Radical Cystectomy for Urothelial Carcinoma of the Bladder Without Neoadjuvant or Adjuvant Therapy: Long-Term Results in 1100 Patients

EUROPEAN UROLOGY 61 (2012) 1039 1047 available at www.sciencedirect.com journal homepage: www.europeanurology.com Bladder Cancer Radical Cystectomy for Urothelial Carcinoma of the Bladder Without Neoadjuvant or Adjuvant Therapy: Long-Term Results in 1100 Patients Richard E. Hautmann a, *, Robert C. de Petriconi a, Christina Pfeiffer b, Bjoern G. Volkmer a,b a Department of Urology, University of Ulm, Ulm, Germany; b Department of Urology, Klinikum Kassel, Kassel, Germany Article info Article history: Accepted February 14, 2012 Published online ahead of print on February 22, 2012 Keywords: Bladder neoplasms Cystectomy Mortality Neobladder Stage Survival Urothelial carcinoma Abstract Background: The optimal treatment strategy for muscle-invasive bladder cancer (BCa) remains controversial. Objective: Better define the long-term outcomes of radical cystectomy (RC) alone for BCa and determine the impact of pathologic downstaging after transurethral resection in a large and homogeneous single-center series. Design, setting, and participants: A cohort of 1100 patients undergoing RC with pelvic lymph node dissection (PLND) without neoadjuvant therapy for urothelial carcinoma of the bladder between January 1, 1986, and December 2009 was evaluated. Patients with other than metastases to the pelvic lymph nodes were excluded. Median age was 65 yr. Clinical course, pathologic characteristics, and long-term outcomes were evaluated. Follow-up was obtained until December 2009 with a median of 38 mo and a completeness of 96.5%. Intervention: RC with PLND; urinary diversion with ileal neobladder whenever possible. Measurements: Primary end points were disease-specific survival (DSS), recurrencefree survival (RFS), and overall survival (OS) according to the tumor stage of the RC specimen versus the maximum tumor stage. The log-rank test was used to compare subgroups. Results and limitations: The 30-d (90-d) mortality rate was 3.2% (5.2%). The 10-yr OS, DSS, and RFS rates were 44.3%, 66.8%, and 65.5%, respectively. Based on the tumor stage of the RC specimen, the 10-yr DSS rate was pt0/a/is/1 pn0: 90.5%, pt2a/b pn0: 66.8%, pt3a/b pn0: 59.7%, pt4a/b pn0: 36.6%, and ptall pn+: 16.7%. Downstaging by transurethral resection of the prostate was observed in 382 patients. Patients with maximum tumor stage pt2a/b pn0 had distinctly better 10-yr DSS rates than those with pt2a/b pn0 in the RC specimen: pt2a pn0: 92.2% versus 73.8%; pt2b: 75.0% versus 62.0%. A total of 49% female and 80% male patients received an ileal neobladder. Conclusions: This contemporary and homogeneous single-center series found acceptable OS, DFS, and RFS for patients undergoing RC. Pathologic downstaging had a significant impact on survival. # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Boschstrasse 4 a, 89231 Neu-Ulm, Germany. Tel.: +49 731 1538750; Fax: +49 731 1538752. E-mail address: richard.hautmann@uni-ulm.de (R.E. Hautmann). 0302-2838/$ see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2012.02.028

1040 EUROPEAN UROLOGY 61 (2012) 1039 1047 1. Introduction Pathologic stage and lymph node (LN) status have consistently been shown to be the most powerful independent predictors of long-term outcome following radical cystectomy (RC) [1 8]. However, significant disparity in the quality of reporting and the lack of universally accepted reporting guidelines, definitions, and grading systems have made it difficult to compare outcomes in urologic oncology patients [9]. Very different definitions of tumor stage (stage of the RC specimen vs maximum stage of transurethral resection of the bladder tumor [TURBT] and RC specimens), different definitions of tumors in the upper urinary tract or the urethra (tumor recurrence vs second primary malignancy), and different end points (recurrence-free survival [RFS] versus disease-specific survival [DSS] versus overall survival [OS]) must be considered when comparing the results of different series. Although neoadjuvant chemotherapy is now considered the standard of care in patients with muscle-invasive bladder cancer (BCa) according to the 2011 European Association of Urology guidelines [8], recommendations for adjuvant radiotherapy and/or chemotherapy are still under debate. Changing concepts about the extent of pelvic node dissection (PLND) are potential relevant factors for survival as well as the attempt of prostate-sparing cystectomy. The aim of this study was to better define long-term results from an extended follow-up of our large and homogeneous contemporary single-center surgery-only series [4]. 2. Patients and methods We established a computerized database containing comprehensive clinical and pathologic information on all 1614 patients who underwent RC at the University of Ulm between January 1986 and December 2009. To analyze a homogeneous population, the following inclusion criteria for this study were defined: Primary malignant tumor of the bladder Urothelial carcinoma (UCa) No neoadjuvant radiotherapy and/or chemotherapy No adjuvant radiotherapy and/or chemotherapy RC with bilateral PLND No positive surgical margins (R1/R2). For the purpose of this study, 514 of 1614 patients were excluded from the analysis (Table 1). All 1100 patients meeting these criteria were included: 892 men (81.1%) and 208 women (18.9%). None of them had LN metastases outside the true pelvis or distant organ metastases in the preoperative assessment or intraoperatively. Our standard preoperative assessment protocol included physical examination, chest x-ray, computed tomography of the pelvis, ultrasonography of the abdomen, bone scan, and excretory urography. All patients underwent a previously described standard surgical procedure, including a meticulous PLND with en bloc RC and urinary diversion [4,10]. PLND included at least the obturator fossa and the lymphatic tissue along the external and internal iliac artery in separate samples. Although the number of positive LNs was available in all pathology reports, the total number of LNs resected was reported in a Table 1 Reasons for exclusion from the study * No. of excluded patients No malignant disease 81 No primary malignant tumor of the bladder 55 Nonurothelial primary malignant 21 tumor of the bladder Carcinoma of the bladder other 101 than urothelial carcinoma Adjuvant radiotherapy and/or chemotherapy 106 Neoadjuvant radiotherapy and/or chemotherapy 87 Distant metastases 49 R1 or R2 resection ** 29 No bilateral pelvic lymph node dissection *** 11 Total no. of patients excluded 514 * Total population: n = 1614. Patients may be excluded for several reasons. ** All patients with R1 resection had adjuvant radiotherapy and/or chemotherapy. All cases with R2 resection had radical cystectomy performed for palliation only. *** Cases with previous radical prostatectomy and pelvic lymph node dissection for prostate cancer or cases with radical cystectomy performed for palliation only. minority of cases until 1994. In 1995 we extended the upper limit of the template of the LN dissection to the aortic bifurcation. Since 2001 an increasing number of patients have had an extended field LN dissection including LNs along the vena cava and the aorta up to the inferior mesenteric artery and from the presacral region. The extent of LN dissection was the only major change in the surgical approach over time. Orthotopic bladder substitution became the preferred form of diversion at our institution for men in 1986 and for womenin1994. Pathologic staging of bladder tumors and LNs was performed according to the 2002 TNM classification [11]. All cases treated before 2002 were reclassified. Pathologic subgroups were defined as organ confined (<pt3a pn0 cm0), non organ confined (>pt2b pn0 cm0), and LN positive (pn+). Reclassification according to the 2010 TNM classification [12] could not be performed because we had no complete information on the precise localization of the positive LNs. In all cases the slides of the TURBT specimens were reviewed. To assess the maximum tumor stage, the tumor was classified after review of the TURBT and the RC specimens. According to a prospective protocol, patients were seen according to a follow-up protocol similar to that presented later on by Bochner et al. [13]. All follow-up data were recorded, including tumor recurrence and therapy, intercurrent diseases, complications, and time andcause of death. Perioperative mortality was defined as any death within 90 d of surgery. The first site of BCa recurrence was classified as local (pelvic) or distant (metastatic). Cases with simultaneous local and distant recurrence were classified as distant metastasis according to the publication by Madersbacher et al. [3]. Tumor recurrence in the urinary tract (upper tract or urethra) was considered a second primary malignancy. Follow-up was defined as the interval from RC until death or until December 2008. The median follow-up for the cohort is 38 mo (range: 0 282 mo); the completeness of follow-up was 96.5% according to the recommendations of Clark et al. [14]. The primary end point for OS was death, for DSS was tumor-related death, and for RFS was the first date of tumor recurrence. Kaplan-Meier plots were used to calculate OS, DSS, and RFS; the log-rank test was used to compare subgroups of patients in terms of survival and time to recurrence. American Society of Anesthesiologists (ASA) score and Charlson index (CI) [15] were retrospectively collected from the preoperative anesthesia assessment before RC.

EUROPEAN UROLOGY 61 (2012) 1039 1047 1041 Table 2 Patient characteristics Total n = 1100 Men n = 892 (81.1%) Women n = 208 (18.9%) Age, yr Range 23 91 Mean 64.3 Median 65 ASA score ASA 1 n = 95 (8.6%) ASA 2 n = 444 (40.4%) ASA 3 n = 386 (35.1%) ASA 4 n = 15 (1.4%) Unknown n = 158 (14.4%) pt0 cystectomy specimen n = 208 (18.9%) Maximum tumor stage (TURBT and cystectomy specimen) pta/is/1 pn0 M0 n = 284 (25.8%) pt2a/b pn0 M0 n = 403 (36.6%) pt3a/b pn0 M0 n = 157 (14.3%) pt4a/b pn0 M0 n = 56 (5.1%) ptall pn+ M0 n = 200 (18.2%) ASA = American Society of Anesthesiologists; TURBT = transurethral resection of bladder tumor. 3. Results Patient characteristics are presented in Table 2. Median age was 65 yr (range: 23 91 yr). The distribution of the tumor stages of the RC specimens is presented in Table 3. RC was performed for a primary tumor in 800 cases and for recurrent BCa in 300 cases. The mean number of previous TURBTs was 1.9 (range: 1 48). The mean time from the first diagnosis of BCa to RC was 14.9 mo (range: 0 283 mo) (primary UCa: 2.4 mo; recurrent UCa: 48.7 mo). RC was performed within 90 d after the first TURBT in 689 patients (62.7%). The mean number of LNs resected was 18 (range: 1 63). A total of 253 men (28.4%) had a synchronous or metachronous adenocarcinoma of the prostate. The 30-d (90-d) mortality rate in this series was 3.2% (5.2%). A total of 36 patients died within 30 d after cystectomy (pulmonary embolism: n = 6; myocardial infarction: n = 4; stroke: n = 2; acute respiratory distress syndrome: n = 3; infarction of the mesenteric artery: n = 1; septicemia: n = 14; pneumonia: n = 5). These deaths were classified as disease related. The 10-yr OS rate in the complete series was 44.3%. The RFS rate and DSS rate at 10 yr were 65.5% and 66.8% (Fig. 1). Increasing pathologic stage and LN-positive disease were associated with significantly higher rates of tumor recurrence and worse OS ( p < 0.001) (Fig. 2). Twenty years postoperatively, the probability of tumorrelated death according to the maximum tumor stage was pta/is/1 pn0: 11.1%; pt2a/b pn0: 35.1%; pt3a/b pn0: 40.3%; pt4a/b pn0: 68.6%; and ptall pn+: 85.7%. The probability of non tumor-related death was 54.6%, 42.2%, 39.7%, 24.8%, and 11.9%, respectively (Figs. 3 7). The mean number of LNs resected increased over time: 1986 1990: 10.5 LNs; 1991 1995: 12.2 LNs; 1996 2000: 17.8 LNs; 2001 2005: 18.3 LNs; 2006 2009: 19.2 LNs. The highest rate of positive LNs was found in patients with the lowest and the highest numbers of LNs resected: 0 5 LNs: 28.6%; 6 10 LNs: 20.7%; 11 15 LNs: 15.8%; 16 20 LNs: 14.3%; 21 25 LNs: 15.9%; 26 30 LNs: 19.6%; 31 LNs: 25.9%. The 5-yr RFS was 67% for patients with 1 10 LNs resected, 73% for those with 11 25 LNs resected, and 72% for patients with 26 LNs resected. Eight hundred patients had their RC performed for a primary UCa, 300 for recurrent UCa. The rate of pt0 pn0 cystectomy specimens in both groups was 17.4% and 18.9%, respectively. Overall survival at 5 and 10 yr was 59% and 45% for primary BCa and 55% and 41% for recurrent BCa, respectively. RFS at 5 and 10 yr was 69% and 65% for primary BCa and 70% and 59% for recurrent BCa, respectively. Among the 1100 patients who met the inclusion criteria, 382 had tumors staged higher in the previous TURBT specimens than in the RC specimen. Of these 382 patients, 224 had documented muscle-invasive disease on TURBT before RC (Table 3). A total of 211 of the 224 patients were downstaged to non muscle-invasive disease (pt1), 116 to stage pt0 in the cystectomy specimen. The RFS in 200 patients classified as T0 N0 was 94% at 5 yr and 92% at 10 yr. If 8 patients with T0 N+ were included, these rates were 91% and 90%, respectively. Downstaging by the previous TURBTs mainly affects muscle-invasive tumors Table 3 Tumor stage of the cystectomy specimen versus maximum tumor stage of all transurethral resection of bladder tumor and cystectomy specimens Maximum tumor stage of TURBT and cystectomy specimens Ta Tis T1 T2a T2b T3a T3b T4a T4b Total Tumor stage of the cystectomy specimen T0 7 10 75 99 17 208 Ta 17 1 7 5 30 Tis 24 58 47 2 2 133 T1 88 33 5 1 127 T2a 105 3 2 110 T2b 127 3 130 T3a 126 126 T3b 125 5 130 T4a 54 54 T4b 52 52 Total 24 35 228 289 154 128 125 65 52 1100 TURBT = transurethral resection of bladder tumor.

1042 [(Fig._1)TD$FIG] EUROPEAN UROLOGY 61 (2012) 1039 1047 Fig. 1 Overall disease-specific and recurrence-free survival rate for the complete series of 1100 patients. (pt2a or pt2b) but also some pt4a tumors. Comparing the DSS rates based on the cystectomy specimen only (Fig. 2) and based on the maximum tumor stage (Fig. 8), a major difference was found for pt2a/b tumors. Patients with pt2a tumors, downstaged by TURBT, had a significantly better DSS (10 yr: 91.2%) than those with pt2a in the cystectomy specimen (73.8%) (Fig. 9). Similar findings were observed for pt2b tumors: 75.0% versus 62.0% at 10 yr (Fig. 10). In univariate analysis, age and the comorbidity indices ASA score and CI had significant prognostic relevance for OS but only in those patients who did not develop a tumor [(Fig._2)TD$FIG] recurrence. The 10-yr OS according to age at the time of RC was 0 50 yr: 83.2%; 51 60 yr: 74.5%; 61 70 yr: 64.1%; 71 80 yr: 45.5%; >80 yr: 0.0%. The 10-yr OS according to the ASA score was ASA 1: 78.8%; ASA 2: 70.6%; ASA 3: 48.3%; ASA 4: 0.0%. Regarding the CI, as initially defined by Mary Charlson in 1987, the 10-yr OS rate was CI 2: 75.4%; CI 3: 66.6%; CI 4-5: 51.5%; CI >5: 21.2%. LN-positive disease had the worst prognosis, even when one single LN was affected (Fig. 11). RFS and DSS rates did not differ significantly when cases of death within 90 d postoperatively, which may be related Fig. 2 Disease-specific survival rates according to the tumor stage of the cystectomy specimen.

[(Fig._3)TD$FIG] EUROPEAN UROLOGY 61 (2012) 1039 1047 1043 [(Fig._6)TD$FIG] Fig. 3 Overall and disease-specific survival for patients with maximum specimen) pta/is/1 pn0 cm0. [(Fig._4)TD$FIG] Fig. 6 Overall and disease-specific survival for patients with maximum specimen) pt4a/b pn0 cm0. [(Fig._7)TD$FIG] Fig. 4 Overall and disease-specific survival for patients with maximum specimen) pt2a/b pn0 cm0. Fig. 7 Overall and disease-specific survival for patients with maximum specimen) ptall pn+ cm0. [(Fig._5)TD$FIG] or radiotherapy with resection of all residual tumors) survived >2 yr. Chemotherapy alone did not cure any patient with tumor recurrence. Overall, 816 of 1100 patients (74.2%) received an ileal neobladder: 714 of 892 male patients (80%) and 102 of 208 female patients since 1986 (49%), and 102 of 165 female patients since we started performing ileal neobladders in women in 1994 (62%). 4. Discussion Fig. 5 Overall and disease-specific survival for patients with maximum specimen) pt3a/b pn0 cm0. to complications of surgery, were excluded. This is reflected by the fact that almost 80% of all patients with recurrence after cystectomy died within 1 yr after diagnosis (Fig. 12). Only patients with combined therapy (chemotherapy and/ Based on the available data at the present time, neoadjuvant therapy should be considered the standard of care for patients undergoing RC for muscle-invasive BCa. Given this situation, why is the neoadjuvant approach not practiced more widely? In a recent update including 2003 2007 from the US National Cancer Data Base, there was an increase of use of neoadjuvant chemotherapy from 6% to 13% in that time period [16]. For stage III BCa, only 0.7% of patients received neoadjuvant chemotherapy [17].

1044 [(Fig._8)TD$FIG] EUROPEAN UROLOGY 61 (2012) 1039 1047 Fig. 8 Disease-specific survival according to the maximum specimens). [(Fig._9)TD$FIG] Should neoadjuvant chemotherapy be administered to all patients with muscle-invasive disease? For pt2 tumors, 8 of 9 patients get unnecessary treatment to rescue one patient. A recent report from the Memorial Sloan-Kettering Cancer Center (MSKCC) found that 55% of patients who underwent nephroureterectomy for upper tract UCa had a preoperative estimated glomerular filtration rate <60 ml/ min per 1.73 m 2 and were not eligible for cisplatin. The high proportion in this patient population with similar comorbidities and risk factors as those with BCa illustrates the imperative for further study [18]. Fig. 9 Tumor specific survival in T2a tumors: maximum tumor stage versus pt of the radical cystectomy specimen versus preoperative T2a with downstaging by transurethral resection of bladder tumor. [(Fig._10)TD$FIG] Fig. 10 Tumor-specific survival in T2b tumors: maximum tumor stage versus pt of the radical cystectomy specimen versus preoperative T2a with downstaging by transurethral resection of bladder tumor. Taken together the vast majority of contemporary RC patients will be treated by surgery only. Almost all studies reporting RC outcomes are based on the tumor stage of the RC specimen, regardless of the histologic results of the TURBT specimens. In this background, the specific question of the prognostic significance of downstaging from muscle-invasive cancer at presentation to non muscle-invasive BCa at RC is not well established in published reports [19 21]. Our results suggest that patients downstaged from muscle-invasive disease on transurethral resection (TUR) to non muscleinvasive disease in the RC specimen had better RFS than those without such downstaging. Despite resecting all gross cancer by TUR, a high percentage of patients still have tumor in their bladders (984 of 1100 patients). Downstaging reduces the risk of recurrence from 26.2% to 8.8% in a pt2a and from 38% to 25% in pt2b disease relative to patients with persistent muscle-invasive disease in the RC specimen. This may be explained by the fact that tumors that can be completely resected tend to be smaller, less invasive, solitary, and less frequently accompanied by carcinomainsituthanthosewithresidualinvasivetumor in the cystectomy specimen. The magnitude of the effect is

[(Fig._1)TD$FIG] EUROPEAN UROLOGY 61 (2012) 1039 1047 1045 Fig. 11 Disease-specific survival according to the lymph node status. [(Fig._12)TD$FIG] Fig. 12 Overall survival after diagnosis of tumor recurrence. similar to that for neoadjuvant chemotherapy. This was also the result of a recent multicenter study on nomograms for pt2a/b, pn0 tumors [19]. The effect of tumor downstaging on BCa recurrence can be confounded by the LN status. Of the downstaged T2a/b patients, 6.9% had positive LNs compared with 10.5% of patients who were not downstaged. It appears that the biologic and prognostic significance of the p0 stage is independent of whether this was achieved by means of the surgeon s skill or chemotherapy [22,23]. Follow-up is a crucial factor when comparing the outcomes of cystectomy series. We did registry searches in 2-yr intervals for the complete series. At the time of final search, 554 of 1100 patients were alive, and 546 patients had died. Looking at the interval from surgery to the database update and registry search (December 1, 2008), all 1100 patients had the potential to survive a total of 129 421 mo. Because we had complete information in all patients who died, the only missing information is in the group of the survivors. There was missing information of 4585 mo of follow-up (3.5%). The potential median followup was 43 mo; the real median follow-up was 38 mo. This missing information results from the time span during which the registry search process was active and from some patients who had their surgery during the year of registry search and had no further contact with our department. The range of follow-up was 0 282 mo; the mean follow-up was 62 mo. For patients who died, the mean follow-up was 45 mo (range: 0 244 mo; median: 23 mo). For survivors, the mean follow-up was 80 mo (range: 0 282 mo; median: 62 mo). Some studies define the follow-up in patients who died in a different way: In these studies it is the time from surgery to the date of search, even if the patient had died years ago. Using this definition, our mean follow-up was 113 mo (range: 0 282 mo; median: 100 mo). For example, in the paper of Stein et al. (University of California-Los Angeles [UCLA]), published in 2001 [1], on a group of 1054 patients with surgery performed between 1971 and 1997, the 10-yr overall survival was 43%, but the median follow-up was 10.2 yr. In 2001 Dalbagni et al. (MSKCC) [2] reported follow-up only for those patients without evidence of disease. Madersbacher et al. (Berne) [3] in 2003 presented in 507 patients with surgery performed between 1985 and 2000 with a median follow-up of only 31 mo and a mean follow-up of 45 mo. In this series, 10-yr OS was quite similar to the Stein series with 37%. This comparison discloses that each of the three groups (UCLA, MSKCC, and Berne) used different definitions of follow-up, making their outcomes difficult to compare. For this study, we elected to use the UCLA definition because otherwise some readers would misinterpret our median follow-up using our former definition as short and insufficient. The most useful parameter is completeness of follow-up, which was 96.5% in this series. These data also demonstrate the problems of definitions: OS provides the most reliable result because the date of a patient s death is easy to obtain and needs no medical interpretation. But it is affected by age, comorbidity, and

1046 EUROPEAN UROLOGY 61 (2012) 1039 1047 other non tumor-related factors to a various extent. RFS needs a clear definition of tumor recurrence. In former studies, we demonstrated that in contrast to local recurrence and distant metastases, tumor recurrence in the upper tract or in the urethra exhibits a stable incidence over years and should be considered an independent second malignancy. RFS depends on the quality of diagnostic tools. As long as many tumor recurrences are diagnosed first by symptoms and not by imaging techniques, survival rates after diagnosis of tumor recurrence will remain low [23]. But can earlier detection of tumor recurrence optimize DSS, or does it just mean lead time bias? In our series no tumor recurrence could be cured by chemotherapy alone. Reports on surgery for metastatic BCa have demonstrated favorable outcomes, but only a very limited number of tumor recurrences offer the opportunity of a surgical approach. A strength of our study is homogeneity in clinical decision making, surgical intervention, and pathologic evaluation. Almost all previous RC series encompass a period during which recommendations on diversion, extent of lymphadenectomy, perioperative chemotherapy, and follow-up strategies have evolved, and, as such, they are more reflective of the trends of urologic oncology and the management of BCa during that time span rather than current practice recommendations [24 26]. The indication for RC over the entire study period remained constant, as well as the small and identical group of dedicated high-volume surgeons using a defined RC technique and primarily only one form of urinary diversion (ie, ileal neobladder). The definitions used were kept constant, and all RC specimens were examined by the same pathologic protocol. Also, studying BCa in a more standardized way with available substage information and excluding patients who received perioperative therapy allowed us to evaluate the prognostic impact of variables without the confounding influence of other therapeutic modalities, which may have led to an undefined impact on analysis. Lack of homogeneity is a problem of almost any RC series [1,2,5 8], including the most frequently referenced series of Stein et al. [1]. From 1971 to 1978, 11% of their patients received a high-dose short course of radiation preoperatively. Chemotherapy was selectively administered in 24% of patients. There is no maximum tumor stage presented for the pt0 stages, and a patient recruitment beginning in 1971 cannot be considered contemporary. RC quality has a major impact on survival. Who performs the surgery, and where and how well it is done matter. The 30-d mortality was 3.2% in our series. These results are quite similar to those of the UCLA (3.0%) [1],MSKCC(2.7%) [3], and Berne series (2.0%) [2]. The early mortality rate depends on age and comorbidity: In octogenarians it may exceed 9.0% [27]. Recent studies show that in-hospital mortality from RC is higher at low-volume versus highvolume hospitals (3.1% vs 0.7%) [28].Experiencedsurgeons who frequently perform RC achieve better survival and fewer complications than surgeons who perform an occasional RC [29]. Compelling evidence of the importance of surgical quality was provided by an analysis involving multiple institutions and surgeons [30,31]. Negative surgical margins and 10 LNs removed were associated with better OS independently of patient age, pathologic stage, nodal status, and whether chemotherapy was given. Our study has limitations common to retrospective studies. Using RFS as one primary end point may have attenuated the impact of confounding noncancer mortality in this elderly population with comorbidities. The mean number of LNs resected for the 1100 patients was 18. Only a few patients with high tumor load underwent an extended form of lymphadenectomy. The tendency to resect more LNs than the standard groups will lead to an increased rate of LN-positive tumors. In the long term this will positively affect the prognosis in LN-negative patients, but there is still a lack of evidence for a survival benefit in those patients with positive LNs. Detecting minimal LN metastasis by more extended LN resection may be curative in 20% of all patients, but it also may help to identify patients suitable for adjuvant chemotherapy. These results should be interpreted as an argument for early RC because RC in early stages can offer excellent cure rates. 5. Conclusions We believe that the long follow-up, the large consecutive patient series, and the consistency of surgical philosophy and technique plus standardized reporting make this study uniquely suited to address the question of what RC alone can do for BCa. This contemporary and homogeneous single-center series found acceptable OS, DFS, and RFS for patients undergoing RC. Pathologic downstaging had a significant impact on survival. Author contributions: Richard E. Hautmann 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: Hautmann, Volkmer. Acquisition of data: Volkmer. Analysis and interpretation of data: Hautmann, de Petriconi, Pfeiffer, Volkmer. Drafting of the manuscript: Hautmann, Volkmer. Critical revision of the manuscript for important intellectual content: Hautmann, de Petriconi, Pfeiffer, Volkmer. Statistical analysis: de Petriconi, Volkmer. Obtaining funding: None. Administrative, technical, or material support: Hautmann, de Petriconi, Volkmer. Supervision: Hautmann, Volkmer. 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.

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