The anatomical limits and oncological benefit of lymphadenectomy in muscle invasive bladder cancer

Actas Urol Esp. 2017;41(5):284---291

Actas Urol´ ogicas Espa˜ nolas www.elsevier.es/actasuro

REVIEW ARTICLE

The anatomical limits and oncological benefit of lymphadenectomy in muscle invasive bladder cancer夽 A. Guijarro ∗ , V. Hernández, C. Llorente Servicio de Urología, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain Received 30 June 2016; accepted 13 July 2016 Available online 29 April 2017

KEYWORDS Lymphadenectomy; Muscle invasive bladder cancer; Lymph node anatomical territory; Oncological value

Abstract Background: Lymphadenectomy is part of standard treatment for muscle invasive bladder cancer. The objective of this review is to provide an up-to-date review on the available scientific evidence in this field. Acquisition of evidence: We conducted a literature review in PubMed of relevant articles up to the present (2016). We found a systematic review published in 2014 that included the comparative studies published up to that year, and we updated the review with new relevant publications since that date. Synthesis of the evidence: The number of lymph nodes is not the best indicator for determining the quality of the lymphadenectomy given that the number can vary depending on numerous factors that depend not only on the surgeon but also on the patient and on the pathologist. The definition of standard anatomical territories and a meticulous extraction of the lymph nodes in these territories are more reproducible than the numbers of nodes removed. The optimal extension of lymphadenectomy is a topic of debate. The evidence published to date indicates that any extension of lymphadenectomy is better than not performing it, although it appears that limited lymphadenectomy is insufficient for the oncological control of the disease and that superextended lymphadenectomy provides no oncological benefit versus extended lymphadenectomy. Conclusions: Despite a certain amount of controversy in terms of the optimal extension of lymphadenectomy, performing lymphadenectomy in all cases appears to be recommendable according to the available evidence. Extended lymphadenectomy provides greater oncological benefit than more limited dissections, while more extensive lymphadenectomies are not recommended. © 2016 AEU. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.

夽 Please cite this article as: Guijarro A, Hernández V, Llorente C. Límites anatómicos y beneficio oncológico de la linfadenectomía en el cáncer urotelial de vejiga con infiltración muscular. Actas Urol Esp. 2017;41:284---291. ∗ Corresponding author. E-mail address: [email protected] (A. Guijarro).

2173-5786/© 2016 AEU. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.

Anatomical limits and oncological benefit of lymphadenectomy

PALABRAS CLAVE Linfadenectomía; Cáncer vesical con infiltración de la muscular; Territorios anatómicos ganglionares; Valor oncológico

285

Límites anatómicos y beneficio oncológico de la linfadenectomía en el cáncer urotelial de vejiga con infiltración muscular Resumen Introducción: La linfadenectomía es parte del tratamiento estándar del cáncer vesical con infiltración de la muscular. El objetivo de esta revisión es dar una visión actualizada de la evidencia científica disponible en este campo. Adquisición de la evidencia: Se realizó una revisión en Pubmed de la literatura relevante hasta la actualidad (2016). Se encontró una revisión sistemática publicada en 2014 que incluía los estudios comparativos publicados hasta ese momento, y se actualizó con las nuevas publicaciones relevantes desde esa fecha. Síntesis de la evidencia: El número de ganglios no es el mejor indicador para determinar la calidad de la linfadenectomía, puesto que puede variar en función de múltiples factores dependientes no solo del cirujano, sino también del propio paciente y del patólogo. Es más reproducible la definición de territorios anatómicos estándares y una meticulosa extracción de los ganglios en estos territorios. La extensión óptima de la linfadenectomía es un tema controvertido. La evidencia publicada hasta el momento dice que cualquier extensión de linfadenectomía es mejor que no realizarla, si bien parece que la linfadenectomía limitada es insuficiente para el control oncológico de la enfermedad y que la linfadenectomía superampliada, no aporta un beneficio oncológico frente a la linfadenectomía ampliada. Conclusiones: A pesar de existir cierta controversia en cuanto a la extensión óptima de la linfadenectomía, según la evidencia disponible parece recomendable realizar linfadenectomía en todos los casos. La linfadenectomía ampliada aporta un mayor beneficio oncológico que las disecciones más limitadas, desaconsejándose linfadenectomías más amplias. © 2016 AEU. Publicado por Elsevier Espa˜ na, S.L.U. Todos los derechos reservados.

Introduction Radical cystectomy (RC) with associated lymphadenectomy remains the standard treatment for patients with muscleinvasive bladder cancer (MIBC).1 Of the patients undergoing RC, 25% present lymph node involvement.2 The value of lymphadenectomy is clearly accepted for staging of the disease. However, the therapeutic value, as well as the optimal limits of the same, remains a subject for debate. It is known that lymph node involvement is one of the prognostic factors with the greatest impact on the survival of patients with MIBC,3 although the scientific evidence published in this regard has conflicting results. Since 2014, and based on the results of a review published in that year, the European guidelines recommend performing an extended lymphadenectomy in all patients undergoing RC. Currently, there are 2 ongoing clinical trials underway that try to analyze the impact of lymphadenectomy depending on the different anatomical territories, but we still do not have results. Our objective is to review the literature and the most important evidences on the oncologic value of RC associated lymphadenectomy in patients with MIBC.

Acquisition of evidence A search was made in Pubmed until April 2016. For the search we used the combination of the following terms: lymphadenectomy, bladder cancer, urothelial carcinomas,

radical cystectomy, lymph node metastasis, lymph node dissection, recurrence and survival. In 2014 a systematic review was published that included, without language limits, all articles published until that time comparing patients with localized MIBC (cT2-4 N0M0) treated with RC associated with some type of lymphadenectomy. All included articles were comparative, and the series of cases with a single study arm were therefore excluded. For this review, the references included in this review have been used and an update of the literature published from that moment to the present has been made.

Synthesis of the evidence Anatomical limits of lymphadenectomy Multiple studies have concluded that the first lymphatic drainage of the MIBC has as its starting point the obturator fossa lymph nodes, external and internal iliac, and the presacral nodes.4,5 The second limit of drainage ascends to the common iliac, and later to paraaortic, interaortocaval, and paracaval nodes. The nomenclature used in different publications is a limitation to compare the results of different series, since the definitions used have been very variable. In an attempt to homogenize the nomenclature of the limits of lymphadenectomy, concepts such as limited, standard, extended, or superextended lymphadenectomy have been developed,6 the following definitions being proposed:

286 - Limited lymphadenectomy: includes territories of the obturator fossa and perivesical lymph nodes. - Limited lymphadenectomy: includes the territories of the obturator fossa and perivesical lymph nodes. - Standard lymphadenectomy: includes the territories of the obturator fossa, the perivesical nodes, and the external and internal iliac artery. - Extended lymphadenectomy: includes the territories described for standard lymphadenectomy, in this case the upper limit being the territory comprised up to the ureteroiliac junction or to the aortic bifurcation ± the presacral nodes. - Superextended lymphadenectomy: in this case, the upper limit of the lymphadenectomy is extended to the inferior mesenteric artery.

Lymphatic drainage pattern in bladder cancer with muscle involvement For more than 10 years, the attempt to define the optimal limit of RC associated lymphadenectomy has been continuous, so that in 2004 Abol-Enein et al.4 carried out a prospective study in 200 patients undergoing RC with lymphadenectomy until the lymph nodes of the inferior mesenteric artery, observing that 48 (24%) had lymph node involvement. In this study, all patients with extrapelvic lymph node involvement also had involvement in the obturator fossa and/or in the iliac chains, and concluded that the region of the internal iliac, external iliac and obturator are the sentinel regions for the MIBC. In contrast, Leissner et al.5 carried out, in the same year (2004), an analysis in 290 patients with the same anatomical limits as the aforementioned study, with a lymph node positivity rate of 27.9% (81 patients), and found that 20 patients (6.9%) had metastases at the level of the common iliac without metastasis in the obturator fossa, in the external iliac, or in the internal iliac, concluding that in order to achieve optimal lymphadenectomy, a dissection had to be performed until the aortic bifurcation. More recently, Jensen et al.7 described that in their series of 265 patients undergoing lymphadenectomy to the root of the inferior mesenteric artery, 61 patients (23%) had positive nodes and 16 patients (6%) had extra-pelvic node involvement without having involvement in the obturator fossa, external or internal iliac, concluding that a superextended lymphadenectomy would make it possible to correctly diagnose the patients with extrapelvic lymph node involvement and who, with a more limited lymphadenectomy, would have been understaged. All these studies are based on the anatomopathological analysis of the dissected territories, without being able to know if all the lymph node material has been removed or if there is lymph node involvement in some other unexplored area. In order to accurately establish the anatomical location of the physiological lymphatic drainage of the bladder, the use of a combination of computed axial tomography (CT) and single-photon emission computed tomography (SPECT) has been proposed.8 Using SPECT/CT with intraoperative probe verification to assign the primary territories of lymphatic drainage of the bladder, it is demonstrated that in the

A. Guijarro et al. territory of the common iliac to the ureteroiliac junction up to 92% of the initial drainage can be detected. In addition, the complexity of the lymphatic drainage pattern of the bladder is well-targeted and the concept of sentinel lymph node for MIBC is discarded.

Prognostic significance of lymph node involvement Number of nodes removed Several authors have used the number of lymph nodes removed as an indicator of the quality of the lymphadenectomy, trying to establish a cut-off point of the minimum number of lymph nodes to consider an adequate quality lymphadenectomy. This cut-off point has been established in 11---16 nodes, depending on the publications.9,10 Rink et al.11 demonstrated that the number of total dissected nodes was associated with recurrence of the disease. For this, they analyzed a series of 3088 patients, of whom none had received neoadjuvant chemotherapy and all were N0 after RC. In the multivariate analysis, the number of dissected nodes was associated with disease relapse: in limited lymphadenectomies (median 9 nodes) the HR was 0.996 (95% CI 0.990---1.000, p = 0.05), in superextended lymphadenectomies (median 38 nodes) the HR was 0.853 (95% CI 0.715---0.993, p = 0.048). In this study, no association was found between total number of nodes extracted and cancerspecific mortality. However, it is established that the total number of lymph nodes is not a good measure of the quality of the technique, since there are multiple factors that directly influence the total number of lymph nodes obtained and that are dependent not only on the surgeon, but also on the characteristics of the patient and the pathologist who analyzes the samples.12 Considering these factors, Dorin et al.13 compared the same sample of patients analyzed in 2 different centers and observed that the median number of nodes counted per patient was 72, compared to 40 in each center. In this case, the differences in the counts were due to the fact that the samples were processed differently in each of the centers and that the departments of pathological anatomy differed in the definition of lymph node. It is important to note that there was no difference in the percentage of detection of patients with positive nodes. Bochner et al.14 published in 2001 that when lymphadenectomy was sent to be analyzed en bloc they obtained fewer nodes than if each of the anatomical territories dissected were sent separately. This is mainly due to a greater surgical effort in dissection, having to send samples for each anatomical territory, and better processing by the pathologist, since it is easier to identify the nodes in less bulky samples. Therefore, it seems that the number of nodes is not a good tool for interinstitutional comparison, and the definition of standard anatomical territories with meticulous removal of the lymph nodes in these territories is more reproducible to evaluate the efficacy of lymphadenectomy. Number of positive lymph nodes and lymph node density Two concepts that have also been studied due to their relationship to oncological prognosis are the total number of positive nodes and lymph node density.

Anatomical limits and oncological benefit of lymphadenectomy As for the number of positive nodes, Stein et al.15 evaluated the factors associated with disease progression in patients with lymphatic metastases, determining that the number of positive lymph nodes was a significant prognostic variable. Patients with less than 8 positive lymph nodes had a higher survival rate than patients with more than 8 positive lymph nodes. Jensen et al.16 showed that the number of positive nodes (comparing a single positive node versus multiple involvement) proved to be an independent predictor of survival. Tarin et al.17 evaluated the effect on relapse-free survival and cancer-specific survival of positive node localization in 591 patients undergoing RC with pelvic lymphadenectomy. In this study, no differences were found between patients with lymph node involvement in the territory of the common iliac or those with involvement in the obturator fossa, the external or the internal iliac. However, the number of positive lymph nodes (none, one, or two or more) was significantly associated with cancer-specific survival. The concept of lymph node density has been used in many studies. Lymph node density is defined as the ratio of number of positive nodes/number of total nodes removed. This concept was developed to try to reduce the interinstitutional difference found in the total lymph node count. Herr18 found that patients with a nodal density greater than 20% had a worse prognosis. Later, the results have been contradictory, since other authors, such as Wiesner et al.19 or May et al.20 , confirmed these findings, although in other series, lymph node density has not had an impact on survival.16,17 In 2015, Ku et al.21 developed a meta-analysis on the prognostic value of lymph node density, concluding that this concept is an independent predictor of oncologic evolution of patients. However, prospective validation is still required to define a cut-off point.

Oncologic value of dissection by anatomical territories The extension of lymphadenectomy and dissected anatomical territories have a significant impact on the survival of patients. However, the optimal extension of lymphadenectomy is the main reason for debate in this field. Several publications have compared the oncological evolution of patients undergoing RC and lymphadenectomy of different anatomical territories, with controversial results. In 2014, the first systematic review6 was published, which analyzes the oncological impact of the various extensions of lymphadenectomy, including --- without language or study design limitations --- all the studies that up to now compared patients submitted to RC with any type of extension of lymphadenectomy (see description of the studies included in supplementary material, Appendix B). The most relevant findings of this review were: 1. Any extension of lymphadenectomy is better than not performing it for all subgroups of patients analyzed.6 This conclusion is obtained from the analysis of 7 studies, and in all of them benefit is obtained in at least some of the cancer results analyzed.

287 2. There are no studies comparing limited vs. standard lymphadenectomy. 3. Limited lymphadenectomy is insufficient for the oncological control of the disease. This is demonstrated after the analysis of 5 studies,7,22---25 in 3 of which7,22,23 an improvement was observed in at least one of the oncological results analyzed in patients undergoing extended or superextended lymphadenectomy vs limited lymphadenectomy (Table 1). 4. Comparing standard lymphadenectomy to extended lymphadenectomy, the results are contradictory, since not all the studies analyzed found differences in oncological results.26---28 However, there is some evidence that consistently demonstrates oncologic benefit in extended lymphadenectomy29---33 (Table 2). 5. Superextended lymphadenectomy to the inferior mesenteric does not provide any oncologic benefit, which is demonstrated by the results of 2 multi-institutional studies.31,34 The conclusions of this review were included in the European guidelines, where it is suggested that any extension of lymphadenectomy is better than not performing it for the oncological control of the disease. The upper limit of the same is still not clearly established, although there is some evidence that supports the benefit in the extended lymphadenectomy, being advised not to extend the dissection beyond the aortic bifurcation. Since 2014, publications in this field have been very scarce. Moschini et al.35 published a series of 1016 patients on which they attempted to graphically explore with ROC the relationship between the number of dissected nodes and the probability of finding one or more metastatic nodes. The conclusions of this study are that it would be necessary to perform extended lymphadenectomy in all patients, regardless of the pathological anatomy prior to RC. A series of 3314 patients has recently been published, demonstrating that in patients aged (>75 years) and with comorbidity (Charlson ≥ 1), performing lymphadenectomy does not have a global or specific survival benefit due to cancer compared to not conducting it. In this study, 322 patients were ≥75 and had associated comorbidity. Overall 5-year survival was 30% both when performing RC alone and when lymphadenectomy was associated (HR 0.99, p = 0.9).36

Complications of lymphadenectomy In some of the studies mentioned above reference is made to the complications derived from the different extensions of lymphadenectomy. Brössner et al.24 reported that extended lymphadenectomy increased intraoperative time versus limited lymphadenectomy, without finding a significant increase in the most frequent complications. In this study, no differences were found in the 30-day complication rate (11% in extended lymphadenectomy versus 9% in limited, p = 0.28), or in 30-day mortality (3 vs 1, respectively; p = 0.57). Other studies corroborate the increase in surgical time when performing extended lymphadenectomy, without a considerable increase in complications.29,30

288

Table 1

Comparative oncologic outcomes of limited versus extended/superextended lymphadenectomy. Type of lymphadenectomy

Hori (2013) Holmer (2009)

Bostrom (2011)

Jensen (2012)

Cancer-specific survival (%) 5 years

Multivariate analysis

Comments

HR

IC 95%

p

Limited

61

p = 0.5

73

p = 0.27

NA

NA

NA

Extended Limited

47 NA

66

50 p = 0.45

HR 1.00

NA −

NA −

NA Only differences in relapse-free survival in >pT2 patients

Extended

NA

73

Cancer-specific mortality All patients: HR 0.81 ≤pT2: HR 0.80 >pT2: HR 0.54 Relapse-free survival All patients: HR 0.73 ≤pT2: HR 0.88 >pT2: HR 0.42 −

0.44---1.47 0.28---2.32 0.26---1.14

0.48 0.68 0.10

0.41---1.30 0.34---2.30 0.20---0.88

0.28 0.79 0.022

−

Greater survival in extended lymphadenectomy

0.31---0.93

0.026

p < 0.05

HR 1.00

−

−

0.45---0.81

<0.01

NA NA

Overall survival HR 0.60 NA NA

Limited

NA

NA

HR 1.00

Extended

NA

NA

Limited

55

p < 0.05

Cancer-specific survival: HR 0.53 67

Extended/ Superextended Limited Superextended

67

NA: not available information.

NA NA

72 NA NA

NA NA

There are no differences

Greater survival in extended lymphadenectomy

A. Guijarro et al.

Brossner (2004)

Overall survival (%) 5 years

Comparative oncologic results of standard versus extended/superextended lymphadenectomy. Overall survival (%) 5 years

Latif (2012) Dharaskar (2011) Wang (2013) Poulsen (1998)

Simone (2012a)

Dhar (2008)

Standard Extended Standard Extended Standard Extended Standard

58 40 0 0 NA NA NA

Extended

NA

Standard Extended

NA NA

Standard

Extended

Abol-Enein (2011)

Standard Superextended

p = 0.14

pT2,N0: 68 pT2,N+: 64 pT3,N0: 26 pT3,N+: 22 pT2,N0: 66 (p = 0.12) pT2,N+: 61 (p = 0.10) pT3,N0: 46 (p = 0.002) pT3,N+: 42 (p = 0.002) NA NA

NA NA NA NA NA NA All: 56 ≤pT3a : 85; >pT3: 27 pN0: 71; pN+: 7 All: 62 (p = 0.33) ≤pT3a : 64 (p < 0.02) >pT3: 39 (p = 0.87) pN0: 90 (p < 0.02) pN+: 24 (p = 0.15) 42.6 p < 0.01 63.1

pT2,N0: 67 pT2,N+: 63 pT3,N0: 23 pT3,N+: 19 pT2,N0: 77 (p = 0.12) pT2,N+: 71 (p = 0.22) pT3,N0: 57 (p < 0.0001) pT3,N+: 49 (p < 0.0001) 54.7 66.6

p = 0.04

Multivariant analysis

Comments

HR

95% CI

p

NA NA NA NA NA NA NA

NA NA NA NA NA NA NA

NA NA NA NA NA NA NA

NA

NA

NA

HR 1.00 Disease-free survival: HR 0.51 Cancer-specific survival: HR 0.56 NA

− 0.40---0.65

− <0.01

0.42---0.73

<0.01

NA

NA

NA

NA

NA

HR 1.45 HR 1.00

1.06---1.99 −

0.02 −

Without differences Without differences Without differences Differences in favor of extended lymphadenectomy in ≤pT3 and pN0

Differences in favor of extended lymphadenectomy

Differences in favor of extended lymphadenectomy in ≥pT3

Differences in favor of superextended lymphadenectomy

289

LPDN: lymphadenectomy; NA: not available information. a ≤pT3a in this study indicates organ-confined disease.

Disease-free survival (%) 5 years

Anatomical limits and oncological benefit of lymphadenectomy

Table 2

290

Evidence based on clinical trials Most of the studies to which we have referred previously are retrospective series. However, two randomized prospective studies are currently under way: - The first is a German multi-institutional trial comparing standard versus superextended lymphadenectomy in RC with curative intent (ClinicalTrials.gov identifier NCT01215071). The main objective of this study is to evaluate the impact of extension of lymphadenectomy on progression-free survival and, as secondary objectives, the type and location of progression, disease-free survival, the influence of adjuvant chemotherapy, and complications. - A second trial is the SWOG-S1011. This is a randomized controlled multi-institutional study comparing standard and extended lymphadenectomy in patients undergoing open RC with curative intent (Clinicaltrials.gov identifier NCT01224665). The main objective of this study is to assess the impact of extension of lymphadenectomy on disease-free survival, with secondary objectives such as overall survival and morbidity. The results of these 2 trials will help answer some of the questions regarding the optimal extent of lymphadenectomy.

Conclusions To evaluate the oncologic results of lymphadenectomy as part of the treatment of MIBC, it is advisable to use the anatomic territories instead of the number of lymph nodes. However, it is necessary to homogenize the nomenclature of the limits of lymphadenectomy to make the different studies comparable. Although the optimal extension of lymphadenectomy is difficult to establish, it is advisable to perform lymphadenectomy in all cases, and that extended lymphadenectomy seems to provide a greater oncologic benefit than the more limited dissections, discouraging broader lymphadenectomies that reach the inferior mesenteric because it has not demonstrated a benefit in oncological terms.

Conflict of interest The authors declare that they have no conflict of interest.

Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.acuroe.2017.04.001.

References 1. Witjes JA, Compérat E, Cowan NC, Gakis G, Lebrét T, van der Heijden AG, et al. Muscle-invasive and metastatic bladder cancer. European Association of Urology Guidelines; 2016. p. 22---33.

A. Guijarro et al. 2. Quek ML, Sanderson KM, Daneshmand S, Stein JP. The importance of an extended lymphadenectomy in the management of high-grade invasive bladder cancer. Expert Rev Anticancer Ther. 2004;4:1007---16. 3. Kluth LA, Black PC, Bochner BH, Catto J, Lerner SP, Stenzl A, et al. Prognostic and prediction tools in bladder cancer: a comprehensive review of the literature. Eur Urol. 2015;68:238---53. 4. Abol-Enein H, el-Baz M, abd el-Hameed MA, Abdel-Latif M, Ghoneim MA. Lymph node involvement in patients with bladder cancer treated with radical cystectomy: a patho-anatomical study --- a single center experience. J Urol. 2004;172:1818---21. 5. Leissner J, Ghoneim MA, Abol-Enein H, Thüroff JW, Franzaring L, Fisch M, et al. Extended radical lymphadenectomy in patients with urothelial bladder cancer: results of a prospective multicenter study. J Urol. 2004;171:139---44. 6. Bruins HM, Veskimae E, Hernandez V, Imamura M, Neuberger MM, Dahm P, et al. The impact of the extent of lymphadenectomy on oncologic outcomes in patients undergoing radical cystectomy for bladder cancer: a systematic review. Eur Urol. 2014;66:1065---77. 7. Jensen JB, Ulhøi BP, Jensen KM-E. Extended versus limited lymph node dissection in radical cystectomy: impact on recurrence pattern and survival. Int J Urol. 2012;19:39---47. 8. Roth B, Wissmeyer MP, Zehnder P, Birkhäuser FD, Thalmann GN, Krause TM, et al. A new multimodality technique accurately maps the primary lymphatic landing sites of the bladder. Eur Urol. 2010;57:205---11. 9. Herr HW, Bochner BH, Dalbagni G, Donat SM, Reuter VE, Bajorin DF. Impact of the number of lymph nodes retrieved on outcome in patients with muscle invasive bladder cancer. J Urol. 2002;167:1295---8. 10. Leissner J, Hohenfellner R, Thüroff JW, Wolf HK. Lymphadenectomy in patients with transitional cell carcinoma of the urinary bladder; significance for staging and prognosis. BJU Int. 2000;85:817---23. 11. Rink M, Shariat SF, Xylinas E, Fitzgerald JP, Hansen J, Green DA, et al. Does increasing the nodal yield improve outcomes in patients without nodal metastasis at radical cystectomy? World J Urol. 2012;30:807---14. 12. Stein JP, Penson DF, Cai J, Miranda G, Skinner EC, Dunn MA, et al. Radical cystectomy with extended lymphadenectomy: evaluating separate package versus en bloc submission for node positive bladder cancer. J Urol. 2007;177:876---81. 13. Dorin RP, Daneshmand S, Eisenberg MS, Chandrasoma S, Cai J, Miranda G, 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;60:946---52. 14. Bochner BH, Herr HW, Reuter VE. Impact of separate versus en bloc pelvic lymph node dissection on the number of lymph nodes retrieved in cystectomy specimens. J Urol. 2001;166:2295---6. 15. Stein JP, Cai J, Groshen S, Skinner DG. Risk factors for patients with pelvic lymph node metastases following radical cystectomy with en bloc pelvic lymphadenectomy: concept of lymph node density. J Urol. 2003;170:35---41. 16. Jensen JB, Ulhøi BP, Jensen KM-E. Evaluation of different lymph node (LN) variables as prognostic markers in patients undergoing radical cystectomy and extended LN dissection to the level of the inferior mesenteric artery. BJU Int. 2012;109:388---93. 17. Tarin TV, Power NE, Ehdaie B, Sfakianos JP, Silberstein JL, Savage CJ, et al. Lymph node-positive bladder cancer treated with radical cystectomy and lymphadenectomy: effect of the level of node positivity. Eur Urol. 2012;61:1025---30. 18. Herr HW. Superiority of ratio based lymph node staging for bladder cancer. J Urol. 2003;169:943---5. 19. Wiesner C, Salzer A, Thomas C, Gellermann-Schultes C, Gillitzer R, Hampel C, et al. Cancer-specific survival after radical cystectomy and standardized extended lymphadenectomy for

Anatomical limits and oncological benefit of lymphadenectomy

20.

21.

22.

23.

24.

25.

26.

27.

28.

node-positive bladder cancer: prediction by lymph node positivity and density. BJU Int. 2009;104:331---5. May M, Herrmann E, Bolenz C, Tiemann A, Brookman-May S, Fritsche H-M, et al. Lymph node density affects cancer-specific survival in patients with lymph node-positive urothelial bladder cancer following radical cystectomy. Eur Urol. 2011;59: 712---8. Ku JH, Kang M, Kim HS, Jeong CW, Kwak C, Kim HH. Lymph node density as a prognostic variable in node-positive bladder cancer: a meta-analysis. BMC Cancer. 2015;15:447. Holmer M, Bendahl P-O, Davidsson T, Gudjonsson S, Månsson W, Liedberg F. Extended lymph node dissection in patients with urothelial cell carcinoma of the bladder: can it make a difference? World J Urol. 2009;27:521---6. Bostrom PJ, Mirtti T, Nurmi M, Laato M, van Rhijn BWG, Fleshner NE, et al. Extended lymphadenectomy and chemotherapy offer survival avantage in muscle-invasive bladder cancer. J Urol. 2011;185:e640. Brössner C, Pycha A, Toth A, Mian C, Kuber W. Does extended lymphadenectomy increase the morbidity of radical cystectomy? BJU Int. 2004;93:64---6. Hori J, Tamaki G, Kita M, Iwata T, Matsumoto S, Kakizaki H. Survival impact of the extent of pelvic lymph node dissection in patients undergoing radical cystectomy for bladder cancer. Eur J Cancer. 2013;49:S16. Latif AAE, Miocinovic R, Stephenson AJ, Campbell S, Fergany A, Gong MC. Impact of extended versus standard lymph node dissection on overall survival among patients with urothelial cancer of bladder. J Urol. 2012;187:e707. Dharaskar A, Kumar V, Kapoor R, Jain M, Mandhani A. Does extended lymph node dissection affect the lymph node density and survival after radical cystectomy. Indian J Cancer. 2011;48:230---3. Wang G. Clinical significance of radical cystectomy with extended lymphadenectomy and influencing factors associated

291

29.

30.

31.

32.

33.

34.

35.

36.

with recurrence of bladder cancer [abstract MP08-19]. In: Presented at: World Congress of Endourology. 2013. Finelli A, Gill IS, Desai MM, Moinzadeh A, Magi-Galluzzi C, Kaouk JH. Laparoscopic extended pelvic lymphadenectomy for bladder cancer: technique and initial outcomes. J Urol. 2004;172 5 Pt 1:1809---12. Poulsen AL, Horn T, Steven K. Radical cystectomy: extending the limits of pelvic lymph node dissection improves survival for patients with bladder cancer confined to the bladder wall. J Urol. 1998;160 6 Pt 1:2015---20. Simone G, Papalia R, Ferriero M, Guaglianone S, Castelli E, Collura D, et al. Stage-specific impact of extended versus standard pelvic lymph node dissection in radical cystectomy. Int J Urol. 2013;20:390---7. Dhar NB, Klein EA, Reuther AM, Thalmann GN, Madersbacher S, Studer UE. Outcome after radical cystectomy with limited or extended pelvic lymph node dissection. J Urol. 2008;179:873---8 [discussion 878]. Abol-Enein H, Tilki D, Mosbah A, el-Baz M, Shokeir A, Nabeeh A, et al. Does the extent of lymphadenectomy in radical cystectomy for bladder cancer influence disease-free survival? A prospective single-center study. Eur Urol. 2011;60:572---7. Zehnder P, Studer UE, Skinner EC, Dorin RP, Cai J, Roth B, et al. Super extended versus extended pelvic lymph node dissection in patients undergoing radical cystectomy for bladder cancer: a comparative study. J Urol. 2011;186:1261---8. Moschini M, Karnes RJ, Gandaglia G, Luzzago S, dell’Oglio P, Rossi MS, et al. Preoperative favorable characteristics in bladder cancer patients cannot substitute the necessity of extended lymphadenectomy during radical cystectomy: a sensitivity curve analysis. Urology. 2016;88:97---103. Larcher A, Sun M, Schiffmann J, Tian Z, Shariat SF, McCormack M, et al. Differential effect on survival of pelvic lymph node dissection at radical cystectomy for muscle invasive bladder cancer. Eur J Surg Oncol. 2015;41:353---60.