative death from any cause within 90 days of surgery or otherwise was recorded. Furthermore, death secondary to urothelial carcinoma or death from any cause was also determined.

Follow-up

Postoperative care followed an institutional enhanced recovery after surgery pathway [13]. Postoperative disease surveillance was performed according to the National Comprehensive Cancer Network (NCCN) guidelines [15]. Specifically, follow-up was conducted every three to six months for the first two years, then biannual visits thereafter. Imaging of the chest, abdomen, and pelvis occurred every six months for the first two years, then for years 3, 4, and 5, a renal ultrasound semiannually and cross-sectional imaging annually.

Statistical analysis

Descriptive statistics were used to summarize all variables, including demographic and clinicopathologic characteristics and postoperative complications. Categorical data were reported as counts and percentages. Continuous variables were reported as medians and interquartile ranges (IQRs). Differences between the cohorts were assessed with the Chi-square/Fisher’s test for categorical variables and the Wilcoxon rank sum test for continuous variables. RFS was measured from the date of surgery to the date of local or distant recurrence. Patients who died without documented recurrence, who were lost to follow-up, or who were still alive without documented recurrence as of their last visit/contact date were censored. OS was measured from the date of surgery to the date of death from any cause. A sub-group analysis of RFS and OS for patients with MIBC (≥ cT2) was performed. Patients who were lost to follow-up or were still alive as of their last visit/contact date were censored. Estimates for RFS and OS were calculated using the Kaplan–Meier method. Data management and statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) and R version 4.3.0 (R Foundation for Statistical Computing). P-values < 0.05 were considered statistically significant.

Results

Descriptive characteristics of patient population

A total of 90 patients who underwent RARC and extended PLND were found to be pN⁺. Overall, the median follow-up time was 17.8 (IQR 7.6–33.1) months, the median age at surgery was 70 (IQR 63–78) years, and most patients were male (74%) and White (81%). Most patients had urothelial histology (80%), followed by squamous histology (11%). Based on the location of LN positivity, 43 (48%) patients were assigned to the sPLN⁺ cohort, and 47 (52%) were assigned to the ePLN⁺ cohort. Patients in the sPLN⁺ cohort were more likely to be younger (68 vs. 75 years, p = 0.019) and have NMIBC (≤ cT1) (26% vs. 9%, p = 0.037) compared to patients in the ePLN⁺ cohort. Rates of neoadjuvant chemotherapy use were similar in both cohorts (ePLN⁺ 38% vs. sPLN⁺ 37%). Baseline characteristics are shown in Table 1. There were no significant differences in pathologic LN yield between groups (p = 0.97). The ePLN⁺ cohort patients had more median positive LNs detected than the sPLN⁺ cohort (median 7 vs. 2, p < 0.001). We did not record a significant difference in the use of adjuvant chemotherapy or radiation between cohorts (both p > 0.05). Tumoral and nodal pathologic data are shown in Table 2.

Table 1 Patient demographic and clinical characteristics

Table 2 Tumoral and nodal pathologic data

Post-operative complications

Overall, the ≥ grade II complication rate was 71%, with the most common complication subcategory being infectious complications (39%), followed by gastrointestinal (24%), genitourinary (16%), and cardiac (16%) complications. There was a comparable rate of ≥ grade II complications between the ePLN⁺ and sPLN⁺ cohorts (66% vs. 77%, p = 0.26), albeit not statistically significant. We recorded a comparable rate of gastrointestinal (23% vs. 26%, p = 0.81), and infectious (38% vs. 40%, p = 0.90) complications between the ePLN⁺ and sPLN⁺ cohorts. Rate differences were recorded for hematologic (23% vs. 14%, p = 0.25) and renal (15% vs. 9%, p = 0.42) complications between the ePLN⁺ and sPLN⁺ cohorts, although these were not statistically significant. Specific rates of complication subcategories between cohorts are shown in Table 3.

Table 3 Complications between ePLN⁺ and sPLN⁺cohorts

Oncologic outcomes and survival analysis

A total of 82 (91%) patients died during follow-up, and 64 (71%) patients had recurrent urothelial carcinoma during the follow-up period. We recorded no significant difference in overall mortality, 90-day mortality, or death from bladder cancer between cohorts (all p > 0.05). We recorded a superior 5-year RFS (17% vs. 10%) and 5-year OS probability (21% vs. 14%) for the ePLN⁺ cohort compared to the sPLN⁺ cohort. A subgroup analysis of patients with MIBC (≥ cT2) revealed a higher 5-year RFS (19% vs. 8.5%) and OS probability (21% vs. 9.7%) in the ePLN⁺ cohort compared to the sPLN⁺ cohort. However, these differences did not reach statistical significance (both p > 0.05). Survival outcomes between cohorts are shown in Figs. 1 and 2.

Fig. 1

Recurrence-free survival (A) and overall survival (B) for patients undergoing RARC based on PLN⁺ template status

Fig. 2

Recurrence-free survival (A) and overall survival (B) for muscle-invasive bladder cancer (MIBC) patients undergoing RARC based on PLN⁺ template status

Discussion

The present study evaluates the oncologic and perioperative outcomes of template-based pelvic nodal positivity location in a uniform treatment group of patients undergoing robotic cystectomy and extended PLND. Our results show that nodal positivity location does not appreciably affect RFS and OS, supporting the notion that extended PLND may not harbor significant oncologic benefits over the standard approach for most patients. This further validates the real-world implications of template-based PLND in the post-SWOG S1011 era.

Recent literature has highlighted conflicting evidence regarding the therapeutic benefit of extended PLND compared to standard PLND. Bi et al. performed a systematic review of 6 studies with 2824 patients undergoing radical cystectomy. Patients were grouped into extended and non-extended PLND cohorts. Their results showed that the extended cohort had improved RFS (HR 0.68; p = 0.007). When stratified by pathological T stage, patients with pT3-T4 disease (HR 0.61; p < 0.001) showed improved RFS compared to patients with ≤ pT2 disease (HR 0.95; p = 0.81) [16]. Conversely, recently published randomized trials by Gschwend et al. and Lerner et al. have failed to demonstrate significant differences in oncologic outcomes between the extended and standard approaches [9, 11]. Our study aligns with the latter findings, showing no significant differences in RFS and OS between patients with LN positivity in the ePLN⁺ and sPLN⁺ cohorts. In a recently published retrospective study, Deimling et al. evaluated 969 patients undergoing radical cystectomy and standard PLND or extended PLND. Their results showed the extended approach improved neither RFS (HR 0.91 [95% CI 0.70–1.19]; p = 0.5) nor OS (HR 0.78 [95% CI 0.60–1.01]; p = 0.06) [17]. To this extent, we adjusted our analysis only to include patients with MIBC (≥ cT2). Results showed that although not statistically significant, there was a trend toward significance (p = 0.08) for OS favoring the ePLN⁺ group.

Our analysis revealed a greater number of positive LNs detected in the ePLN⁺ cohort (median 7 [IQR 4–14]) compared to the sPLN⁺ cohort (median 2 [IQR 1–3]) (p < 0.001). This finding supports the hypothesis that extended PLND may provide more accurate staging by encompassing a broader range of LN specimens, particularly for patients with more advanced disease stages, but may not greatly impact survival [18]. The lack of significant differences in survival outcomes between both cohorts suggests that the therapeutic role of extended dissection remains limited. While extended PLND may be advantageous by offering better disease staging and guiding adjuvant therapy decisions, its impact on long-term survival appears limited based on our findings and those of recent randomized trials [9, 11]. Although the SWOG S1011 randomized controlled trial provides the highest level of evidence regarding the oncologic efficacy of extended PLND, our study offers complementary insights into the real-world clinical application of this approach. Consequently, the choice of a specific lymph node dissection template should not be based on oncologic benefit but rather on a multidisciplinary decision that considers the surgeon’s expertise, institutional experience, and the patient’s clinical characteristics.

Deciding if extending the LN dissection field is necessary for a given patient is a multifactorial conundrum, where age, comorbidities, and overall health status impact the decision-making process. Improved pre-surgical evaluation techniques could aid in determining the appropriate field for lymph node dissection. Longoni et al. assessed the diagnostic performance of 18 F-FDG positron emission tomography (PET)/computed tomography (CT) in nodal staging prior to radical cystectomy. Their findings showed a sensitivity of 30%, specificity of 91%, positive predictive value of 57%, and negative predictive value of 77%. These results emphasize the value of 18 F-FDG PET/CT in accurately identifying lymph node-positive disease during preoperative evaluation, thereby aiding in developing individualized surgical plans for patients [19]. Moschini et al. developed a nomogram incorporating pre-surgical clinical and pathological parameters to predict lymph node invasion (LNI) within the extended pelvic lymph node dissection template. The variables included in the model were age, clinical T stage, clinical node stage, lymphovascular invasion, and carcinoma in situ at the last transurethral resection prior to surgery. The nomogram yielded an accuracy of 73% in predicting LNI, highlighting the potential of using pre-surgical variables to predict LNI and guide surgical plans for patients [20]. However, these findings should be interpreted in the context of a single-center, retrospective study design. Clinicians should carefully balance the potential benefits of more extensive LN dissection with the surgical complexity and perioperative risks associated with radical cystectomy. Developing and validating accurate pre-surgical staging tools could help optimize surgical decision-making.

Our results indicate considerable overall complication rates, with no significant differences between the ePLN⁺ and sPLN⁺ groups for ≥ grade II complications and specific complication subcategories, meaning that nodal positivity location does not appear to impact complications. Abdi et al. evaluated 314 bladder cancer patients undergoing PLND, of which 105 underwent extended PLND and 105 standard PLND. They found no differences in complication rates between the two groups other than increased blood loss in the extended PLND cohort (1047.3 ml vs. 584.5 ml; p < 0.001) [21]. However, the authors hypothesize that this could be explained by the longer surgical time with ongoing blood loss in the cystectomy bed, blood loss from PLND itself, or other patient-related factors, and not by the extent of PLND [21]. Our results align with this study and show that while some specific complication subcategories depict a different rate based on LN positivity template, they fail to show statistically significant differences. However, by focusing on surgical morbidity and complications in a real-world setting, our study provides clinically relevant data that complements existing randomized trials.

Some limitations of the present study include the small sample size and the single-center design, which could affect the generalizability of the results. Complication reporting is also subject to underrepresentation, though we do capture complications extensively throughout the patient’s hospital stay and if subsequent readmissions occur, even to outside facilities. We included a small fraction of non-muscle-invasive cases, which limits the statistical impact of the measured rates on this subpopulation.

Conclusion

The location of lymph node positivity within the extended or standard template does not appear to impact oncologic outcomes in patients undergoing RARC and extended PLND. Our findings emphasize the real-world relevance of lymph node mapping and demonstrate a comparable post-operative complication profile between the ePLN⁺ and sPLN⁺ cohorts. Given the lack of significant oncologic benefit associated with extended PLND over the standard template, the decision to pursue a broader nodal dissection should be individualized, considering patient-specific factors, institutional experience, and surgeon expertise.