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The Impact of the Extent of Lymphadenectomy on Oncologic Outcomes in Patients Undergoing Radical Cystectomy for Bladder Cancer: a Systematic Review

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The Impact of the Extent of Lymphadenectomy on Oncologic Outcomes in Patients Undergoing Radical Cystectomy for Bladder Cancer: a Systematic Review EUROPEAN UROLOGY 66 (2014) 1065–1077 available at www.sciencedirect.com journal homepage: www.europeanurology.com Review – Bladder Cancer The Impact of the Extent of Lymphadenectomy on Oncologic Outcomes in Patients Undergoing Radical Cystectomy for Bladder Cancer: A Systematic Review Harman M. Bruins a,*, Erik Veskimae b, Virginia Hernandez c, Mari Imamura d, Molly M. Neuberger e, Philip Dahm e,f, Fiona Stewart d, Thomas B. Lam d, James N’Dow d, Antoine G. van der Heijden a, Eva Compe´rat g, Nigel C. Cowan h, Maria De Santis i, Georgios Gakis j, Thierry Lebret k, Maria J. Ribal l, Amir Sherif m, J. Alfred Witjes a a Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands; b Department of Urology, Tampere University Hospital, Tampere, Finland; c Department of Urology, Hospital Universitario Fundacio´n Alcorco´n, Madrid, Spain; d Academic Urology Unit, University of Aberdeen, Scotland, UK; e Department of Urology, University of Florida, Gainesville, FL, USA; f Malcom Randall Veterans Affairs Medical Center, Gainesville, FL, USA; g Department of Pathology, Groupe Hospitalier Pitie´—Salpeˆtrie`re, Paris, France; h Department of Radiology, Queen Alexandra Hospital, Portsmouth, UK; i 3rd Medical Department/LBI-ACR VIEnna—LBCTO and ACR-ITR VIEnna, Kaiser Franz Josef Spital, Vienna, Austria; j Department of Urology, Eberhard-Karls University, Tu¨bingen, Germany; k Department of Urology, Foch Hospital, Suresnes, France; l Department of Urology, Hospital Clinic, University of Barcelona, Barcelona, Spain; m Department of Surgical and Perioperative Science, Umea˚ University, Umea˚, Sweden Article info Abstract Article history: Context: Controversy exists regarding the therapeutic value of lymphadenectomy (LND) in patients Accepted May 21, 2014 undergoing radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). Objective: To systematically review the relevant literature assessing the impact of LND on oncologic and perioperative outcomes in patients undergoing RC for MIBC. Keywords: Evidence acquisition: Medline, Medline In-Process, Embase, the Cochrane Central Register of Con- trolled Trials, and the Latin American and Caribbean Center on Health Sciences Information (LILACS) Bladder neoplasms were searched up to December 2013. Comparative studies reporting on no LND, limited LND (L-LND), Radical cystectomy standard LND (S-LND), extended LND (E-LND), superextended LND (SE-LND), and oncologic and Lymphadenectomy perioperative outcomes were included. Risk-of-bias and confounding assessments were performed. Evidence synthesis: Twenty-three studies reporting on 19 793 patients were included. All but one Lymph node dissection study were retrospective. Planned meta-analyses were not possible because of study heterogeneity; Standard therefore, data were synthesized narratively. There were high risks of bias and confounding across most studies as well as extreme heterogeneity in the definition of the anatomic boundaries of LND extended templates. All seven studies comparing LND with no LND favored LND in terms of better oncologic or superextended dissection outcomes. Seven of 14 studies comparing (super)extended LND with L-LND or S-LND reported a Oncologic outcomes beneficial outcome for (super)extended LND in at least a subset of patients. No difference in outcome was reported in two studies comparing E-LND and S-LND. The comparative harms of different extents of LND remain unclear. Conclusions: Although the quality of the data was poor, the available evidence indicates that any kind of LND is advantageous over no LND. Similarly, E-LND appears to be superior to lesser degrees of dissection, while SE-LND offered no additional benefits. It is hoped that data from ongoing randomized clinical trials will clarify remaining uncertainties. Patient summary: The current literature suggests that removal of lymph nodes in bladder cancer surgery is beneficial and might result in better outcomes in terms of prolonging survival; however, the quality of the available studies is poor, and high-quality studies are needed. # 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Radboud University Medical Centre, Department of Urology, Geert Groo- teplein Zuid 10 (659), P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Tel. +31 24 361 37 35; Fax: +31 24 354 10 31. E-mail address: [email protected] (H.M. Bruins). http://dx.doi.org/10.1016/j.eururo.2014.05.031 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved. 1066 EUROPEAN UROLOGY 66 (2014) 1065–1077 1. Introduction observational studies with a comparator arm, and retro- spective comparative studies. Registry or database studies Lymphadenectomy (LND) combined with radical cystec- were also eligible if the analysis was clearly structured as a tomy (RC) is considered the standard of care for patients comparison between control and intervention groups. with muscle-invasive bladder cancer (MIBC). Up to 25% of Studies with no comparator group (eg, single-arm case patients harbor lymph node (LN) metastases at the time of series), noneffectiveness studies (eg, nomogram studies), RC, and the staging role of LND is unequivocal. In 1982, reviews, and studies with <10 patients in each arm were Skinner [1] was the first to report long-term survival in excluded. LN-positive patients undergoing RC and LND without The study population was limited to patients with systemic treatment. The therapeutic value of LND, however, localized muscle-invasive urothelial or squamous cell remains a topic of continuous debate. While the results of carcinoma of the bladder (cT2–4 N0M0). Studies including two ongoing randomized clinical trials (RCTs) evaluating predominantly patients with variant histology other than the impact of different LND templates on survival are squamous cell carcinoma were excluded because of low awaited, the current evidence base remains uncertain with incidence and the potentially different biologic behavior of regard to the true benefits and harms of LND. In this study these cancers. Clinical staging was preferred, but if it was we systematically reviewed the available literature to not reported, staging based on RC specimen was accepted. evaluate the impact of the extent of LND on survival and Studies with mixed populations (eg, cTa, cTis, cT1) were perioperative outcomes in patients undergoing RC for MIBC. retained for consideration for inclusion if there were no studies that included patients with MIBC exclusively. 2. Evidence acquisition Studies including patients who underwent neoadjuvant or adjuvant treatment were also retained. 2.1. Search strategy The types of interventions included LND undertaken during RC for bladder cancer (BCa). Because of the expected The review was performed in accordance with the Preferred heterogeneity in defining the extent of LND across studies, Reporting Items for Systematic Reviews and Meta-analyses the extent of LND was determined a priori based on statement and principles outlined in the Cochrane Handbook discussion in an expert panel (EAU Working Group on MIBC) for Systematic Reviews of Interventions [2,3]. Highly sensitive and was categorized as follows: (1) limited LND (L-LND): electronic searches were conducted to identify all reports of LND confined to the obturator and/or perivesical fossa only; RCTs or nonrandomized comparative studies (NRCSs) (2) standard LND (S-LND): LND performed up to the assessing LND in patients undergoing RC for MIBC. The common iliac arteries; (3) extended LND (E-LND): LND searches were not limited by language or publication date. performed up to the proximal boundary of the crossing of The databases searched were Medline (1946 to December the common iliac vessels with the ureters or the aortic 2013), Medline In-Process (December 20, 2013), Embase bifurcation, with or without the presacral LNs; and (4) (1974 to December 2013), the Cochrane Central Register of superextended LND (SE-LND): LND performed up to the Controlled Trials (The Cochrane Library, Issue 8, 2013), and proximal boundary of the inferior mesenteric artery. The the Latin American and Caribbean Center on Health primary outcome was overall survival (OS); secondary Sciences Information (LILACS; December 2013). The data- outcomes included recurrence-free survival (RFS), disease- base search was complemented by additional sources, free survival (DFS), progression-free survival, cancer- including the reference lists of included studies, which were specific survival, and perioperative outcomes (eg, operative hand searched, and additional reports identified by an time, blood loss, lymphocele). expert panel (European Association of Urology [EAU] Working Group on MIBC). Ongoing trials were identified 2.3. Assessment of risks of bias at ClinicalTrials.gov. The full search strategy is presented in Supplement 1. Two reviewers independently assessed the risk of bias (RoB) Two reviewers independently screened titles and of individual studies. Any disagreement was resolved by abstracts of all citations identified by the search strategies. discussion or reference to a third reviewer. The standard Full-text copies of all potentially relevant reports were Cochrane Collaboration RoB tool [4] was used to assess the obtained and independently assessed by the reviewers to RoB in RCTs, while for NRCSs, the RoB tool recommended by determine whether they met the predefined inclusion the Cochrane Non-Randomised Studies Methods Group was criteria. Any disagreements were
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