SWOG S1011 is a randomized Phase 3 trial that tested the hypothesis that an extended bilateral pelvic and iliac lymphadenectomy performed at the time of radical cystectomy would be associated with improved disease-free (DFS) and overall survival (OS) compared to a bilateral standard pelvic lymphadenectomy. Eligible patients had predominant urothelial cancer clinical stage T2-4aN0-2 and neoadjuvant chemotherapy (NAC) was allowed. We registered 659 and randomized 592 eligible patients at 27 sites in the United States and Canada, and the surgery was performed by 37 credentialed surgeons. Patients were stratified by type and receipt of NAC, T2 vs T3-4a, and PS 0-1 vs 2, and randomized intraoperatively after intraabdominal and pelvic exploration ruled out unresectable disease (T4b) and lymph node metastases in the extended template. The standard template included external and internal iliac nodes with circumferential mobilization of the external iliac artery and vein and the obturator nodes, with complete removal of all potential node-bearing tissue from the pelvic sidewall to the bladder (Figure 1). The extended template included bilateral common iliac and presciatic (or Fossa of Marseilles) and the presacral nodes. Surgeons could extend the node dissection up to the inferior mesenteric artery to include the distal aorta and inferior vena cava nodes (Figure 2) but were required only to go up to the aortic bifurcation based on surgeon preference.

Figure 1. Standard pelvic lymph node dissection includes external and internal iliac and obturator (A) and extends laterally to the pelvic sidewall and genitofemoral nerve (B).

Figure 2. Extended pelvic lymph node dissection includes bilateral common iliac, presciatic fossa laterally (A) and presacral fascia (B).

Clinical stage was T2 in 71% of patients in both arms; hydronephrosis was present in 26% and variant histology in 13%. NAC was administered in 57% of patients, with 87% receiving cisplatin-based treatment, which far exceeds that reported in any contemporary cohort through the course of the trial. Pathologic tumor stage was similar in both arms with pT0N0 in 20% of patients while 38% were <pT2N0. Pathologic pelvic lymph node metastases were present in 24% and 26% of standard lymph node dissection (SLND) and extended lymph node dissection (ELND), respectively. The median number of nodes (range) was 24 (6-61) and 39 (15, 94), respectively.

Median follow-up was 6.1 years and there was no difference in DFS or OS between the 2 arms. The estimated 5-year DFS probability was 55% for ELND and 58% for SLND (HR = 1.11 [95% CI 0.87, 1.42], 2-sided P = .40). Similarly, for OS the 5-year OS probability was 59% and 63%, respectively (HR = 1.11 [95% CI 0.87, 1.42], 2-sided P = .40). The DFS and OS event rates were progressively higher with more advanced pathologic tumor stage; patients with node metastasis had the highest event rates. We compared DFS and OS by the prespecified stratification factors and pathologic stage, and there was an association of pathologic stage pT3-pT4aN0 with better DFS with an HR of 1.91 (95% CI 1.19, 3.06) and OS HR of 2.05 (1.25, 3.36), but this is hypothesis-generating only.

We analyzed toxicity and focused on grade 3-5 events regardless of attribution to the node dissection. The most common grade 3 and 4 toxicities were anemia, urinary tract infections, wound infections, ileus, and venous thrombotic events. Grade 4 sepsis occurred in 3.7% and 6.2% in SLND and ELND, respectively. Fatal events occurred in 1.5% of patients within 30 days of surgery and 4.4% within 90 days and were more common in the ELND arm compared to the SLND (2.7% vs 0.3% and 6% vs 6.5% vs 2.4% at 30 and 90 days, respectively).

In summary, we successfully completed this innovative surgical trial and answered a critical question regarding the anatomic extent of pelvic lymphadenectomy performed at the time of radical cystectomy for curable muscle-invasive urothelial bladder cancer. Juergen Gschwend led a similar multicenter trial in Germany (LEA) and reported that there was no benefit to an extended node dissection. There are several key differences between these 2 trials: (1) in the LEA trial patients with clinical T1 disease were eligible; (2) in SWOG S1011 a majority received NAC while this was not allowed in the LEA trial; (3) the standard or “limited” dissection did not include the nodes posterior to the obturator nerve. This trial was recently updated at the European Association of Urology 2023 meeting, with long-term outcomes still showing no benefit for time to progression and OS with a signal of possible benefit for cancer-specific survival.

SWOG S1011 and the LEA trial thus clearly establish that a bilateral standard bilateral pelvic lymphadenectomy is standard of care for patients undergoing radical cystectomy for cT2-4a/N0-2 urothelial cancer.