Lymphadenectomy at the Time of Nephroureterectomy for Upper Tract Urothelial Cancer

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1 EUROPEAN UROLOGY 60 (2011) available at journal homepage: Collaborative Review Urothelial Cancer Lymphadenectomy at the Time of Nephroureterectomy for Upper Tract Urothelial Cancer Marco Roscigno a, *, Maurizio Brausi b, Axel Heidenreich c, Yair Lotan d, Vitaly Margulis d, Shahrokh F. Shariat e, Hendrik Van Poppel f, Richard Zigeuner g a Department of Urology, Ospedali Riuniti di Bergamo, Bergamo, Italy; b Department of Urology, Ausl Modena, Italy Ospedale Sant Agostino Estense, Modena, Italy; c Department of Urology, RWTH University Aachen, Aachen, Germany; d Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA; e Department of Urology, Weill Medical College of Cornell University, New York, NY, USA; f Department of Urology, University Hospital of Leuven, Leuven, Belgium; g Department of Urology, Medical University of Graz, Graz, Austria Article info Article history: Accepted July 4, 2011 Published online ahead of print on July 14, 2011 Keywords: Upper tract urothelial neoplasms Lymphadenectomy Lymphatic metastases Nephroureterectomy Survival Abstract Context: The role of lymph node dissection (LND) in patients treated with radical nephroureterectomy (RNU) for upper tract urothelial cancer (UTUC) is still controversial. Objective: To analyze the impact of lymph node invasion on the outcome of patients, the staging, and the possible therapeutic role of LND in UTUC. Evidence acquisition: A Medline search was conducted to identify original articles, review articles, and editorials addressing the role of LND in UTUC. Keywords included upper tract urothelial neoplasms, lymphadenectomy, lymph node excision, lymphatic metastases, nephroureterectomy, imaging, and survival. Evidence synthesis: Regional nodes are frequently involved in UTUC and represent the most common metastatic site. Regional nodal status is a significant predictor of patient outcomes, especially in invasive disease. Therefore, select patients treated with RNU at high risk for regional nodal metastases should undergo LND to improve disease staging, which would identify those who could benefit from adjuvant systemic therapy. Several retrospective studies suggested the potential therapeutic role of LND in UTUC. An accurate LND could remove some nodal micrometastases not identified on routine pathologic examination, thus improving local control and cancer-specific survival. Radical surgery and LND might be curative in a subpopulation with limited nodal disease, as described in bladder cancer. A clear knowledge of the limits of LND and a template of LND for UTUC are still needed. Conclusions: An extended LND can provide better disease staging and may be curative in patients with limited nodal disease. However, current evidence is based on retrospective studies, which limits the ability to standardize either the indication or the extent of LND. Prospective trials are required to determine the impact of LND on survival in patients with UTUC and identify patients for a risk-adapted approach such as close follow-up or adjuvant chemotherapy. # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Tel address: roscigno.marco@gmail.com (M. Roscigno). 1. Introduction Upper tract urothelial carcinoma (UTUC) is a relatively rare neoplasm, accounting for about 5% of all urothelial cancers [1]. Up to 30% of patients with muscle-invasive UTUC have metastasis in the regional lymph nodes (LNs) [2], which represents a well-established poor prognostic factor [3]. Pelvic lymph node dissection (LND) is known to be an essential component of the surgical management of urothelial cancer of the bladder. It allows for postoperative /$ see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 EUROPEAN UROLOGY 60 (2011) risk stratification [4] and possible improvement in cancerspecific survival (CSS) and overall survival (OS) [5 9], although this has still not been proven in prospective trials. On the contrary, the practice of a meticulous LND for invasive UTUC has not been adopted by urologists worldwide [10]. This is at least in part due to the relatively low incidence of UTUC and, consequently, to an incomplete understanding of the optimal LND template, which varies according to the location of the disease. This review evaluates the role of LND in the treatment of patients with UTUC. 2. Evidence acquisition A Medline search was conducted to identify original articles, review articles, and editorials addressing the role of LND in UTUC. Keywords included upper tract urothelial neoplasms, lymphadenectomy, lymph node excision, lymphatic metastases, nephroureterectomy, imaging, and survival. Links to related articles and citations in related articles were surveyed. The panel of the consensus group reviewed the records to identify the articles with the highest evidence based on the recommendation of the US Agency for Health Care Policy and Research. This review is the result of an interactive peer-reviewing process by an expert panel of coauthors. 3. Evidence synthesis 3.1. Lymph node dissection: from bladder cancer to upper tract urothelial cancer Owing to the relatively low incidence of UTUC, there is still no consensus regarding the indication for LND at radical nephroureterectomy (RNU) for UTUC, and LND is not currently performed in all patients worldwide [10]. In contrast, a complete and meticulous full bilateral LND has been recommended for invasive bladder cancer [4]. Leissner et al [6] showed that both survival and time to recurrence were significantly improved in patients in whom at least 16 LNs had been removed. Herr and coworkers [7] observed significantly better survival after dissection of >11 and 13 LNs from pn0 and pn+ patients, respectively. In contrast, Koppie et al [5] showed that survival continued to rise as the number of LNs removed increased in a cohort of patients with bladder cancer who underwent radical cystectomy. Dhar et al [11] showed that the 5-yr recurrence-free survival rate of patients with pn+ disease was 7% for limited dissection and 35% for extended LND. There is consensus that LND for bladder cancer should at least include nodes from the external and internal iliac vessels, together with those of the obturator fossa, and should encompass the distal part and the bifurcation of the common iliac vessels on both sides. Whether a more extensive LND is beneficial should be addressed in prospective randomized trials [4]. On this basis, a growing number of clinical researchers are evaluating the impact of LND in UTUC. Unfortunately, most studies are single-institution reports based on very limited study populations. These reports used different templates and indications mostly based on the surgeon s individual preference [12 16]. In 2009, a multi-institution collaboration, the Upper Tract Urothelial Carcinoma Collaboration (UTUCC), was created to collect data on the RNUs performed in 13 tertiary care institutions and to investigate the role of LND for staging and therapeutic purposes in UTUC [17 19] Lymph node invasion in upper tract urothelial cancer Incidence of node-positive upper tract urothelial carcinoma Regional LNs are frequently involved in UTUC and represent the most common metastatic site [20]. The incidence of node involvement varies according to stage and grade. Kondo et al [21] showed that the incidence of positive LNs was 0%, 5%, 24%, and 84% in patients with Tis/Ta/T1, T2, T3, and T4 disease, respectively. LN invasion was present in 0%, 11%, and 35% of patients with G1, G2, and G3 tumors, respectively. Evidence from the multicenter UTUCC studies [18,19] indicated an overall 25% incidence of node-positive disease, with 6%, 16%, and 35% of patients with positive LNs in pt1, pt2, and pt3 4 disease, respectively. Furthermore, 94% of patients with LN metastases had high-grade tumors; only 6% of patients had low-grade disease, according to the new twotiered tumor grading system. The presence of tumor necrosis and concomitant carcinoma in situ proved to be associated with higher risk on nodal involvement [22,23]. There is some inherent bias in these reports because they were primarily surgical, and some patients with extensive LN involvement may not have been selected to undergo surgery. No data were provided whether the LNs were sent in separate packages or whether the work-up of the LN specimens was identical. Finally, it is possible that patients with less aggressive clinical stage or grade were also less likely to undergo LND, resulting in understaging. Another important factor to consider is the impact of the extent of LN dissection and number of LNs removed on the incidence of LN metastases. One publication highlighted that at least eight LNs need to be removed at RNU to achieve a 75% probability of finding one or more positive nodes [17]. However, better knowledge regarding the variability of lymphatic drainage of the upper urinary tract could help standardize the template for LND, as proposed by Kondo et al [21], and consequently could result in an increased detection of positive LNs (Fig. 1) Prognosis in node-positive upper tract urothelial carcinoma Patients with LN metastases generally have a poor outcome [2,16 20]. Novara et al [24] demonstrated that nodal invasion was an independent predictor of CSS: Patients with pn+ disease had a threefold increased risk of cancer mortality compared with node-negative patients. In the paper of Margulis et al [25], positive LNs were detected in 23% of patients undergoing LND, underscoring the virulent behavior of UTUC. However, despite LN involvement, the recurrence-free survival rates of these patients were 29% at 5 yr and 25% at 10 yr. Moreover, 35% of these patients were alive at 5 yr and 32% at 10 yr after RNU. The authors

3 778 [(Fig._1)TD$FIG] EUROPEAN UROLOGY 60 (2011) Fig. 1 Regional lymph node template according to primary tumor location: (A) renal pelvis; (B) upper two thirds of ureter; (C) lower third of ureter [21]. suggested that these results could be explained by the potentially curative role of LND in a subset of these patients The role of lymph node dissection Definition of an anatomic template for upper tract urothelial carcinoma Kondo et al [21] retrospectively examined the primary site and incidence of nodal metastases of UTUC. The novel findings of this report are that retrocaval nodes are important sites of metastasis for tumors of the right renal pelvis and the upper two thirds of the right ureter, in addition to the hilar and paracaval sites. Interaortocaval nodes are also an important primary site of metastasis for tumors of the upper two thirds of the right ureter. Tumors of the left renal pelvis mainly spread to the renal hilum and para-aortic nodes; tumors of the upper two thirds of the left ureter metastasized into the para-aortic nodes. Finally, tumors of the lower thirds of the ureter on each side tended to spread to pelvic LNs below the aortic bifurcation (Fig. 1). However, these data derived from a single-institution retrospective series require validation Staging role The presence of nodal involvement represents a poor prognostic indicator, significantly affecting patient outcome. Therefore, LND allows adequate postoperative patient counseling and risk stratification, thereby identifying patients for a risk-adapted approach such as close follow-up or adjuvant chemotherapy. Table 1 shows CSS reported in different studies according to nodal status. Several papers have investigated the role of LND and nodal status on DFS and CSS. Abe et al [26] evaluated a Table 1 Cancer-specific survival according to nodal status Study Year of publication Study interval No. of patients Nodal status (No. of patients) 5-yr CSS, % Komatsu et al [12] pn0 (25) 100 pn+ (11) 21 Miyake et al [13] pn0 (22) 64 pnx (37) 50 pn+ (13) 0 Roscigno et al [16] pn0 (69) 73 pnx (37) 48 pn+ (26) 39 Roscigno et al [18] pn0 (412) 77 pnx (578) 69 pn+ (140) 35 Novara et al [24] pn0 (242) 82 pn+ (27) 12 Abe et al [26] pn0 (139) 88 pnx (146) 65 pn+ (27) 22 Brown et al [27] pn0 (105) 56 pnx (119) 73 pn+ (28) 0 Secin et al [28] pn0 (89) 80 pnx (71) 77 pn+ (24) 35 Lughezzani [29] pn0 (1835) 81 pnx (747) 78 pn1 (242) 34 CSS = cancer-specific survival.

4 EUROPEAN UROLOGY 60 (2011) cohort of 312 patients with UTUC treated with RNU, including 166 patients who underwent LND. The 5-yr CSS probability was 88% for pn0 patients, which was significantly higher than the 22% of pn+ patients ( p < 0.001). Of interest, patients with pn0 disease had a significantly better prognosis than pnx patients, where the nodes were left behind. Roscigno et al [16] observed 132 consecutive patients with muscle-invasive UTUC who underwent radical surgery at a single institution. A statistically significant difference in terms of actuarial 5-yr CSS emerged between pn0 and pn+ and between pn0 and pnx patients but not between pnx and pn+ patients. This was confirmed at multivariable Cox regression analyses, where nodal status emerged as an independent predictor of both DFS and CSS. These data were in contrast with those presented by Brown et al [27],showing that survival of pnx and pn0 patients was similar and significantly higher than that of pn+ patients. Nevertheless, the MD Anderson series also included noninvasive tumors, whereas in the Italian group only patients with muscleinvasive UTUC were considered. In this population a higher percentage of pnx patients probably would have had positive nodes if LND had been performed. The UTUCC collected data on 1130 consecutive patients with pt1 4 upper urinary tract transitional cell carcinoma treated with RNU [18]. Of those patients, 552 (49%) underwent LND. The 5-yr CSS estimate was significantly lower in patients with pn+ compared with those with pnx disease, which in turn was lower than in patients with pn0 disease. In the subgroup of pt1 patients (n = 345), CSS rates were not different in patients with pn0 and pnx disease. In pt2 4 cases (n = 813), CSS estimates were lowest in pn+ patients, intermediate in pnx, and highest in pn0 (33% vs 58% vs 70%; p = 0.017). Moreover, pn+ was an independent [(Fig._2)TD$FIG] predictor of reduced CSS, after adjusting for the effect of standard clinicopathologic features. On the contrary, pnx was significantly associated with worse prognosis than pn0 in pt2 4 UTUC only (Fig. 2). These findings suggest that LND should always be performed in patients with muscleinvasive or more advanced disease to better discriminate patients with a high risk of progression and death who might benefit from adjuvant systemic therapy. On the contrary, LND does not seem to improve staging in pt1 disease, but it could be due to the low probability of LN metastasis. Because only seven patients with non muscleinvasive UTUC had LN metastasis, this study may be underpowered to correctly analyze the prognostic significance of positive nodes in pt1 patients. However, the main advantage of performing LND would be to eliminate the Nx category, thus avoiding a staging bias. A major concern is that it is not easy to predict whether a patient has muscle-invasive or more advanced disease at RNU because imaging studies, cytology, and/or biopsy findings cannot reliably diagnose disease stage and identify patients with LN invasion preoperatively [28]. Thus, in the absence of accurate prediction tools, it may be prudent to perform LND in all patients treated with RNU if accurate staging is desired. Conversely, Lughezzani et al [29] recently analyzed nine Surveillance, Epidemiology and End Results cancer registries, with a study population of >2800 patients. After stratification according to pnx versus pn0 stage, they found no statistically significant difference in cancer-specific mortality (CSM) rates. The same results were observed when the survival analysis was stratified according to type of surgery, T stage, and tumor grade. The authors concluded that patients left unstaged (pnx) probably were most likely identified by their respective surgeons as low risk for nodal Fig. 2 Cancer-specific survival according to nodal status in 813 patients with muscle-invasive upper tract urothelial cancer treated with radical nephroureterectomy [18].

5 780 EUROPEAN UROLOGY 60 (2011) invasion. They suggest this may signify that clinicians are good at judging patients who require LND and those patients who may not need this potentially morbid additional surgery. Nonetheless, because it is extremely difficult to differentiate between high-grade and low-grade cancer, and between T1 and T2 cancer, identification of objective preoperative prognostic markers is needed. To address this vacuum, Margulis et al recently developed a prognostic model for the prediction of non organ-confined UTUC [30]. A nomogram including information on grade, architecture, and location of the tumor achieved 76.6% accuracy in predicting non organ-confined disease. This simple preoperative prediction model can be useful for guiding the performance and the extent of LND during RNU. Brein et al demonstrated that preoperative evaluation for hydronephrosis, ureteroscopic biopsy grade, and positive cytology can identify patients at risk for advanced UTUC [31]. Although most of the studies just cited highlight the need for LND, especially in patients with pt2 4 UTUC, the major question is how to assess the overall quality of the LND. Efforts to determine the adequacy of LND have included the assessment of the number of LNs removed, the definition of the LND template, and the concept of LN density. Indeed, to obtain accurate disease staging, a crucial point is the extent and template of the LND. Roscigno et al [17] tried to determine the minimum threshold number of nodes for detecting one or more positive nodes in a multicenter population of patients undergoing RNU. They found that 13 LNs need to be removed and examined to achieve a 90% probability of detecting LN invasion. The removal of at least eight LNs resulted in a 75% probability of detecting one or more positive nodes. Unfortunately, this study does not provide a template for LND because it was often performed based on a surgeon s individual preference. In a multivariate analysis that adjusted for the effects of pathologic stage and grade, removal of eight or more LNs was an independent predictor of LN invasion: The removal of eight or more LNs increases the probability of a yield of positive nodes by 50%. A more accurate LND may improve disease staging, thereby identifying pn+ patients who could be candidates for adjuvant systemic therapy. A higher number of LNs removed may better predict a nodenegative status. From a practical point of view, pn0 patients with fewer than eight nodes removed may need closer follow-up because they could have been understaged. Nonetheless, the need for and intensity of follow-up to detect disease recurrence, as shown in bladder cancer, remains controversial [32,33]. Although the number of LNs removed and examined could be considered as a surrogate of the extent of LND, the better way to provide accurate staging is the correct knowledge of lymphatic drainage of the upper urinary tract. A complete excision of all primary sites of nodal metastases, as described by Kondo et al [14], should improve detection of node-positive disease. As an extension of the bladder cancer literature, Bolenz et al [34] proposed LN density as a valuable prognostic tool for risk stratification of patients with nodal involvement in UTUC. Although the total number of LNs examined and the total number of metastatic LNs were not associated with DFS and CSS, patients with a LN density 30% were at a significantly greater risk of both recurrence and mortality than those with a LN density <30%. Because LN density is determined by the proportion of the number of positive LNs and the number of LNs removed and examined, such findings reinforce the hypothesis of the usefulness of LND for both staging and potential therapeutic purposes Therapeutic role Several studies have investigated the potential therapeutic role of LND in UTUC. Komatsu et al [12] evaluated a limited cohort of 36 patients and suggested LND may provide a therapeutic benefit by selecting patients with nodal metastases as candidates for adjuvant treatment. Miyake et al [13] reported on 72 patients with UTUC. They found a prognostic advantage for patients undergoing LND who had no evidence of lymphovascular invasion. Nonetheless, because this parameter is not known until the definitive pathology, these findings are not helpful to indicate LND during surgery. Brausi et al [15] showed that in patients with muscle-invasive UTUC, DFS and CSS were significantly higher in patients who received a retroperitoneal LND in conjunction with RNU than in patients who did not undergo LND. Roscigno et al [16] found actuarial 5-yr DFS was 64% and 37% in patients with muscle-invasive UTUC undergoing LND or not, respectively. The 5-yr CSS was 67% and 40% in patients with or without LND, respectively. Patients treated with LND had a significantly better prognosis when compared with those managed with tumor excision only, even though in the group of patients undergoing LND, about a quarter of them had nodal metastases. An accurate LND could remove some nodal micrometastasis not identified on routine pathologic examination, thus improving locoregional control and CSS. Radical surgery and LND might be curative in a subpopulation with limited nodal disease, as described in bladder cancer [35]. LND may reduce the residual tumor burden in patients who are candidates for adjuvant chemotherapy. Roscigno et al [16] also demonstrated that the number of LNs emerged as an independent predictor of both DFS and CSS. When the number of LNs removed was coded according to the most informative cut-off, a better clinical outcome was observed in those patients in whom at least six LNs had been removed and examined. In the multicenter study from the UTUCC [19], the number of LNs removed was an independent predictor of CSM in node-negative patients. The 5-yr survival of patients in whom eight or more LNs had been removed was significantly higher than in those with fewer than eight LNs removed (84% vs 73%). But an established number of LNs removed is not enough to optimize survival, as demonstrated by Koppie et al [5] for bladder cancer. Indeed, when the variable was coded as a cubic spline curve to allow for nonlinear effects, the curve depicting the relationship between the number of LNs removed and CSM did not plateau but continued to decrease as the number of LNs increased [19] (Fig. 3). Although these results seem to support the possible therapeutic impact of

6 [(Fig._3)TD$FIG] EUROPEAN UROLOGY 60 (2011) removed did not affect CSS. They suggest that the extent of LND would be better determined by the template of the dissection rather than by the number of LNs removed and examined Controversies regarding the performance of lymph node dissection in upper tract urothelial carcinoma Fig. 3 The plots depict the (A) linear and (B) nonlinear effects of the number of lymph nodes (LNs) removed on cancer-specific mortality in 412 patients with pn0 upper tract urothelial carcinoma [19]. LND, the Will Rogers phenomenon must be remembered when evaluating such findings [36]. Indeed, patients diagnosed with a node-negative disease by a limited LND may have been inaccurately staged, and some positive nodes may have been skipped during the surgery. In this case, the improvement in CSS of pn0 patients could simply be the result of better staging that eliminates the negative impact on survival for patients with nodal metastases that have been erroneously classified as pn0. In contrast, Kondo et al, focusing on the identification of all the primary sites of nodal metastases in UTUC, considered as nodal sites those where the incidence of metastases was 30% [21]. When all primary sites of nodal metastases were resected, LND was considered complete. In cases where not all the primary sites were removed, LND was considered incomplete. In a first report [14], a complete LND proved to be an independent predictor of CSS in patients with locally advanced disease (pt3). Nonetheless, patients treated with complete LND had 7% recurrence in retroperitoneal LNs, whereas 14% and 9% nodal recurrence rates were found in patients treated with incomplete or no LND, respectively. They updated their study recently and confirmed that, in patients with clinically node-negative UTUC, a complete LND is associated with a better survival in patients with muscle-invasive clinical node-negative UTUC [37]. On the contrary, they found that the number of LNs Although the recent literature dealing with UTUC supports the role of an accurate LND, this is not reflected in general practice. Secin et al [28] demonstrated that, after adjusting for tumor and patient characteristics, the surgeon remained an independent predictor of LND. A lack of standardization in performing LND still exists even among academic institutions, where the percentage of patients undergoing any form of LND varies from 44% to 67% [12 18]. These figures are even lower during minimally invasive approaches such as fully laparoscopic RNU [38,39]. Abouassaly et al [40] examined the number of LNs removed as a measure of surgical quality in patients treated for UTUC. The pathology reports from the Ontario Cancer Registry were available for 422 patients treated for UTUC. Only 27% of patients had one or more LNs identified in the specimen, with most having only one LN assessed. In the vast majority of patients, LNs were assessed from the RNU specimen rather than sent as separate specimens. However, assessing the status of LNs using the RNU specimens simply means that no LND was performed. Also in the papers from the UTUCC, which support the need of a more thorough LND, the median number of LNs removed was only five, thus reflecting a significant problem of surgical quality when performing LND in patients with UTUC. As indicated by Russo [10], the scant number of nodes being removed during RNU is likely the norm whether the surgery is performed using open or laparoscopic techniques, and it reflects the lack of consensus regarding the therapeutic role of LND and its extent Lymph node dissection: difference between open and laparoscopic surgery The current standard of care for UTUC consists of open RNU [41]. Laparoscopic RNU, however, is becoming an established alternative to open RNU at centers with adequate laparoscopic expertise [41]. Recent data showed the evidence for equivalent DFS and CSS between open and laparoscopic RNU, especially in patients with predominantly favorable clinical and pathologic features [39]. The ability to perform an LND during laparoscopy is still a major concern, potentially affecting patient staging and possibly survival. In the study of Capitanio et al [39], LND was performed in 42% and 24% of patients treated with open and laparoscopic RNU, respectively. However, this difference may not result in worse patient outcomes due to the fact that patients treated laparoscopically had a more favorable pathologic stage, more frequent papillary architecture, and less lymphovascular invasion. Simone et al [38] prospectively evaluated 80 patients surgically treated for UTUC with open or laparoscopic RNU. They did not perform LND during laparoscopy. DFS and CSS of pt3 tumors were significantly better in

7 782 EUROPEAN UROLOGY 60 (2011) patients undergoing open RNU than in those who underwent a laparoscopic procedure. One possible explanation may be the omission of LND during laparoscopy in this subset of patients at high risk for nodal metastases. In contrast, Busby et al [42] tried to compare the quality of LND in patients who underwent open RNU with a contemporary series of patients who underwent laparoscopic RNU. The median number of LNs removed during laparoscopic procedure was six compared with a median number of three LNs removed during open surgery in an older series. The paper highlighted the feasibility of LND during laparoscopic RNU; however, the limitation of the research is that in both groups the number of LNs removed could be an expression of a limited LND template. However, with the wide endorsement of laparoscopy in patients undergoing RNU, it could be predicted that LND as suggested by Kondo et al [21] will not be performed routinely, even if a dedicated effort is made Role of chemotherapy in node-positive patients LND ideally improves disease staging, thereby identifying patients who could benefit from adjuvant systemic therapy. Nonetheless, whether improved staging results in improved outcomes depends on the decision to deliver chemotherapy and on the efficacy of the regimen. Although a single study has shown adjuvant chemotherapy in UTUC might be as effective as neoadjuvant chemotherapy for bladder cancer [43], in a large multi-institutional retrospective study, Hellenthal et al [44] showed that adjuvant chemotherapy confers minimal impact on OS and CSS in high-risk UTUC patients. The same results were obtained in the subgroup of pn+ patients. Not all patients will be able to receive this treatment because of comorbidities and impaired renal function after radical surgery [45]. Based on these findings, data are currently insufficient to provide evidence of the effectiveness of adjuvant chemotherapy. On the contrary, neoadjuvant therapy followed by aggressive radical surgery seems to achieve favorable oncologic outcomes in patients with UTUC with initial locoregional nodal metastases [46], providing a 14% rate of complete remission and a significant rate of downstaging [47]. However, there is still an absence of randomized prospective studies to support either neoadjuvant or adjuvant therapy. 4. Conclusions Regional LNs are frequently involved in UTUC and represent the most common metastatic site. Nodal status has been proved to be a significant predictor of DFS and CSS, especially in patients with pt2 4 disease. Therefore, development of better predicting tools is needed to identify those patients who might benefit most from LND, thus improving disease staging and thereby identifying those patients who could potentially benefit from adjuvant systemic therapy. Unfortunately, there are no conclusive studies on the efficacy of adjuvant chemotherapy in patients with UTUC. Several studies have suggested the potential therapeutic role of LND in UTUC, similar to that proposed for bladder cancer. However, all these data are retrospective. Thus it is impossible to standardize either the indication or the extent of LND. A clear knowledge of the limits of LND and a template for UTUC disease are still lacking. Prospective trials are required to address these questions and clearly determine the impact of LND on survival in patients with UTUC. Author contributions: Marco Roscigno 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: Roscigno. Acquisition of data: Roscigno. Analysis and interpretation of data: Roscigno. Drafting of the manuscript: Roscigno. Critical revision of the manuscript for important intellectual content: Brausi, Heidenreich, Lotan, Margulis, Shariat, Van Poppel, Zigeuner. Statistical analysis: None. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Brausi, Heidenreich, Lotan, Margulis, Shariat, Van Poppel, Zigeuner. 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] Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, CA Cancer J Clin 2007;57: [2] Zigeuner R, Pummer K. Urothelial carcinoma of the upper urinary tract: surgical approach and prognostic factors. Eur Urol 2008;53: [3] Ozsahin M, Zouhair A, Villa S, et al. Prognostic factors in urothelial renal pelvis and ureter tumours: a multicentre Rare Cancer Network study. Eur J Cancer 1999;35: [4] Karl A, Carroll PR, Gschwend JE, et al. 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