No Prostate Cancer Survival Benefit With More Extensive Lymph Node Assessment

WASHINGTON — Extended pelvic lymph node dissection (ePLND) after radical prostatectomy failed to improve survival in intermediate- and high-risk prostate cancer over standard lymphadenectomy, long-term follow-up from a randomized trial showed.

After a median follow-up of almost 11 years, more extensive lymph node assessment did not significantly improve any survival outcome in the overall patient population, as compared with limited PLND (lPLND). A subgroup analysis suggested that patients with high-grade disease (grade group [GG] 3-5) might have better biochemical relapse-free survival (BRFS), consistent with an earlier analysis, and after additional follow-up, patients with high-grade disease might also have better metastasis-free survival (MFS) with ePLND.

“This phase III randomized, controlled trial did not demonstrate oncological superiority of extended pelvic lymph node dissection over limited pelvic lymph node dissection among unselected intermediate- and high-risk prostate cancer patients,” said Jean Lestingi, MD, of the University of Sao Paolo in Brazil, at the American Urological Association (AUA) meeting. “In patients with biopsies of grade group 3-5, after a long-term follow-up, a significant and sustainable benefit in biochemical recurrence-free survival was shown and we now demonstrate the benefits in metastasis-free survival.”

“We suggest that extended pelvic lymph node dissection could be considered a standard in these subgroups undergoing radical prostatectomy, and guideline recommendations should consider this updated data.”

Although among a handful of studies billed as “practice-changing, paradigm-shifting” by the AUA, the trial should not change clinical practice, according to Alexander Kutikov, MD, of Fox Chase Cancer Center in Philadelphia.

“The pre-specified primary endpoint [BRFS in the overall population] remains negative at long-term follow-up,” Kutikov told MedPage Today. “Metastasis-free survival, cancer-specific survival [CSS], and OS [overall survival] are all flat. The ‘new’ finding is an MFS signal in the biopsy GG 3-5 subgroup of just 31 versus 38 patients with a wide confidence interval [HR 0.26, 95% CI 0.07–0.93]. That was already a hypothesis-generating observation in the 2021 paper. A positive p-value with longer follow-up in the same handful of patients does not convert it into level 1 evidence.”

The trial has a number of issues and limitations, Kutikov added. The design had statistical power to show a 15% absolute BRFS advantage at 5 years, “an implausibly large effect for any oncologic surgical intervention.” The results conflict with a much larger U.S. trial, which also showed no BRFS benefit and whose authors attributed an MFS signal to post-BRFS events rather than a direct surgical effect.

Enrollment in the Brazilian study ended in 2016, before the introduction of prostate-specific membrane antigen (PSMA) PET imaging. The diagnostic case for ePLND is “much weaker in the PSMA era.”

“Most importantly, morbidity is not trivial,” said Kutikov. “In their own data, ePLND added about 50 minutes to OR [operating room] time, 150 mL of blood loss, a day of hospitalization, and a day of drain. Symptomatic lymphocele was 4% versus 0%. Clavien-Dindo I–II [surgical complications] at 90 days was 28% versus 17.3%.”

A study in bladder cancer also evaluated extended lymphadenectomy at cystectomy and found no disease-free survival or OS benefit, but 90-day mortality of 6.5% versus 2.4%.

“More pelvic dissection is not free — at all,” said Kutikov.

Lestingi reported findings from a randomized trial to address the unresolved issue of whether ePLND offered a survival advantage over lPLND. The study involved 300 patients who underwent radical prostatectomy for newly diagnosed intermediate- and high-risk prostate cancer. Patients were randomized to ePLND (a median of 17 lymph nodes) or lPLND (three lymph nodes), and the primary endpoint was BRFS at 5 years. As Kutikov noted, investigators tested the hypothesis that ePLND would result in a 15% absolute improvement in BRFS in the overall population.

With the extended follow-up, BRFS did not differ significantly between patients randomized to ePLND or lPLND (HR 0.92, 95% CI 0.66-1.29). MFS, a secondary endpoint, also did not differ significantly between the groups (HR 0.60, 95% CI 0.32-1.15), nor did CSS (HR 1.18, 95% CI 0.36-3.85) or OS (HR 0.99, 95% CI 0.62-1.58).

The earlier report from the trial showed improvement in BRFS in patients with GG 3-5 prostate cancer (HR 0.48, 95% CI 0.26-0.91), and that advantage persisted in the update (HR 0.54, 95% CI 0.29-0.99). Additionally, the GG 3-5 subgroup seemed to derive an MFS benefit from ePLND (HR 0.26, 95% CI 0.07-0.93), which was not evident in the earlier analysis. A trend toward increased time to radiotherapy favored ePLND (not reached vs 43.7 months with lPLND, P=0.098), as well as time to androgen deprivation therapy (not reached vs 66.5 months, P=0.055).