Does the Extent of Lymphadenectomy in Radical Cystectomy for Bladder Cancer Influence Disease-Free Survival? A Prospective Single-Center Study

EUROPEAN UROLOGY 60 (2011) 572 577 available at www.sciencedirect.com journal homepage: www.europeanurology.com Bladder Cancer Does the Extent of Lymphadenectomy in Radical Cystectomy for Bladder Cancer Influence Disease-Free Survival? A Prospective Single-Center Study Hassan Abol-Enein a,1, Derya Tilki a,b,1, *, Ahmed Mosbah a, Mahmoud El-Baz c, Ahmed Shokeir a, Adel Nabeeh a, Mohamed A. Ghoneim a a Department of Urology, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt; b Department of Urology, Ludwig-Maximilians-University, Klinikum Grosshadern, Munich, Germany; c Department of Pathology, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt Article info Article history: Accepted May 31, 2011 Published online ahead of print on June 12, 2011 Keywords: Urinary bladder Urothelial carcinoma Extended lymphadenectomy Prognosis Abstract Background: Controversy exists regarding the optimal extent of lymphadenectomy and the number of lymph nodes to be retrieved at radical cystectomy (RC). Objective: To compare the disease-free survival of patients with standard lymphadenectomy (endopelvic region composed of the internal, external iliac, and obturator groups of lymph nodes) versus extended lymphadenectomy (up to the level of origin of the inferior mesenteric artery) at RC in a prospective cohort of patients at a single, high-volume center. Design, setting, and participants: Prospective data were collected from 400 consecutive patients treated with RC for bladder cancer by two high-volume surgeons at Mansoura Urology and Nephrology Center. Of the 400 patients, 200 (50%) received extended lymphadenectomy and the other 200 (50%) underwent standard lymphadenectomy at RC. The patients did not receive any neoadjuvant or adjuvant therapy. Measurements: Patient characteristics and outcomes are evaluated. Results and limitations: Median patient age for the entire group was 53.0 yr. Ninety-six patients (24.0%) had lymph node metastases. Median follow-up was 50.2 mo. Estimates of 5-yr disease-free survival in the extended lymphadenectomy group were 66.6% compared with 54.7% for patients with standard lymphadenectomy ( p = 0.043). Extended lymphadenectomy was associated with better disease-free survival after adjusting for the effects of standard pathologic features ( p = 0.02). When restricting the analyses to lymph node positive patients, patients with extended lymphadenectomy had much better 5-yr disease-free survival compared with patients with standard lymphadenectomy (48.0% vs 28.2%; p = 0.029). The study was nonrandomized. Conclusions: Extended lymphadenectomy is associated with better disease-free survival for bladder cancer patients with endopelvic lymph node involvement and should be considered in these patients. # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. 1 Both authors contributed equally. * Corresponding author. Urology and Nephrology Center, Mansoura University, Mansoura, Egypt. Tel. +20502262222; Fax: +20502263717. E-mail address: dtilki@me.com (D. Tilki). 0302-2838/$ see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2011.05.062

EUROPEAN UROLOGY 60 (2011) 572 577 573 1. Introduction For patients with muscle-invasive bladder cancer and for those with high-risk non muscle-invasive bladder cancer, radical cystectomy (RC) with bilateral pelvic lymphadenctomy provides accurate staging and adequate local and regional control [1 3]. Pathologic tumor (pt) category and lymph node status are the strongest prognostic factors in patients with bladder cancer [1 3]. Although the importance of lymphadenectomy in the management of muscle-invasive bladder cancer is beyond doubt, no consensus exists regarding the optimal extent of lymphadenectomy, the number of lymph nodes to be retrieved, and the procedure s prognostic and therapeutic role for patients with bladder cancer undergoing RC [4,5]. Recent studies have suggested that an extended lymphadenectomy leads to improved survival [6 13]; however, to a large extent, these studies were limited by their multicenter and retrospective natures with multiple surgeons and pathologists. Furthermore, most of these studies used lymph node count as a surrogate for extent of lymphadenectomy without unification of the field of lymphadenectomy [6 10,12,13]. To define the optimal extent of lymphadenectomy with cystectomy, we have previously performed a prospective patho-anatomical single-center study with a total of 200 patients who underwent RC and extended lymphadenectomy up to the level of origin of the inferior mesenteric artery [14]. We did not find skipped lesions, and we defined the endopelvic site composed of the internal, external iliac, and obturator groups of lymph nodes as a sentinel region, concluding that a more proximal dissection should be reserved for patients with positive lymph nodes in this region. The purpose of the current study was to evaluate the longterm disease-free survival outcome of these patients [14] and to compare it with that of patients with standard lymphadenectomy in a large, prospective, single-institution cohort. 2. Patients and methods 2.1. Patient selection This was an institutional review board approved, prospective, nonrandomized study. Preoperative patient evaluation included routine clinical assessment, bimanual examination under anesthesia, cystoscopy, and biopsy. Abdominal sonography, chest x-ray, and computed tomography with contrast material were done. Informed consent was obtained from all patients prior to surgery. Between 1999 and 2003, 400 consecutive patients with invasive bladder cancer were treated with RC and standard (n = 200) or extended (n = 200) lymphadenectomy at the Urology and Nephrology Center of Mansoura University. The 200 patients with extended lymphadenectomy have been previously analyzed in a patho-anatomical study [14]. The patients did not receive any neoadjuvant or adjuvant therapy. 2.2. Operation The procedure was performed by only two surgeons (HA-E, MAG), as described previously [14]. The proximal extent of lymphadenectomy was at the level of origin of the inferior mesenteric artery for the extended lymphadenectomy group [14] and at the level of the bifurcation of the common iliac vessels (distal inch of the common iliac artery) for the standard lymphadenectomy group, as described previously [15]. Extended lymphadenectomy was performed for study purposes [14] and is not routine in our current practice. The surgeon decided about the performance of an extended lymphadenectomy intraoperatively, depending on liver status. Body mass index, performance status, and clinical tumor stage and grade did not play a role. 2.3. Pathologic evaluation All surgical specimens were processed according to standard pathologic procedures by a single uropathologist. Harvested nodes were identified by visual inspection and/or tactile sensation. No fat clearing technique was done. The number of retrieved nodes per anatomical group was determined. Each detected node was sharply bisected, and multiple sections were obtained for histologic examination. The fixed bladder specimen was opened, and tissue sections from the tumor were obtained. The TNM classification was used for pathologic staging, and the World Health Organization classification was used for histologic typing and grading. 2.4. Follow-up Follow-up was performed according to our institutional protocol. In general, patients were seen postoperatively at least every 3 4 mo for the first year, semiannually for the second year, and annually thereafter. Follow-up visits consisted of physical examination and serum chemistry evaluation. Diagnostic imaging of the upper tracts and chest radiography were performed at least annually or when clinically indicated. Additional radiographic evaluation was performed at the discretion of the treating physician. When patients died, the cause of death was determined by the treating physicians, by chart review, by family interrogation, or by death certificates alone. 2.5. Statistical analysis Continuous variables were compared between groups using either the two-sample t test or the Wilcoxon rank-sum test; categoric variables were compared using the chi-square test. Disease-free survival was estimated by the Kaplan-Meier method, and differences were assessed with the log-rank statistic. The period of disease-free survival was defined as the time between the date of surgery and death (from cancer) or the development of local recurrence or distant metastasis. Death from an unknown cause was considered death from cancer. Censored survival values represent patients who were alive without clinical evidence of disease at last follow-up. Multivariate Cox proportional hazards regression analysis was used to study the simultaneous effects of prognostic factors on disease-free survival. All reported p values are twosided, and statistical significance was set at p < 0.05. Statistical tests were performed with SPSS v.16.0.0 (IBM Corp., Somers, NY, USA). 3. Results 3.1. Clinical and pathologic characteristics Four hundred patients with bladder cancer underwent RC with lymphadenectomy. Median age in the entire patient group was 53.0 yr (interquartile range [IQR]: 13.0). Of the 400 patients, 200 (50.0%) had standard lymphadenectomy and the other 200 (50.0%) received extended lymphadenectomy. The clinical and pathologic features for these patients

574 EUROPEAN UROLOGY 60 (2011) 572 577 Table 1 Clinical and pathologic characteristics of 400 patients with standard versus extended lymphadenectomy at radical cystectomy Standard lymphadenectomy Extended lymphadenectomy p value No. of patients % No. of patients % Overall 200 50 200 50 Age, yr, median (IQR) 50.5 (12.0) 55.0 (12.0) 0.013 Age <40 26 13.0 15 13.0 0.006 41 50 74 37.0 52 26.0 51 60 72 36.0 88 44.0 >60 28 14.0 45 22.5 Gender Males 155 77.5 162 81.0 0.388 Females 45 22.5 38 19.0 Pathologic stage pt1 and/or CIS 29 14.5 23 11.6 0.141 pt2 32 16.0 47 23.6 pt3 139 69.5 129 64.8 Grade 1 48 24.0 35 17.6 <0.001 2 102 51.0 54 27.1 3 50 25.0 110 55.3 Histology TCC 89 44.5 115 57.5 0.129 SCC 89 44.5 68 34.0 Adenocarcinoma 16 8.0 17 8.5 Other 6 3.0 0 0.0 Lymph node status Negative 152 76 152 76 1 Positive 48 24 48 24 No. of lymph nodes removed, median (IQR) 16 (8.0) 49.0 (18.75) <0.001 CIS = carcinoma in situ; IQR = interquartile range; SCC = squamous cell carcinoma; TCC = transitional cell carcinoma. are compared in Table 1. Ninety-six of all patients (24.0%) had lymph node metastasis. There were no significant differences in gender, pathologic stage, histology, and proportion of lymph node positive patients between the groups (Table 1). Median age of patients with extended lymphadenectomy was significantly higher when compared with patients with standard lymphadenectomy (55.0 vs 50.5 yr; p = 0.013). As expected, patients with extended lymphadenectomy had a significantly higher lymph node count compared with patients with standard lymphadenectomy (49.0 vs 16.0 lymph nodes; p < 0.001), 3.2. Clinical outcomes Median follow-up was 50.2 mo (IQR: 69.0) for patients alive at last follow-up. Disease recurrence occurred in 141 patients (35.3%). In the extended lymphadenectomy group, a total of 85 patients (42.5%) were deceased at the time of analysis, including 59 patients (29.5%) who died of bladder cancer. In the standard lymphadenectomy group, a total of 90 patients (45%) were deceased at the time of analysis, including 73 patients (36.5%) who died of bladder cancer. In univariate analyses, age at time of RC, gender, grade, and histology (all p values >0.05) were not associated with disease-free survival. In multivariate analyses, pt category ( p < 0.001), lymph node involvement ( p < 0.001), and extended lymphadenectomy ( p = 0.02) were independently associated with disease-free survival (Table 2). When restricting analyses to the patients with transitional cell carcinoma (TCC), extended lymphadenectomy was still an independent predictor of disease-free survival in lymph node positive patients with TCC ( p = 0.01) but not in the whole group of patients with TCC ( p = 0.10). Five-year disease-free survival estimates in the extended lymphadenectomy group were 66.6% (95% confidence interval [CI], 60 73%) compared to 54.7% (95% CI, 48 61%) for patients with standard lymphadenectomy ( p =0.043) (Fig. 1a). The difference in survival did not remain significant when restricting analyses to lymph node negative patients (Fig. 1b). In contrast, lymph node positive patients with extended lymphadenectomy had much better 5-yr diseasefree survival when compared with patients with standard lymphadenectomy (48.0% vs 28.2%; p = 0.029) (Fig. 1c). Table 2 Multivariate analysis predicting disease-free survival in 400 bladder cancer patients Variable Multivariate analysis (stepwise backward elimination) HR 95% CI p value Pathologic category pt2 Referent pt3 4 3.6975 1.7854 7.6573 <0.001 Lymph node involvement 2.1718 1.5546 3.0339 <0.001 Extended lymphdenectomy 1.4510 1.060 1.9858 0.02 CI = confidence interval; HR = hazard ratio. *Age, gender, grade, and histology were nonsignificant variables.

[(Fig._1)TD$FIG] EUROPEAN UROLOGY 60 (2011) 572 577 575 A 100 Whole patient group Number of patients at risk Disease-free Survival (%) 80 60 40 20 p=0.043 Ext LAE: 66.6% Std LAE: 54.7% Years 0 1 3 5 Ext LAE 200 163 123 87 Std LAE 200 149 108 84 Number of cumulative events Years 1 3 5 Ext LAE 22 52 60 Std LAE 40 69 83 0 0 1 2 3 4 5 Time (years) B Disease-free Survival (%) 100 80 60 40 20 0 LN negative patients Ext LAE: 72.3% p=0.238 Std LAE: 66.2% 0 1 2 3 4 5 Number of patients at risk Years 0 1 3 5 Std LAE 152 120 94 78 Number of cumulative events Years 1 3 5 Ext LAE 10 31 38 Std LAE 24 38 47 Time (years) C 100 LN positive patients Disease-free Survival (%) 80 60 40 20 0 p=0.029 Ext LAE: 48.0% Std LAE: 28.2% 0 1 2 3 4 5 Number of patients at risk Years 0 1 3 5 Ext LAE 48 31 20 14 Std LAE 48 32 14 9 Number of cumulative events Years 1 3 5 Ext LAE 12 21 22 Std LAE 16 31 36 Time (years) Fig. 1 (a) Probability estimates of disease-free survival in 400 patients with bladder cancer stratified by extent of lymphadectomy. Probability estimates of disease-free survival in (b) 304 patients with lymph node negative bladder cancer and (c) 96 patients with lymph node positive bladder cancer, stratified by extent of lymphadectomy. LN = lymph node; LAE = lymphadenectomy; ext = extended; std = standard. 4. Discussion Despite the considerably large body of literature regarding the impact of lymphadenectomy on the outcomes after RC in patients with bladder cancer, there are conflicting data on the required extent of lymphadenectomy and its possible therapeutic effect. At present, clear recommendations about the field or extent of lymphadenectomy are missing in the European Association of Urology guidelines [16]. Several studies have indicated that the number of lymph nodes removed is a prognostic factor in bladder cancer patients [6 10,12,13]. Although several groups defined a minimum number of lymph nodes to be removed to confer a survival benefit [9,10,12,13], Koppie et al reported that the probability of survival rises as the number of lymph node removed increases [8]. Lymph node density describes the ratio of positive lymph nodes to the total number of retrieved nodes [17,18]. In a

576 EUROPEAN UROLOGY 60 (2011) 572 577 retrospective study, Herr found that cases with a ratio of 20% positive nodes after pelvic lymphadenectomy had significantly better survival than those with a ratio of >20% [17]. Stein et al analyzed their results with extended lymphadenectomy up to the aortic bifurcation and confirmed the prognostically relevant threshold of 20% [1]. However, the median number of nodes removed was 13 in the study by Herr [17] and 30 in the study by Stein et al [1]. Since then, lymph node density has been the subject of several reports, with wide variation in the number of retrieved nodes and different threshold values of lymph node density [19 21]. In our opinion, useful ratio-based lymph node staging would need a unified definition of the required extent of lymphadenectomy and an agreement on the optimal number of lymph nodes to be retrieved [22]. Only limited data are available regarding the impact of a defined anatomically extended lymphadenectomy on clinical outcome of bladder cancer patients. Poulsen et al compared extended lymph node dissection up to the aortic bifurcation and endopelvic lymph node dissection only [23]. The authors found that the extended dissection improved recurrence-free survival for patients with pt3 disease. Leissner et al reviewed their experience with extended lymphadenectomy up to the aortic bifurcation, but onethird of their cases were unfollowed [9]. They noted a significant survival advantage when 16 nodes were removed. Both studies were retrospective and lacked anatomic mapping of the retrieved lymph nodes [9,23]. Mills and associates reported their experience with lymph node positive patients treated by cystectomy and pelvic dissection up to the bifurcation of the common iliac arteries and found capsular infiltration to be the only independently significant prognostic factor [5]. Anatomic mapping of harvested lymph nodes was performed, but lymphadenectomy was limited to the pelvic lymph nodes [5,22]. As described, the number of lymphadenectomy studies from reputable centers is high, but to our knowledge, all have the inherent limitations of retrospective studies. The limits of lymphadenectomy were variable, and the mean numbers of retrieved nodes were different. Most studies involved multiple surgeons and pathologists, and this has most likely influenced results because the number of lymph nodes dissected is largely dependent on surgeon and pathologist [24,25]. To overcome the shortcomings of earlier studies, we performed a prospective, single-center study evaluating the impact of performance of a defined extended lymphadenectomy on disease-free survival. The operative procedure was performed by only two high-volume surgeons to subdue an operator-dependent variable. Specimens from individual anatomical regions were sent separately and were evaluated by a single uropathologist. We found that lymph node positive patients with standard lymphadenectomy had significantly worse 5-yr disease-free survival compared with lymph node positive patients who underwent extended lymphadenectomy (28.2% vs 48.0%). In multivariate analysis, extended lymphadenectomy was an independent prognostic factor for disease-free survival. These data support the conclusion that a considerable proportion of bladder cancer patients with nodal involvement can be cured by meticulous extended lymphadenectomy. To our knowledge, this is the first prospective, surgically controlled, single-center study with standardized pathologic work-up to evaluate the impact of an anatomically defined extended lymphadenectomy versus standard lymphadenectomy with regard to clinical outcome in bladder cancer patients. Debatable data exist regarding the distribution and spread of lymph node metastases in bladder cancer patients [4,14,26,27]. In our previous pathoanatomical study, we performed extended lymphadenectomy up to the level of origin of the inferior mesenteric artery to clarify the pattern of lymph node spread and the optimal extent of lymphadenectomy [14]. We showed that extrapelvic nodal metastasis was always associated with involvement of the obturator and/ or internal iliac nodes, suggesting that there were no skipped lesions. Thus we defined the endopelvic site as a sentinel region, concluding that a more proximal dissection should be reserved for patients with positive lymph nodes in this region [14]. This is supported by our present data showing no evidence of a difference in clinical outcomes of lymph node negative patients with extended versus standard lymphadenectomy. Several studies have documented that extended lymphadenectomy is not associated with increased morbidity [4,9,14,23,28]. Based on our previous [14] and present findings showing a possible disease-free survival advantage for the patients who underwent extended lymphadenectomy, we propose the following algorithm in our center: In case of suspicious or positive (frozen section) endopelvic lymph nodes, lymphadenectomy should be extended to the level of the aortic bifurcation. In patients with nonsuspicious endopelvic nodes, an extended lymphadenectomy is not necessary. Our study has important limitations. First and foremost are the limitations inherent in nonrandomized analyses. The surgeon decided about the performance of an extended lymphadenectomy, resulting in a possible selection bias. Theoretically, significant comorbidities might have led to more limited lymphadenectomy in a few patients compared with healthier patients. In this series, however, the only limiting factor for performance of extended lymphadenectomy was the patient s hepatic function. Furthermore, tumor recurrence was the primary focus of our study and is not affected by this. Another limitation is that our patient population consisted of 39.3% of patients with squamous cell carcinoma. However, it has been shown previously that the incidence of nodal disease and prognosis following cystectomy are independent of the tumor histology [29]. 5. Conclusions In this prospective, single-center cohort, we found that an anatomically defined extended lymphadenectomy up to the level of origin of the inferior mesenteric artery is associated with better disease-free survival for lymph node positive bladder cancer patients independent of

EUROPEAN UROLOGY 60 (2011) 572 577 577 other clinicopathologic features. Our data suggest that nodal disease by frozen section in the endopelvic region (standard lymphadenectomy) necessitates dissection up to the aortic bifurcation. Author contributions: Derya Tilki 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: Abol-Enein, Tilki, Ghoneim. Acquisition of data: Abol-Enein, Tilki, Mosbah, El-Baz, Shokeir, Nabeeh, Ghoneim. Analysis and interpretation of data: Abol-Enein, Tilki, Ghoneim. Drafting of the manuscript: Tilki, Abol-Enein. Critical revision of the manuscript for important intellectual content: Abol- Enein, Tilki, Ghoneim. Statistical analysis: Tilki, Abol-Enein. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Abol-Enein, Tilki, Ghoneim. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None. References [1] Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001;19:666 75. [2] Shariat SF, Palapattu GS, Karakiewicz PI, et al. Discrepancy between clinical and pathologic stage: impact on prognosis after radical cystectomy. Eur Urol 2007;51:137 51, discussion 149 51. [3] Hautmann RE, Gschwend JE, de Petriconi RC, Kron M, Volkmer BG. 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