In Advanced Kidney Cancer, Surgery No Longer Sole Standard of Care

Nick Mulcahy

June 03, 2018

CHICAGO — There's now a gentler, less traumatic best practice for managing many patients with advanced kidney cancer, as they no longer need to have their affected kidney surgically removed, according to the investigators of a practice-changing phase 3 clinical trial.

"Cytoreductive nephrectomy should no longer be considered the standard of care in metastatic renal cell carcinoma," said lead study author Arnaud Méjean, MD, PhD, from the Hôpital Européen Georges Pompidou - Paris Descartes University in France.

Patients can now be treated with systemic therapy alone — namely with the targeted therapy sunitinib (Sutent, Pfizer), according to the results of the multinational Clinical Trial to Assess the Importance of Nephrectomy (CARMENA).

The randomized trial, conducted among 450 patients with poor- and intermediate-risk disease, found that median overall survival was noninferior in the patients who received sunitinib alone compared with those who first had surgery and then received sunitinib (18.4 vs 13.9 months).

The results were presented here at a plenary session at the American Society of Clinical Oncology (ASCO) 2018 and simultaneously published in the New England Journal of Medicine (NEJM).  

The new study "flips the existing paradigm" for the treatment of advanced kidney cancer, said Monty Pal, MD, an ASCO expert from the City of Hope Cancer Center in Los Angeles, California, who spoke at a press conference where the study was highlighted.

He explained that targeted therapies such as sunitinib have dramatically improved the overall survival of these patients in the past decade, but until now oncologists have still opted for surgery to remove the affected kidney because "there seemed to be benefit with the approach."

However, that perception and that practice have been largely based on retrospective studies of national data repositories, which "isn't a very high level of evidence," Pal acknowledged.

Not Everyone Agrees

However, other experts say the new trial results need closer inspection.

In an NEJM editorial published alongside  the study, Robert Motzer, MD, and Paul Russo, MD, from the Memorial Sloan Kettering Cancer Center in New York City, say "it's not surprising the noninferiority end point was reached" because CARMENA "was heavily weighted toward poor-risk patients." Forty-three percent of the patients had poor-risk disease.

They explain that poor-risk patients are less likely to benefit from surgery (and more likely to be harmed by it) because they are less robust in withstanding the invasive procedure and potential complications.

Indeed, in the trial, surgery was not a boon to the poor-risk patients, observed Naomi Haas, MD, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, who was approached for comment.

"The patients with the poorer performance status did about the same, with or without surgery. However, the patients with intermediate-risk disease appeared to do better with sunitinib alone than with an initial surgery," she observed.

The surgery plus sunitinib group also had a higher percentage of locally advanced stage T3 or T4 tumors than the sunitinib-alone group (70.1% vs 51.0%), "which could have affected surgical outcomes," say the editorialists.

Furthermore, interpretation of the results is "complicated" by some treatment anomalies in the trial, they say.

For example, in the surgery plus sunitinib group, 40 patients (17%) did not receive the drug and 16 (7%) did not undergo surgery. In the sunitinib alone group, only 11 patients (4.9%) did not receive drug and 38 (17%) underwent delayed surgery. In other words, the sunitinib-alone group may have been given a boost by many patients getting extra treatment (ie, surgery). On the other hand, the surgery plus sunitinib group may have been harmed because relatively more patients got less treatment, especially less drug treatment.

The editorialists argue that CARMENA's data "should not lead to the abandonment of nephrectomy but instead emphasize the importance of careful selection of patients undergoing nephrectomy, on the basis of published risk models."

The "main focus" for deciding about surgery and which patients are  most likely to benefit are pretreatment risk features, the pair say. These include the resectability of the primary tumor, health status, and presence of other medical conditions.

Furthermore, the editorialists argue that it may be wise to withhold systemic therapy in patients with limited or slow-growing metastatic disease after surgery. Then, if and when distant metastases show up, systemic therapy can be started.

The study investigators counter some of these thoughts in their study discussion. The point out that the study results are not "generally applicable" to patients with a poor performance status, minimal primary tumor burden, and high volumes of metastatic disease. These patients are not currently offered surgery anyway, they say.

Nephrectomy may have a role in controlling symptoms in some patients with metastatic kidney cancer, the authors add. "There is no 'one-size-fits-all' approach," they write.

The team also points out the lack of data on the use of nephrectomy before immunotherapy with  checkpoint inhibitors..

However, ASCO expert Pal observed that the immunotherapy combination of nivolumab and ipilimumab has now been approved for use in this setting. "We may have to go back to the drawing board again" to assess the relevance of nephrectomy with these newer drugs, he said.

Another expert agreed.

"The completion of the CARMENA trial is enormously beneficial because it paves the way for a similar study to look at whether cytoreductive nephrectomy is beneficial or not in the setting of immune checkpoint inhibitor therapy," said Haas.

The study was funded by Pfizer and PHRC (French governmental grants for clinical research). Méjean and other study authors, as well as Motzer, have financial ties to industry, including Pfizer. Russo has disclosed no relevant financial relationships.

American Society of Clinical Oncology (ASCO) 2018 Annual Meeting. Presented June 3, 2018. Abstract LBA 3.  

N Engl J Med. Published online June 3, 2018.

Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick

For more from Medscape Oncology, follow us on Twitter: @MedscapeOnc


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