Lymphadenectomy in Renal Cell Carcinoma: No Benefit?

Nick Mulcahy

January 02, 2018

In a disappointing result, the surgical removal of lymph nodes did not provide a survival benefit compared with no lymphadenectomy among patients with fully resected, high-risk renal cell carcinoma (RCC) who were part of the ASSURE (Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma) trial, indicates a new secondary analysis of the data.

The trial compared two different kinase inhibitors used in this setting with a placebo control arm.

However, because the goal of postsurgery systemic therapy is to wipe out any remaining micrometastatic disease, the trial also sought to find whether removing any suspicious lymph nodes at the time of the nephrectomy might improve results, explain the study authors.

The results from this secondary analysis were published in the January issue of the Journal of Urology.

The team of researchers, led by Benjamin Ristau, MD, from Fox Chase Cancer Center in Philadelphia, Pennsylvania, reviewed data on the 701 patients who were deemed high risk (36% of the 1943 total participants) and underwent retroperitoneal lymphadenectomy in the trial. This included all patients whose nodes were clinically positive (cN+) and about 30% of those with clinically negative nodes (cN0).

At a median follow-up of 67.9 months, there was no association between lymphadenectomy and overall survival (hazard ratio, 1.14; P = .20).

Patients With Positive Nodes

The authors report that a median of three lymph nodes were removed during the procedures and that 23.4% of the total were positive upon pathologic examination (pN+).

These patients with pN+ disease who underwent lymphadenectomy and received adjuvant sorafenib or sunitinib were, theoretically, the most likely to benefit from the effort to wholly remove micrometastases in affected nodes. But, again, disappointment held. Overall and disease-free survival did not improve among these patients.

On the reassuring side, lymphadenectomy did not result in an increased risk for surgical complications vs nephrectomy alone (14.2% vs 13.4%; P = .63).

The way in which the trialists used surgery likely reflects current practice, say the study authors: that is, lymphadenectomy was "almost universal" among the cN+ patients and "not routine" among the cN0 patients.

Despite its use in clinical practice, lymphadenectomy has not yet been proven to provide an oncologic benefit in this setting, the authors observe.

Lead author Dr Ristau summed up the study in an email to Medscape Medical News: "These data add to prior published work suggesting that routine lymph node dissection does not confer a survival benefit in patients with high-risk renal cell carcinoma."

He added that decisions to remove clinically suspicious lymph nodes at the time of radical nephrectomy "should be made after weighing surgical risk against a limited survival benefit."

In an accompanying editorial, Paul Russo, MD, from the Department of Urology at the Weill Cornell School of Medicine Memorial Sloan Kettering Cancer Center in New York City, points out that in this trial, lymph node management was at the surgeon's discretion.

"Only 701 of 1,943 patients (36%) had any lymph nodes removed, a median of only 3 nodes were removed and more than 10 were removed in only 17% of patients," he points out. "The authors should replace retroperitoneal LND [lymphadenectomy]  in the title with lymph node sampling."

"Surgeons were apt to resect grossly positive nodes, which was done in 99% of cases, but not resect 70% of normal appearing nodes," he writes. "Not surprisingly patients undergoing such limited lymph node sampling did not have improved OS [overall survival] or DFS [disease-free survival] whether or not they received adjuvant systemic therapy."

"This analysis again leads us to conclude that only by performing a prospective and randomized trial of nephrectomy with and without full bilateral retroperitoneal LND will the therapeutic value of node dissection in high risk RCC be determined," Dr Russo concludes. 

But There Is Value

Approached for comment, James Porter, MD, a urologist at the Swedish Hospital Medical Center in Seattle, Washington, suggested that there is value in carrying out lymphadenectomy in patients with RCC.

"Removing lymph nodes may not have a therapeutic benefit, but there may be staging information from lymphadenectomy with RCC that can facilitate patient counseling and help with discussions around prognosis," said Dr Porter, who was not involved with the study.

The hard truth here is that "patients with lymph node involvement and RCC have a high systemic recurrence rate," he told Medscape Medical News.

Patients with lymph node involvement and RCC have a high systemic recurrence rate. Dr James Porter

 

Like the editorialist, both Dr Porter and Dr Ristau and colleagues call for a prospective randomized clinical trial designed to evaluate the effect of lymph node removal on outcomes among patients with high-risk RCC.

But the answer still might be that there is no oncologic benefit here, Dr Porter suggested in a recent editorial in European Urology on the subject.

RCC is a "recalcitrant" and "unpredictable" cancer, he observed.

Lymph node removal has oncologic benefit in other urologic cancers, where there is a stepwise progression of disease from the organ to the nodes and then metastasis. But not RCC, where lymphatic involvement "almost never" precedes metastatic disease, he writes.

Dr Porter also explains that it is possible that RCC may have progressed too extensively by the time there is clinically evident lymph node enlargement — and that removing nodes on the basis of size alone may be ineffective.

ASSURE is not the first study to examine this issue.

In fact, a prospective randomized clinical trial examined the treatment of RCC with and without lymphadenectomy, European Organization for Research and Treatment of Cancer (EORTC) trial 30881. This  trial compared 389 patients treated with radical nephrectomy alone with 383 patients treated with radical nephrectomy combined with lymphadenectomy (Eur Urol. 2009;55:28-34). There was no difference in overall survival or progression-free survival.

However, the problem with the EORTC trial was that the patients were mostly low risk (about 70%) and not the high-risk patients who, theoretically, are the most likely beneficiaries of lymph node removal.

Hence the call for a prospective trial in patients with high-risk disease as its focus, which has never happened.

The study was supported by the National Institutes of Health and the Canadian Cancer Research Institute. One of the study authors has financial ties to Pfizer, Novartis, and Argos. Dr Porter has disclosed no relevant financial relationships.

J Urol. 2018;199:53-59, 59. Abstract, Editorial

Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick

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