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CHICAGO -- Patients with newly diagnosed metastatic renal cell carcinoma (mRCC) did just as well, if not better, if they skipped surgery in favor of medical treatment, a multicenter randomized trial showed.

Patients with intermediate- and poor-risk disease had a median overall survival of 18.4 months if they received only the targeted agent sunitinib (Sutent) versus 13.9 months if they had surgery and then received sunitinib. The proportion of patients alive at 3 years also favored medical treatment without surgery, and progression-free survival (PFS) did not differ significantly between the treatment groups, as reported here at the (ASCO) meeting.

"Sunitinib alone is not inferior to nephrectomy followed by sunitinib," said Arnaud Mejean, MD, of Paris Descartes University. "Cytoreductive nephrectomy should no longer be considered the standard of care in metastatic renal cell carcinoma, at least when medical treatment is required."

The results were published simultaneously in the .

The study reflects the broader impact of targeted therapy on outcomes in mRCC over the past decade, during which time median survival has improved from about 1 year to about 3 years today, said ASCO expert Sumanta Pal, MD, of City of Hope in Duarte, California.

"One of the practices we've held to, even in the context of patients with advanced disease, has been removal of the kidney, but admittedly, this isn't based on a very high level of evidence until now," said Pal. "The highest bar is what Dr. Mejean has presented: a randomized, prospective clinical trial. [The study] has firmly demonstrated, in my opinion, that the context of the targeted therapy sunitinib, there doesn't necessarily seem to be a need to remove the kidney in patients with advanced and metastatic disease.

"This has really flipped the paradigm for the management of advanced kidney cancer."

Nonetheless, the results should be taken with a grain of salt, Pal added. Recent studies have suggested that newer targeted and therapeutic agents may lead to even better outcomes in mRCC, which may necessitate a reassessment of the need to remove the kidney.

Since the 1990s, cytoreductive nephrectomy has been standard of care for mRCC. Even so, almost a dozen novel therapies have demonstrated efficacy in mRCC since 2006, which has contributed to a about the role of surgery in mRCC. and have suggested a benefit for nephrectomy in the era of modern systemic treatment, but no randomized trials have compared surgery and medical therapy.

For a patient with good performance status and a small metastatic burden, nephrectomy makes sense, said Mejean. At the opposite end of the risk spectrum, nephrectomy does not make sense for a frail patient with a high metastatic tumor burden. For the large population of patients in between, "Who knows if nephrectomy is useful?"

To address the unanswered question, investigators at 79 centers in France, England, and Norway conducted a randomized trial to compare upfront surgery plus sunitinib versus sunitinib alone. The study involved 450 patients with intermediate- or poor-risk mRCC and ECOG performance status of 0-1. Randomized patients had upfront surgery and adjuvant sunitinib or received sunitinib alone as sole therapy.

Patients had a median tumor size of 88 mm, a median of two metastatic sites, and total tumor burden of 140-144 mm. The lung was the most common site of metastasis (75%-80% of patients), followed by bone, lymph nodes and "other" sites (35%-40%).

The trial had statistical power to evaluate the noninferiority sunitinib alone versus surgery and adjuvant sunitinib. The primary endpoint was overall survival, and the median follow-up was 50.9 months.

The 4.5-month difference in median overall survival represented an 11% reduction in the survival hazard in favor of single-agent sunitinib. The difference did not achieve statistical significance (95% CI 0.71-1.10) but fell well within the prespecified upper limit for noninferiority (HR 1.20).

Three separate landmark analyses showed a consistent numerical advantage in favor of single-agent sunitinib: 64.4% versus 55.2% at 12 months, 42.6% versus 35.0% at 24 months, and 29.1% versus 25.9% at 36 months. An analysis of the data by Memorial Sloan Kettering risk category also showed a trend in favor of single-agent sunitinib for patients with intermediate-risk (23.4 versus 19.0 months) and poor-risk mRCC (13.3 versus 10.2 months), although neither difference achieved significance.

For patients randomized to the surgery arm, treating physicians had the option to omit adjuvant sunitinib, and 29 patients randomized to surgery did not receive the targeted agent. Separate analyses of patients who had surgery followed by adjuvant sunitinib or surgery alone also yielded numerical advantages for the patients who received sunitinib without surgery.

An analysis of PFS (a secondary endpoint) yielded median values of 8.3 months for single-agent sunitinib and 7.2 months for surgery plus sunitinib (HR 0.82, 95% CI 0.67-1.00). Objective response and disease control rates were 29.1% and 74.6%, respectively, with single-agent sunitinib versus 27.4% and 61.8% for the surgery arm.

A comparison of clinical benefit rates (disease control for >12 weeks) produced a statistically significant difference in favor of single-agent sunitinib (47.9% versus 36.6%, P=0.022).

Adverse events related to treatment with sunitinib occurred in similar proportions of patients in the two treatment arms.

Mejean reported that 38 patients randomized to sunitinib alone subsequently required nephrectomy for emergency treatment of the primary tumor or to achieve complete or near-complete response of metastases. Median time from randomization to surgery was 11.1 months, and about a third of the patients resumed sunitinib treatment after surgery.

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