Survival Improves in mRCC With Surgical Metastasectomy

Alexander M. Castellino, PhD

May 04, 2017

In patients with metastatic renal cell carcinoma (mRCC), the surgical removal of metastases — complete metastasectomy (CM) — is associated with significantly longer overall survival compared with incomplete metastasectomy. This conclusion comes from a meta-analysis that included more than 2000 patients and was reported in the January issue of the Journal of Urology.

Patients who did not undergo CM were 2.4 times more likely to die of their disease than were patients with mRCC who underwent CM, report the authors.

In a press release, Bradley Leibovich, MD, a urologist from the Mayo Clinic, Rochester, Minnesota, and the paper's senior author, said, "The research found patients who had surgery to remove metastases were about half as likely to have died from their metastatic disease at every point in time after diagnosis."

These data confirm reports from observational studies, cohort studies, and case series, which were "considered to have selection bias," so it was  "important to look at studies with highest quality of data to eliminate the bias," Dr Leibovich told Medscape Medical News.

Medscape Medical News reached out to medical oncologists who were not associated with the study for their expert insights.

"The paper is a careful analysis of relevant literature, but as the authors note, the literature on this topic is extremely biased," kidney cancer specialist Brian I. Rini, MD, from the Cleveland Clinic Taussig Cancer Institute, Ohio, told Medscape Medical News.

The work reflects our move away from the conventional thinking that surgery is reserved for localized disease. Dr Ana Molina

"Although there are limitations to the observational data presented in this article, the work reflects our move away from the conventional thinking that surgery is reserved for localized disease and systemic therapy is for metastatic disease," Ana Molina, MD, medical oncologist at Weill Cornell Medicine and New York-Presbyterian, New York City, told Medscape Medical News. "The role of surgery in the management of patients with advanced RCC is of great interest and significance," she added.

Details of the Meta-analysis

For their meta-analysis, the Mayo Clinic researchers included eight studies with a total of 2267 patients — 958 of whom underwent CM and 1309 who did not. Overall survival ranged between 8.4 and 27 months for patients who did not undergo CM and jumped to between 36.5 and 142 months for patients who underwent CM. With an adjusted hazard ratio of 2.37 (95% confidence interval,  2.03 - 2.87), the non-CM group had an increased risk for overall mortality.

"Based on these data, CM should be considered in appropriate patients with mRCC who are surgical candidates with potentially resectable disease," Dr Leibovich told Medscape Medical News.

Appropriate patients include those with relatively limited metastatic disease that can be dealt with surgically, he explained. "At the Mayo Clinic, this approach has been successful in patients with solitary pulmonary, bone, renal, or liver metastasis," he added.

The researchers argue that although the National Comprehensive Cancer Network already recommends this approach (and nephrectomy), it may also be appropriate in patients with metastases at multiple organ sites. Indeed, in six of the studies chosen for the meta-analysis, 36% to 56% of patients had metastases to multiple organs. A sensitivity analysis, which excluded patients with single-organ metastases, found a persistent survival benefit for patients who underwent CM.

"The analysis proves that if you are taking a patient to metastasectomy, it should only be done when surgery can remove all visible disease (ie, complete metastasectomy), but again this does not say this is the right approach in most patients who have disseminated disease," Dr Rini said.

"In our clinical practice, we are referring patients to undergo metastasectomy when possible. Typically these patients have oligometastatic RCC," Dr Molina said.

The Evolving Treatment Landscape of mRCC

Dr Leibovich provided the context for CM against the evolving treatment landscape of mRCC.

Patients with mRCC do not respond to traditional chemotherapy, he explained, and before 1992 surgery was the only treatment option.

The approval of high-dose interleukin-2 in 1992 provided a benefit only for a minority of patients who were healthy and could withstand the side effects of interleukin-2.

In 2001, data from a few clinical trials suggested that resection of the primary tumor before interferon treatment given off-label provided durable survival benefits in some patients. Since 2005, 10 new drugs, including targeted agents, have been shown to improve survival in patients with mRCC.

"This report should raise the awareness that CM is a viable treatment strategy for appropriate patients," Dr Leibovich said. He explained that large-volume centers with surgical specialties already incorporate this approach in standard clinical practice.

In his comments to Medscape Medical News, Dr Rini said, "Metastatic RCC has always been a disease when surgical removal of metastases should be considered in select patients as part of an overall management approach…. This is not the same as saying that all patients are candidates for CM. In my experience it is not very common and is applicable to a very small subset of patients."  

However, it is likely that in community settings, medical oncologists may be satisfied with the expanded armamentarium of drugs currently available and may not consider surgical resection as an option even in appropriate patients, Dr Leibovich noted.

"Is that so bad if we have all these drugs? The answer is maybe yes, because the drugs, while they have improved survival, are not usually curative," Dr Leibovich said. "If they work for only a finite period, and if surgery can lengthen the time before we need to enter that period, then we think that's potentially additive to overall survival," he added.

The researchers point out that the reported median overall survival with the targeted agents does not exceed 27 months — similar to survival seen in the no-CM patients.

Indeed, as reported by Medscape Medical News in 2016, after the approval of the first targeted agent, the use of cytoreductive nephrectomy, another surgical option, declined significantly — from 31% in 2005 to under 15% in 2010. Yet, the combination of cytoreductive nephrectomy and targeted therapy was associated with significantly higher survival compared with targeted therapy alone. 

No randomized trials have prospectively provided support for CM. Dr Leibovich explained why. "They will have to be open-label," he said. "Most patients will not want to be randomized and will opt to be in the surgical arm," he added.

Dr Molina indicated that the role of systemic therapy after metastasectomy is being formally studied in a prospective study. The ECOG-ACRIN (NCT01575548) cooperative group study is enrolling patients with completely resected metastatic clear cell RCC to pazopanib vs placebo for 12 months. 

In addition, a randomized study comparing the programmed cell death ligand-1 antibody atezolizumab vs placebo recently opened for patients with high-risk RCC after nephrectomy. This study is also enrolling fully resected patients after metastasectomy (NCT03024996), Dr Molina pointed out.  

"Results from these studies will provide much-needed information on the role of systemic therapy and metastasectomy for patients with advanced RCC," Dr Molina said.

The Mayo Clinic researchers have disclosed no relevant financial relationships. Dr Rini acts as a consultant for Pfizer, Bristol-Myers Squibb, Roche, and Novartis. Dr Molina receives consulting or advisory fees from Eisai and Novartis.

J Urol. 2017;197:44-49.  Full text  

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