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Does cytoreductive nephrectomy remain an essential component of care for advanced renal cell carcinoma?
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Yes.
Patients with newly diagnosed metastatic renal cell carcinoma with the primary in place may have variable clinical presentations ranging from highly symptomatic disease with paraneoplastic syndromes to incidental discovery.
The rationale for cytoreductive nephrectomy is to remove a massive immunosuppressive tumor burden and potential source of complicating bleeding or pain during subsequent systemic therapy. Cytoreductive nephrectomy also provides a precise pathologic diagnosis and materials for molecular tumor assessment, which could shape choice of systemic agents. Two randomized trials from the EORTC and SWOG published separately in 2001, and in combination in 2004, showed a significant survival advantage to cytoreductive nephrectomy combined with interferon alpha 2b vs. interferon alpha 2b alone (5.8 months in the combined analysis). OS at that time for patients with metastatic renal cell carcinoma treated with cytoreductive nephrectomy was approximately 1 year.
Within the past 18 years, there has been an explosion in our understanding of the molecular biology of metastatic renal cell carcinoma with 11 new systemic agents, including the tyrosine kinase, mTOR and, recently, checkpoint blockade inhibitors, all FDA approved after randomized and prospective clinical trials. OS in metastatic renal cell carcinoma is approaching 40 months depending on risk category. As these recent trials were conducted, surgeons worldwide continued to carefully select intermediate-risk patients for cytoreductive nephrectomy prior to the start of systemic treatment. Poor-risk patients were advised to undergo a percutaneous tumor needle biopsy with referral to medical oncology to initiate systemic therapy, and later consideration for an “integrated” cytoreductive nephrectomy if the patient’s metastatic tumor burden significantly regressed and their overall condition stabilized.
A noninferiority trial, CARMENA, published last year, did not demonstrate an OS advantage to cytoreductive nephrectomy. However, when one looks behind the curtains, there are problems with the trial. During an 8-year time frame, only 450 patients of a planned 576-patient trial were accrued and randomly assigned to receive sunitinib alone or with cytoreductive nephrectomy. This slowly accruing trial consisted of a high percentage (43%) of poor-risk patients not usually considered for cytoreductive nephrectomy, raising the possibility that healthier intermediate-risk patients were still undergoing cytoreductive nephrectomy in Europe and, therefore, not available for entry into CARMENA. Although this trial had an intention-to-treat design, 40 patients in the cytoreductive nephrectomy arm (17.7%) did not receive sunitinib and 16 patients (7%) did not undergo cytoreductive nephrectomy. In the sunitinib-alone group, 11 patients (4.9%) did not receive the drug but 38 patients (16.9%) underwent delayed cytoreductive nephrectomy. In addition, more than 50% of patients received systemic agents other than sunitinib with uncertain impact on OS. The OS for patients treated on CARMENA reflects the poorer-risk patient population studied (cytoreduction nephrectomy group, 13.9 months; vs. sunitinib alone, 18.4 months).
Careful selection of patients with intermediate-risk — not poor-risk — metastatic renal cell carcinoma, coupled with cytoreductive nephrectomy performed by surgeons at high-volume centers, with later exposure to newer generations of systemic agents alone or in combination and often given sequentially, can extend median OS to 40 months. Under these selective conditions, there is no doubt that cytoreductive nephrectomy continues to play a central role for metastatic renal cell carcinoma and will continue to do so in the future as more effective systemic agents are developed.
References:
Bex A, et al. JAMA Oncol. 2018;doi:10.1001/jamaoncol.2018.5543.
Flanigan RC, et al. J Urol. 2004;doi:10.1097/01.ju.0000110610.61545.ae.
Mejean A, et al. Abstract LBA3. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.
Paul Russo, MD, FACS, is professor of urology at Weill Cornell School of Medicine, and attending surgeon at Memorial Sloan Kettering Cancer Center. He can be reached at russop@mskcc.org. Disclosure: Russo reports no relevant financial disclosures.
No.
During the past 15 years, there have been important advances in the management of metastatic renal cell carcinoma with the incorporation of antiangiogenic drugs and immunotherapy. Until recently, the standard of care for advanced-stage renal cell carcinoma was nephrectomy. This standard was based on the publication of two randomized studies in the era of the use of interferon for advanced disease, which showed survival benefit among patients undergoing surgery for advanced renal cell carcinoma.
However, despite the number of patients and randomized designs, these studies had several imbalances or flaws, including selection bias for younger patients with better performance status, which drove better prognosis in the group undergoing nephrectomy.
Recently, the prospective randomized CARMENA study showed that nephrectomy in addition to the use of sunitinib did not demonstrate a survival benefit for intermediate- and high-risk patients. OS, the study’s primary endpoint, was 18.4 months for sunitinib alone vs. 13.9 months in the sunitinib-plus-nephrectomy group, and the HR for death was 0.89. This new evidence should guide treatment decisions toward restriction of nephrectomy, particularly for low-risk patients with good prognosis and low burden of disease in general, and discourage its use unless it is justified for palliative reasons, including control of local symptoms such as pain and bleeding.
The accumulating new body of evidence favoring the use of immunotherapy among certain groups of patients with intermediate- and high-risk disease as a first-line treatment for advanced renal cell carcinoma has raised questions regarding the true role of nephrectomy when these new therapies are used. Thus, new — and ideally prospective — clinical trials are needed to reassess the role of nephrectomy in advanced renal cell carcinoma. Until then, available prospective clinical evidence and clinical judgment must guide our decisions regarding when to pursue nephrectomy.
References:
Flanigan RC, et al. N Eng J Med. 2001;doi:10.1056/NEJMoa003013.
Flanigan RC, et al. J Urol. 2004;doi:10.1097/01.ju.0000110610.61545.ae.
Mejean A, et al. Abstract LBA3. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.
Mauricio Burotto, MD, is medical director at Bradford Hill Clinical Research Center and attending medical oncologist at Clinica Universidad de los Andes in Santiago, Chile. He can be reached at mauricioburotto@gmail.com. Disclosure: Burotto reports no relevant financial disclosures.