Immediate Surgery No Help in Metastatic RCC

Treating metastatic kidney cancer with immediate cytoreductive nephrectomy (CN) did not ward off disease progression, the randomized SURTIME trial confirmed.

In the study of 99 metastatic renal cell carcinoma (mRCC) patients, the progression-free rate at 28 weeks was 43% in patients who received sunitinib (Sutent) before CN vs 42% in the group that received immediate CN followed by the targeted agent (P=0.61), Axel Bex, MD, PhD, of The Netherlands Cancer Institute, and colleagues reported.

Progression-free survival was also no different between the groups (HR 0.88, 95% CI 0.56-1.37, P=0.57), they wrote in JAMA Oncology.

At 32.4 months vs 15.0 months, overall survival (OS) was longer in the intention-to-treat population for patients in the deferred surgical arm compared with those in the immediate surgical arm (HR 0.57, 95% CI 0.34-0.95, P=0.03), yet in the per-protocol population this benefit lost significance (HR 0.71, 95% CI 0.40-1.24, P=0.23).

But these OS findings prompted the researchers to suggest that initiating treatment with sunitinib first and offering nephrectomy only to patients whose disease does not progress might be superior than upfront nephrectomy followed by sunitinib.

“Pretreatment with sunitinib may identify patients with inherent resistance to systemic therapy before planned CN,” they wrote. “These data suggest that performing deferred CN in patients with non-progressing disease may confer a survival benefit instead of limiting CN to only the few patients who need surgery after treatment with sunitinib alone.”

The main purpose of SURTIME (Immediate Surgery or Surgery After Sunitinib Malate in Treating Patients With Metastatic Kidney Cancer) was to test whether or not pretreatment with a vascular endothelial growth factor receptor (VEGFR) inhibitor could improve outcomes by selecting out patients who are inherently resistant to VEGFR inhibitors and therefore unlikely to benefit from CN.

Patients were randomized to either immediate CN followed by sunitinib (n=50), or 3 cycles of sunitinib followed by deferred CN if disease had not progressed (n=49) plus more sunitinib, which was administered at a dose of 50 mg per day for 4 weeks, then 2 weeks rest.

Accrual to the study, from 2010 to 2016, was very slow and only 99 patients were enrolled by study endpoint. All but one patient in the deferred CN arm received presurgical sunitinib, and 83% of the group received the requisite 3 cycles prior to surgery. Of those who received treatment, 23% achieved a partial response while 29% had progressive disease prior to their scheduled nephrectomy.

In the immediate CN arm, 92% of patients underwent nephrectomy and 80% of the group received sunitinib. Four weeks after CN, 20% had progressed.

Most of the patients in either arm discontinued treatment because of progressive disease at the time of the analysis, at which point 35 of 50 patients in the immediate CN arm had died, as had 28 of 49 patients in the deferred CN arm, almost all due to progressive disease.

An earlier study, CARMENA (Clinical Trial to Assess the Importance of Nephrectomy) showed that sunitinib alone was not inferior to nephrectomy followed by sunitinib. As such, Bex’s group concluded that CN should no longer be considered the standard of care in mRCC for patients who require medical therapy.

“The results of SURTIME support data from CARMENA that showed that immediate CN does not result in additional benefit and may even be detrimental in patients with primary clear cell mRCC who require sunitinib,” they wrote.

In a commentary that accompanied the study, Primo Lara Jr., MD, and Christopher Evans, MD, both of the University of California Davis in Sacramento, argued that both SURTIME and CARMENA provide evidence that may be viewed as “practice confirming” rather than practice changing.

“Both affirm the current requirement for careful patient selection and the abandonment of indiscriminate use of CN in certain high-risk patient subsets for whom immediate systemic therapy alone is likely to be best unless local tumor morbidity mandates surgical intervention,” they wrote.

Importantly, Lara and Evans also underscored the fact that the slow accrual into SURTIME might have rendered the primary objective of the trial obsolete in that over the time it took to close the study — 5.7 years — newer, more active treatment options including the immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy) have emerged for the treatment of mRCC — innovations which again challenge the role of CN in mRCC.

“So what else have we learned?” Lara and Evans asked. Firstly, CN is not for every patient and nephrologists must assess each individual carefully before offering surgical treatment. Also, without prognostic biomarkers only “rudimentary endpoints” such as disease progression and treatment response are available to determine those likely or unlikely to benefit from CN.

“Ultimately, it may be that the disease rather than the physician decides who should undergo surgery,” they concluded.