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Extended Versus Limited Lymph Node Dissection in Bladder Cancer Patients Undergoing Radical Cystectomy: Survival Results from a Prospective, Randomized Trial

  • Jürgen E. Gschwend 1,
  • Matthias M. Heck 1,
  • Jan Lehmann 2,
  • Herbert Rübben 3,
  • Peter Albers 4,
  • Johannes M. Wolff 5,
  • Detlef Frohneberg 6,
  • Patrick de Geeter 7,
  • Axel Heidenreich 8,
  • Tilman Kälble 9,
  • Michael Stöckle 10,
  • Thomas Schnöller 11,
  • Arnulf Stenzl 12,
  • Markus Müller 13,
  • Michael Truss 14,
  • Stephan Roth 15,
  • Uwe-Bernd Liehr 16,
  • Joachim Leißner 17,
  • Thomas Bregenzer 2,
  • Margitta Retz 1
1 Department of Urology, Rechts der Isar Medical Center, Technical University of Munich, Munich, Germany 2 AUO Study Group, Germany 3 Department of Urology, University of Essen, Germany 4 Department of Urology, Heinrich Heine University, Düsseldorf, Germany 5 Department of Urology, Paracelsus Hospital Golzheim Düsseldorf, Düsseldorf, Germany 6 Department of Urology, Hospital of Karlsruhe, Germany 7 Department of Urology, Hospital of Kassel, Germany 8 Department of Urology, University of Cologne, Cologne, Germany 9 Department of Urology, Hospital of Fulda, Germany 10 Department of Urology, Saarland University Medical Center, Homburg, Germany 11 Department of Urology, Ulm University, Germany 12 Department of Urology, Eberhard Karls University, Tübingen, Germany 13 Department of Urology, Hospital Ludwigshafen, Germany 14 Department of Urology, Hospital Dortmund, Germany 15 Department of Urology, Helios Hospital, Wuppertal, Germany 16 Department of Urology, Otto von Guericke University, Magdeburg, Germany 17 Department of Urology, Hospital Holweide, Cologne, Germany

Publication: European Urology, September 2018

DOI: https://doi.org/10.1016/j.eururo.2018.09.047

Background

The extent of lymph node dissection (LND) in bladder cancer (BCa) patients at the time of radical cystectomy may affect oncologic outcome.

Objective

To evaluate whether extended versus limited LND prolongs recurrence-free survival (RFS).

Design, setting, and participants

Prospective, multicenter, phase-III trial patients with locally resectable T1G3 or muscle-invasive urothelial BCa (T2-T4aM0).

Intervention

Randomization to limited (obturator, and internal and external iliac nodes) versus extended LND (in addition, deep obturator, common iliac, presacral, paracaval, interaortocaval, and para-aortal nodes up to the inferior mesenteric artery).

Outcome measurements and statistical analysis

The primary endpoint was RFS. Secondary endpoints included cancer-specific survival (CSS), overall survival (OS), and complications. The trial was designed to show 15% advantage of 5-yr RFS by extended LND.

Results and limitations

In total, 401 patients were randomized from February 2006 to August 2010 (203 limited, 198 extended). The median number of dissected nodes was 19 in the limited and 31 in the extended arm. Extended LND failed to show superiority over limited LND with regard to RFS (5-yr RFS 65% vs 59%; hazard ratio [HR] = 0.84 [95% confidence interval 0.58–1.22]; p = 0.36), CSS (5-yr CSS 76% vs 65%; HR = 0.70; p = 0.10), and OS (5-yr OS 59% vs 50%; HR = 0.78; p = 0.12). Clavien grade ≥3 lymphoceles were more frequently reported in the extended LND group within 90 d after surgery. Inclusion of T1G3 tumors may have contributed to the negative study result.

Conclusions

Extended LND failed to show a significant advantage over limited LND in RFS, CSS, and OS. A larger trial is required to determine whether extended compared with limited LND leads to a small, but clinically relevant, survival difference (ClinicalTrials.gov NCT01215071).

Patient summary

In this study, we investigated the outcome in bladder cancer patients undergoing cystectomy based on the anatomic extent of lymph node resection. We found that extended removal of lymph nodes did not reduce the rate of tumor recurrence in the expected range.

Commentary by Marco Moschini

Radical cystectomy with bilateral pelvic lymph node dissection (LND) is the standard of care treatment of patients with very high-risk non-muscle invasive and muscle invasive bladder cancer. On one hand, LND is a crucial staging procedure; on the other hand, survival benefit of an extended LND has not been yet prospectively demonstrated. The authors of this prospective, randomized controlled trial randomized 401 patients in two groups: the first (n=203) received a limited LND (obturator, and internal and external iliac nodes) versus the second group (n=198) who received an extended LND (in addition, deep obturator, common iliac, presacral, paracaval, interaortocaval, and para-aortal nodes up to the inferior mesenteric artery).

In this trial, extended LND failed to show superiority over limited LND with regards to disease recurrence-free survival, cancer-specific survival and overall survival. Considering complications, authors found that Clavien grade ≥ lymphoceles were more frequently reported in the extended LND group within 90 days after surgery.

In this study, authors investigated the added benefit associated with performing an extended lymphadenectomy during radical cystectomy over a limited template. Authors failed to find any survival benefit for patients treated with extended LND compared to those treated with limited LND. Although authors have to be complimented for performing this prospective surgical trial, some limitations could have affected the outcomes.

First, the definition of the extension of the lymphadenectomy may be questionable with the inclusion in the same group of the extended and super extended templates.

Second, patients treated with neoadjuvant chemotherapy were excluded and adjuvant chemotherapy was optional. One could argue that the latter could represent a suboptimal treatment of MIBC patients.

Third, the authors included as well high-risk non muscle-invasive bladder cancer patients and the latter could have impacted the oncological outcomes.