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1 Outcomes of radical cystectomy with extended lymphadenectomy alone in patients with lymph node-positive bladder cancer who are unfit for or who decline adjuvant chemotherapy Pascal Zehnder*, Urs E. Studer, Siamak Daneshmand*, Frédéric D. Birkhäuser, Eila C. Skinner*, Beat Roth, Gus Miranda*, Fiona C. Burkhard, Jie Cai*, Donald G. Skinner*, George N. Thalmann and Inderbir S. Gill* *USC Institute of Urology, Catherine and Joseph Aresty Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA, and Department of Urology, University of Bern, Bern, Switzerland Objective To analyse the long-term outcomes of patients with lymph node (LN)-positive bladder cancer, who did not receive any adjuvant therapy after radical cystectomy (RC) and extended pelvic lymph node dissection (eplnd). Patients and Methods We conducted a retrospective, combined cohort analysis based on two prospectively maintained cystectomy databases from the University of Southern California and the University of Bern. Eligible patients underwent RC with eplnd for cn0m0 disease but were found to have LN-positive disease. No patient had neoadjuvant therapy, and all had negative surgical margins. Kaplan Meier plots were used to estimate recurrence-free survival (RFS) and overall survival (OS). Subgroup comparisons were performed using log-rank tests, and multivariable analysis was based on Cox proportional hazard models. Results Of 521 patients with LN-positive disease, 251 (48%) never received adjuvant therapy. Although the pathological stage distribution was similar, the 251 patients who did not receive adjuvant therapy were older and had both fewer total and positive LNs than those who underwent adjuvant therapy. The median RFS for patients treated with RC alone was 1.6 years. Recurrences mainly occurred <2 years after RC, resulting in 5- and 10-year RFS rates of 32 and 26%, respectively. Pathological T stage, the total number of LNs and the number of positive LNs detected were independent predictors of RFS and OS. Conclusions In this study, 25% of patients with documented LN metastases who did not receive adjuvant therapy were cured with RC and eplnd; however, a few relapses may occur later than 3 years. Predictors of survival were pathological T stage, the number of total LNs and the number of positive LNs identified. Keywords cystectomy, extended lymphadenectomy, no chemotherapy, outcome Introduction Up to 25% of patients undergoing radical cystectomy (RC) and extended pelvic lymph node dissection (eplnd) for carcinoma invading the bladder muscle are unexpectedly found to have lymph node (LN) metastases [1 6]. This reflects the low sensitivity of preoperative nodal staging with the imaging techniques currently available [7] and also shows there is early extravesical tumour involvement in a substantial number of patients. The majority of recurrences in patients with LN-positive disease occur within the first 2 years of radical surgery. The overall survival (OS) rate at 5 years has been observed to be 15 30% [3,8]. It is often argued that this survival may be attributable to adjuvant chemotherapy. To find out whether there is a chance of survival for patients with LN-positive disease who do not receive postoperative chemotherapy and/or radiation, we analysed their long-term outcomes in a large combined cohort of patients with unexpectedly LN-positive disease after RC with eplnd alone. BJU Int 2014; 113: wileyonlinelibrary.com BJU International 2013 BJU International doi: /bju Published by John Wiley & Sons Ltd.

2 Long-term outcomes after RC with eplnd alone in patients with LN-positive bladder cancer Patients and Methods Study Population The University of Southern California (USC) and the University of Bern (UB) maintain two independent, institutional review board- and ethical committee-approved bladder cancer databases, which have prospectively accrued data on >4100 patients who have undergone cystectomy since The present study consists of data collected from the two participating sites, which provided the necessary institutional data-sharing agreements. The study included 521 patients who underwent RC and eplnd with curative intent for clinically non-metastatic urothelial carcinoma invading the bladder muscle (cn0m0: CT or MRI no enlarged LNs; in patients treated before 1980, no palpable LNs at surgery), but were found to have LN metastasis on histopathological analysis. None of the patients received neoadjuvant therapy and all had negative surgical margins. Both USC and UB performed an eplnd, but the cephalad boundaries differed between the two institutions; at USC, the boundary was typically at the inferior mesenteric artery, while cephalad dissection at UB was performed up to the mid-upper third of the common iliac artery [9]. For pathological staging, the 1997 TNM American Joint Committee and Cancer classification was used [10]. In terms of follow-up, patients at USC were seen at 4-month intervals in the first year, 6-month intervals in the second year, and annually thereafter. At UB, patients were examined at 3, 6 and 12 months in the first year, every 6 months for 5 years, and annually thereafter. At both institutions, basic follow-up visits consisted of a physical examination and blood tests. At USC, CT scans and bone scans were performed 4 months postoperatively, semi-annually for the second year, and annually thereafter. At UB, patients with LN-positive disease underwent CT scans and bone scans at 6, 12 and 18 months. In the pre-ct era, patients were followed with urine cytology, radiographical evaluation of the upper urinary tract and urinary diversion as well as chest radiography at both institutions. With regard to recurrences, any pelvic soft tissue density 2 cm inferior to the aortic bifurcation was defined as a local recurrence, while all other sites were captured as systemic recurrences. Statistical Analysis Recurrence-free survival (RFS) and OS were analysed according to pathological T stage subgroup (< pt3, pt3), total number of LNs (<20, 20) and number of positive LNs identified (1 2, 3 10, >10). For statistical evaluation, the software package SAS version 9.2 (SAS Institute Inc., Cary, NC, USA) was used. The association between categorical demographic and clinical variables was examined using Pearson s chi-squared or Fisher s exact test. Differences in not normally distributed continuous variables were assessed using the Wilcoxon rank-sum test. Survival probabilities were estimated using Kaplan Meier plots and log-rank tests were used to compare the differences in subgroups. Through backward stepwise elimination within Cox proportional hazard models, independent predictive factors were evaluated in the multivariable setting. A P value <0.05 was considered to indicate statistical significance and all P values reported are two-sided. Results Of the 521 patients who underwent RC and had LN-positive disease, 256 patients received adjuvant chemotherapy while 14 patients underwent both adjuvant radiation and chemotherapy. The median follow-up was 9.2 years (range: 3 days to 28.2 years). A total of 251 patients (48%) did not receive any adjuvant therapy. The latter cohort was significantly (P < 1) older at intervention (median [range] age: 70 [38 89] years) than those who received adjuvant therapy (median [range] age: 64 [35 87] years), but the pathological tumour stage distribution between these groups was similar (P = 0.41). Focusing on LN variables, a lower number of total LNs (P < 1) and fewer positive LNs (P = 3) were identified in patients treated with RC alone (Table 1). The median (range) RFS and OS for patients who underwent RC alone were 1.6 ( ) years and 1.5 years (3 days to 23.9 years), respectively, and for patients who received Table 1 Demographic and pathological characteristics of patients with LN-positive disease treated with RC alone or combined with adjuvant chemotherapy. Characteristic RC alone With adjuvant therapy No of patients, n (%) Age at surgery Median (range) 70 (38 89) 64 (35 87) <1 65 years, n (%) 180 (72) 124 (46) Gender: M/F 186/65 209/ pt stage, n (%) 0.41 pt0 2 (1) 0 ptis pta 2 (1) 3 (1) pt1 11 (4) 15 (6) pt2a 21 (8) 24 (9) pt2b 20 (8) 36 (13) pt3a 50 (20) 55 (20) pt3b 96 (38) 96 (36) pt4a 45 (18) 39 (14) pt4b 4 (2) 2 (1) Organ-confined disease:<pt3, n (%) 56 (22) 78 (29) 0.09 Extravesical disease: pt3, n (%) 195 (78) 192 (71) Number of total LNs identified Median (range) 29 (6 140) 39 (6 142) <1 Patients with <20 LNs, n (%) 74 (29) 51 (19) 5 Patients with 20 LNs, n (%) 177 (71) 219 (81) Number of positive LNs detected Median (range) 2 (1 97) 3 (1 63) positive LNs, n (%) 151 (60) 126 (47) positive LNs, n (%) 73 (29) 108 (40) >10 positive LNs, n (%) 27 (11) 36 (13) P BJU International 2013 BJU International 555

3 Zehnder et al. Fig. 1 Recurrence-free survival of patients with LN-positive disease after RC alone or combined with adjuvant chemotherapy. RC alone n = RC with adjuvant chemotherapy n = Years Patients (n) Years Patients (n) Radical surgery alone With adjuvant therapy P-value Recurrence-free survival P=2 5 years (%) 32 ± 4 40 ± 3 10 years (%) 26 ± 4 36 ± 3 Table 2 Recurrence-free and overall survival at 5 and 10 years, according to pathological subgroup, number of total LNs and number of positive LNs identified in patients with LN-positive disease after RC alone. Patients 5-year RFS, % 10-year RFS, % P 5-year OS, % 10-year OS, % P Pathological subgroup Organ-confined disease (< pt3) ± 8 39± ± 7 31± 7 <1 Extravesical disease ( pt3) ± 4 22± 4 18± 3 10± 3 Number of total of LNs identified Patients with <20 LNs ± 5 17± ± 4 7± Patients with 20 LNs ± 4 31± 5 27± 4 19± 4 Number of positive LNs identified 1 2 positive LNs ± 5 31± 5 <1 32 ± 4 20± 4 < positive LNs ± 7 24± 7 15± 5 8± 4 >10 positive LNs 36 6 ± 5 0 3± 3 0 adjuvant therapy they were 2.5 ( ) years and 2.8 ( ) years, respectively. The majority of recurrences occurred within the first 2 years, with 5- and 10-year RFS rates of 32 and 26%, respectively, after RC alone and 40 and 36%, respectively, after RC combined with adjuvant therapy. The 5- and 10-year OS rates after RC alone were significantly (P < 1) lower (23 and 15%) compared with rates of patients with adjuvant therapy (39 and 33% [Fig. 1]). After RC alone, RFS was negatively influenced by extravesical disease (P = 1) and an increasing number of positive LNs (P < 1 [Table 2, Figs 2,3]). RFS was not significantly poorer in patients with <20 total LNs (P = 0.08 [Fig. 4]). The probability of OS decreased with extravesical disease (P < 1), <20 total LNs (P = 0.02) and an increasing number of positive LNs (P < ). In the Cox regression model for multivariate analysis, significant risk factors predictive of worse RFS were pathological T stage ( pt3), no adjuvant chemotherapy, fewer total LNs identified (<20) and a higher number of positive LNs (3 10 or >10 LNs [Table 3A]). In addition to these factors, patient age ( 65 years) was also predictive of worse OS (Table 3B). Among the 13 patients with LN-positive disease with >10 years RFS after RC alone, 77% were <65 years old at intervention and 54% had organ-confined primary tumours at histopathology. Equally 69% had >20 total LNs identified and LN metastasis limited to a solitary LN. There was no distinction in terms of age and pathological features when compared with long-term survivors after RC combined with adjuvant therapy (Table 4). Discussion For patients with carcinoma invading the bladder muscle, RC with eplnd is the mainstay of therapy. With the implementation of neoadjuvant chemotherapy, a survival benefit of 5% has been reported, with younger patients more 556 BJU International 2013 BJU International

4 Long-term outcomes after RC with eplnd alone in patients with LN-positive bladder cancer Fig. 2 Recurrence-free survival of patients with LN-positive disease according to pt stage of the primary tumour after RC alone. P = 1 <pt3 (n = 56) pt3 (n = 195) Years Patients (n) <pt pt Fig. 3 Recurrence-free survival of patients with LN-positive disease according to the number of P < 1 positive LNs after RC alone. 1 2 LNs (n = 151) 3 10 LNs (n = 64) >10 LNs (n = 36) Years Patients (n) 1 2 +LN LN >10 +LN likely to receive chemotherapy [11]. There are insufficient data to prove the survival benefit of adjuvant chemotherapy [12]. Patient s compliance and postoperative convalescence play an important role. Although early systemic therapy is thought to potentially treat micrometastases, even in the context of randomized trials only 48 69% of participants finally receive the planned adjuvant treatment dose [13 15]. Within our combined cohort, 48% of patients (n = 251) with unexpected LN metastases after RC for clinical stage cn0m0 bladder cancer never received any adjuvant therapy. Despite this, we found that RC including a meticulous eplnd provided long-term RFS in 25% of these patients. In addition, pathological T stage, the total number of LNs and the number of positive LNs identified were further predictors of survival that significantly influenced outcome. Focusing on the two small subgroups of patients with >10-year RFS, no differences in terms of age and pathological features were found. Overall, patients with an organ-confined primary tumour and limited nodal involvement [16] after radical surgery have the best chance of long-term cure. Once the tumour has breached the lymphatic defence and systemic spread is reached, patients can rarely be cured. Our survival rates are consistent with a recently published surgery-only series [17], but the pelvic lymph node dissection (PLND) template within that large single-centre cohort changed over time. Moreover, the total number of LNs BJU International 2013 BJU International 557

5 Zehnder et al. P = total LNs (n = 177) <20 total LNs (n = 74) Fig. 4 Recurrence-free survival of patients with LN-positive disease according to total number of LNs identified after RC alone. Years Patients (n) 20 LNs <20 LNs Table 3 Multivariable Cox regression model addressing (A) RFS and (B) OS in patients with LN-positive disease. Variables Hazard ratio (95% CI) P (A) RFS Age ( 65 vs <65 years) 1.11 ( ) 0.37 Pathological subgroup ( pt3 vs<pt3) 1.90 ( ) <1 Adjuvant chemotherapy (Yes vs No) 0.64 ( ) <1 Number of total LNs ( 20 vs <20) 0.71 ( ) 9 Number of positive LNs (3 10 vs 1 2) 1.75 ( ) <1 Number of positive LNs (>10 vs 3 10) 3.06 ( ) <1 (B) OS Age ( 65 vs <65 years) 1.40 ( ) 3 Pathological subgroup ( pt3 vs<pt3) 2.08 ( ) <1 Adjuvant chemotherapy (Yes vs No) 0.51 ( ) <1 Number of total LNs ( 20 vs <20) 0.66 ( ) <1 Number of positive LNs (3 10 vs 1 2) 1.90 ( ) <1 Number of positive LNs (>10 vs 3 10) 3.67 ( ) <1 resected in patients who underwent surgery until 1994 was only reported in a minority of cases. Similarly, the results from a large multicentre analysis focusing on outcomes and prognostic factors in patients with a single LN metastasis at time of RC require cautious interpretation because the extent of PLND at the 12 participating centres was at the surgeon s discretion [18]. This underlines the challenge when comparing such studies. While it is recognized that a smaller absolute number of involved LNs offers a significantly better survival rate [3,16,19], there are conflicting data on the impact on survival of the number of total LNs identified [6,20,21]. Interestingly, the threshold of 20 total LNs identified in the present combined series of patients with unexpectedly LN-positive disease was an independent predictor of survival for the two institutions, despite obvious differences regarding the median number of LNs identified per patient [9]. A nodal yield of 20 Table 4 Demographic and pathological characteristics of patients with long-term (>10 years) RFS after RC alone or combined with adjuvant chemotherapy. RC alone, n (%) With adjuvant therapy, n (%) No. of patients Age at surgery 0.49 <65 years 10 (77) 26 (67) 65 years 3 (23) 13 (33) Pathological subgroup 0.63 Organ-confined disease: <pt3 7 (54) 18 (46) Extravesical disease: pt3 6 (46) 21 (54) Number of total LNs 0.58 Patients with <20 LNs 4 (31) 9 (23) Patients with 20 LNs 9 (69) 30 (77) Number of positive LNs positive LN 9 (69) 18 (46) 2 positive LNs 2 (15.5) 9 (23) 3 5 positive LNs 2 (15.5) 9 (23) >5 positive LNs 0 3 (8) is in line with the mean number of LNs identified by an autopsy study [22]; however, the authors of that study detected striking inter-individual differences ranging from only 8 to 56 pelvic LNs per patient. In addition to the substantial physiological inter-individual variability, total LN yield is further influenced by multiple factors such as lymphadenectomy template, tissue submission technique, pathological evaluation, including the definition of a LN etc [23 26]. Ultimately, these variables result in substantial inter-institutional distinctions; therefore, the number of total LNs identified may serve at most as an institutional average standard but cannot be used as a generally applicable surrogate for the quality of an eplnd in the individual case. Further comparison of LN variables in the present series showed that a lower number of total LNs and fewer positive P 558 BJU International 2013 BJU International

6 Long-term outcomes after RC with eplnd alone in patients with LN-positive bladder cancer LNs were identified within the specimens of the more elderly patients with RC alone. As shown recently, numerous patient characteristics such as age, body mass index, clinical tumour stage, type of tumour growth, multifocality and surgical margins can influence the number of lymph nodes identified [27]. Additionally, even at our two institutions with a policy of performing a thorough eplnd, older and potentially sicker patients may have undergone an abbreviated eplnd, despite the fact that all patients underwent surgery with curative intent. Potentially, the performance of a less meticulous eplnd in these significantly older patients may have left LNs with micrometastatic disease behind, and consequently may have provided a less accurate postoperative nodal staging. At least part of the better RFS and OS times in patients after RC combined with adjuvant therapy could therefore simply reflect the Will Rogers phenomenon [28]. Undoubtedly, a thorough eplnd prolongs the surgical procedure but it can offer long-term survival to patients with even grossly LN-positive bladder cancer [29]. Careful perioperative management makes it possible that even elderly patients can tolerate the procedure without the need to abbreviate parts of it [30 32]. Our main focus of interest was the oncological outcomes of patients with LN-positive disease undergoing RC alone. The retrospective, non-randomized design of the present study does not allow us to draw any conclusions regarding the efficacy of adjuvant therapy. By contrast, the comparison of demographic and pathological characteristics of patients undergoing RC alone with features of patients who received adjuvant therapy shows significant differences and confirms the substantial underlying patient selection bias. It is also likely, that patients with fewer positive LNs may have been less strongly recommended to undergo chemotherapy. These types of selection biases may partly explain the observations in the present study. Another limitation is that we were unable to make any comments about the number of patients who were initially recommended to undergo adjuvant chemotherapy but never received it, nor were we aware of the reasons for not undergoing it. It remains an open question if, given the choice preoperatively, more of the elderly patients at risk would have undergone neoadjuvant chemotherapy and if they would have done even better with such a treatment. Finally, although extranodal extension has been shown to be an independent prognosticator, this variable could not be analysed in the present study because it was not available for the patients at the USC. Nevertheless, we believe that the long follow-up, the large consecutive patient series, and the consistency of surgical technique and education at the two institutions make this combined cohort uniquely suited to address the long-term outcomes of a surgery-only series. The present study shows that high-quality RC with a thorough eplnd alone can offer long-term RFS in 25% of patients with LN-positive disease who do not qualify for or who refuse adjuvant therapy. Predictors of survival were pathological T stage, the number of total LNs identified and the number of positive LNs detected. In summary, the relatively young patient with limited nodal involvement has the best chance of cure with RC alone. Conflict of Interest None declared. References 1 Leissner J, Ghoneim MA, Abol-Enein H et al. Extended radical lymphadenectomy in patients with urothelial bladder cancer: results of a prospective multicenter study. J Urol 2004; 171: Vazina A, Dugi D, Shariat SF, Evans J, Link R, Lerner SP. 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7 Zehnder et al. 17 Hautmann RE, de Petriconi RC, Pfeiffer C, Volkmer BG. Radical cystectomy for urothelial carcinoma of the bladder without neoadjuvant or adjuvant therapy: long-term results in 1100 patients. Eur Urol 2012; 61: Rink M, Hansen J, Cha EK et al. Outcomes and prognostic factors in patients with a single lymph node metastasis at time of radical cystectomy. BJU Int 2013; 111: Lerner SP, Skinner DG, Lieskovsky G et al. The rationale for en bloc pelvic lymph node dissection for bladder cancer patients with nodal metastases: long-term results. J Urol 1993; 149: ; discussion Leissner J, Hohenfellner R, Thuroff JW, Wolf HK. Lymphadenectomy in patients with transitional cell carcinoma of the urinary bladder; significance for staging and prognosis. BJU Int 2000; 85: Fleischmann A, Thalmann GN, Markwalder R, Studer UE. Extracapsular extension of pelvic lymph node metastases from urothelial carcinoma of the bladder is an independent prognostic factor. J Clin Oncol 2005; 23: Weingartner K, Ramaswamy A, Bittinger A, Gerharz EW, Voge D, Riedmiller H. Anatomical basis for pelvic lymphadenectomy in prostate cancer: results of an autopsy study and implications for the clinic. J Urol 1996; 156: Dorin RP, Daneshmand S, Eisenberg MS et al. Lymph node dissection technique is more important than lymph node count in identifying nodal metastases in radical cystectomy patients: a comparative mapping study. Eur Urol 2011; 60: Svatek R, Zehnder P. Role and extent of lymphadenectomy during radical cystectomy for invasive bladder cancer. Curr Urol Rep 2012; 13: Fang AC, Ahmad AE, Whitson JM, Ferrell LD, Carroll PR, Konety BR. Effect of a minimum lymph node policy in radical cystectomy and pelvic lymphadenectomy on lymph node yields, lymph node positivity rates, lymph node density, and survivorship in patients with bladder cancer. Cancer 2010; 116: Bochner BH, Cho D, Herr HW, Donat M, Kattan MW, Dalbagni G. Prospectively packaged lymph node dissections with radical cystectomy: evaluation of node count variability and node mapping. J Urol 2004; 172 (4 Pt 1): Mitra AP, Syan R, Skinner EC et al. Factors influencing lymph node yield during radical cystectomy with extended pelvic lymphadenectomy: single-institution experience with a standardized dissection template. Abstract Annual American Urological Association Meeting Atlanta GA, USA Gofrit ON, Zorn KC, Steinberg GD, Zagaja GP, Shalhav AL. The Will Rogers phenomenon in urological oncology. J Urol 2008; 179: Herr HW, Donat SM. Outcome of patients with grossly node positive bladder cancer after pelvic lymph node dissection and radical cystectomy. J Urol 2001; 165: 62 4; discussion Stroumbakis N, Herr HW, Cookson MS, Fair WR. Radical cystectomy in the octogenarian. J Urol 1997; 158: Froehner M, Brausi MA, Herr HW, Muto G, Studer UE. Complications following radical cystectomy for bladder cancer in the elderly. Eur Urol 2009; 56: Brossner C, Pycha A, Toth A, Mian C, Kuber W. Does extended lymphadenectomy increase the morbidity of radical cystectomy? BJU Int 2004; 93: 64 6 Correspondence: Pascal Zehnder, Department of Urology, University Hospital of Bern, Inselspital, 3010 Bern, Switzerland. pascal.zehnder@insel.ch Abbreviations: LN, lymph node; RC, radical cystectomy; PLND, pelvic lymph node dissection; eplnd, extended PLND; RFS, recurrence-free survival; OS, overall survival; USC, University of Southern California; UB, University of Bern. 560 BJU International 2013 BJU International