What is the appropriate extent of lymphadenectomy for bladder cancer?

Intraoperative photograph after extended lymphadenectomy
A. Intraoperative photograph after extended lymphadenectomy, with removal of all tissue up to the aortic bifurcation and distally along the iliac vessels, including the presacral area. B. Demonstration of removal of all tissue lateral to the iliac vessels (retracted medially on the right) with visualization of the obturator nerve and the presciatic fossa of Marseilles (tip of suction).
Images courtesy of Sia Daneshmand, MD, associate professor of urology, director of clinical research, University of Southern California Institute of Urology, Los Angeles, CA.



Quality of health care in the U.S. has come under increased scrutiny, given its rising costs—now accounting for nearly 20 percent of the gross domestic product—and passage of the Affordable Care Act, which expands access to care for a greater number of Americans.1,2 However, assessing the quality of surgical care remains difficult and largely unstandardized.

The American College of Surgeons (ACS) has had a longstanding goal of improving care of the surgical patient and has helped promulgate a validated, outcomes-based program to measure quality via the ACS National Surgical Quality Improvement Program (ACS NSQIP®). The data disseminated through ACS NSQIP allow hospitals and other stakeholders to conduct risk-adjusted assessments of complication rates and surgical outcomes across a variety of surgical specialties.3

Beyond assessing complications after surgery, the ACS is in the process of developing surgical standards and checklists based on available evidence and results of clinical trials. For example, the results from the Clinical Outcomes of Surgical Therapy Study Group trial comparing laparoscopic and open colectomy for adenocarcinoma of the colon suggested that a lymph node count of 12 or higher could serve as a marker of surgical quality.4 Similarly, results from two American College of Surgeons Oncology Group trials (Z0010 and Z0011) have informed us regarding the need and type of node dissection required in women with breast cancer.5,6

The critical role of lymphadenectomy

Within urologic surgery, lymphadenectomy plays a critical role in a variety of malignancies, including cancer of the prostate, bladder, and testis. Although the primary benefit is in providing accurate staging information to inform prognosis and direct early adjuvant therapy, lymphadenectomy has a proven therapeutic benefit in men with testicular cancer both before and after systemic chemotherapy, as well as squamous cell carcinoma of the penis. An area of ongoing controversy is the role, benefit, and extent of lymph node dissection in patients with urothelial carcinoma of the bladder.

Pelvic lymphadenectomy has been an integral component of radical cystectomy for invasive urothelial carcinoma of the bladder for decades. Up to 25 percent of patients with muscle-invasive disease who undergo an operation will harbor nodal metastases, which negatively impacts cancer-specific survival. Nevertheless, approximately one-third of patients with positive lymph nodes will be free of disease five years after the operation, suggesting that adequate removal of local and regional disease may have a positive therapeutic impact.


The traditional limits of a standard pelvic lymph node dissection include removal of all tissue between the bladder and pelvic sidewall and along the external and internal iliac artery and vein, cranially to the bifurcation of the common iliac vessels and laterally to the genitofemoral nerve. The caudal limit is the crossing of the circumflex iliac vein over the external iliac artery and the node of Cloquet. The most common location of involved lymph nodes is in the obturator fossa or along the internal iliac artery; however, mapping studies have suggested that nodal metastases are frequently identified in the presacral and retroperitoneal regions. Thus, some surgeons have advocated for extended lymphadenectomy at the time of cystectomy to include tissue along and between the common iliac arteries, and even up the distal aorta and vena cava to the takeoff of the inferior mesenteric artery (see photo).

Several reports suggest that removal of at least 10 lymph nodes represents a minimal quality standard, while other researchers have proposed that 12 to 18 nodes represents an adequate lymph node yield.7 It should be noted, however, that these data are based on retrospective studies, expert opinions, or analysis of large administrative datasets. The optimal lymphadenectomy technique more likely is defined by anatomic boundaries rather than lymph node number, which is dependent on factors such as method of pathologic examination and number of individual specimens submitted for analysis. Current evidence suggests significant variation in practice patterns of lymphadenectomy at the time of cystectomy with respect to boundaries and even whether or not any lymph nodes are removed.8

NCI-supported clinical trial

Given the uncertainty surrounding the benefit of more extended lymphadenectomy and the absence of adequate studies, the Southwest Oncology Group initiated a trial (NCT01224665) to determine whether extending the limits of lymphadenectomy at the time of radical cystectomy to include the common iliac and presacral nodes improves progression-free and overall survival; the Alliance for Clinical Trials in Oncology and the Eastern Cooperative Oncology Group both have endorsed the National Cancer Institute (NCI)-supported trial. The German Association of Urogenital Oncology recently completed a similar randomized trial of standard and extended node dissection for bladder cancer (NCT01215071).

Patients with T2-T4a urothelial carcinoma of the bladder undergoing radical cystectomy are eligible to participate in the trial, and they may have received neoadjuvant systemic chemotherapy. An important aspect of the trial is the standardization of surgery and rigorous credentialing of surgeons, as documented by operative and pathology reports and intraoperative images demonstrating appropriate lymphadenectomy. The trial is limited to patients undergoing open surgery and not laparoscopic or robotic-assisted cystectomy. All operations performed in conjunction with the study will undergo a central surgical review, assessing both arms of the study—standard versus extended lymph-node dissection.

The primary goal of the study is to evaluate disease-free survival in patients who undergo the procedure, with secondary objectives of comparing overall survival and perioperative variables, such as operative time, 90-day morbidity and mortality, and length of hospitalization. Pathologic features, such as lymph node counts and lymph node density (number of positive lymph nodes/total number of lymph nodes examined), also are included in the analysis. Formalin-fixed, paraffin-embedded blocks of the primary tumor will be collected for correlative studies with planned analysis for biomarkers associated with metastasis and epithelial-mesenchymal transformation, and blood will be collected to assay for circulating tumor cells. The target accrual for the trial is 620 patients over five years.


This trial will test the ability of urologic surgeons to complete an important trial addressing surgical technique. The results will have clinical implications and will determine what type of lymph node dissection should be the standard of care going forward.

It is possible that the removal of additional lymph nodes may have only a small but beneficial therapeutic impact in patients with bladder cancer. It is important to note that neoadjuvant platinum-based combination chemotherapy for invasive bladder cancer yields a 5 percent absolute improvement in survival at five years; however, this significant difference was consistent in two large U.S. and European randomized trials and represents a current standard of care.9


  1. OECD iLibrary. Country statistical profile: United States. Available at: www.oecd-ilibrary.org/economics/country-statistical-profile-united-states_20752288-table-usa. Accessed May 21, 2013.
  2. Public Law 111–148. 111th Congress. Available at: www.gpo.gov/fdsys/pkg/PLAW-111publ148/html/PLAW-111publ148.htm. Accessed May 21, 2013.
  3. ACS NSQIP. Available at: http://site.acsnsqip.org/. Accessed May 21, 2013.
  4. The Clinical Outcomes of Surgical Therapy Study Group. A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med. 2004;350(20):2050-2059.
  5. Giuliano AE, Hawes D, Ballman KV, Whitworth PW, Blumencranz PW, Reintgen DS, Morrow M, Leitch AM, Hunt KK, McCall LM, Abati A, Cote R. Association of occult metastases in sentinel lymph nodes and bone marrow with survival among women with early-stage invasive breast cancer. JAMA. 2011;306(4):385-393.
  6. Guiliano AE, Hunt KK, Ballman KV, Beitsch PD, Whitworth PW, Blumencranz PW, Leitch AM, Saha S, McCall LM, Morrow M. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: A randomized clinical trial. JAMA. 2011;305(6):569-575.
  7. Herr H, Lee C, Chang S, Lerner S; Bladder Cancer Collaborative Group. Standardization of radical cystectomy and pelvic lymph node dissection for bladder cancer: A collaborative group report. J Urol. 2004;171(5):1823-1828.
  8. Konety BR, Joslyn SA, O’Donnell MA. Extent of pelvic lymphadenectomy and its impact on outcomes in patients diagnosed with bladder cancer: Analysis of data from the Surveillance, Epidemiology and End Results Program database. J Urol. 2003;169(3):946-950.
  9. Neoadjuvant chemotherapy in invasive bladder cancer: Update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol. 2005;48(2):202-205.

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