Is Underutilization of Cytoreductive Nephrectomy in Patients With Metastatic Renal Cancer Contributing to Inferior Survival?

Abstract

In the 1990s, a debate raged about the benefit of cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC). Many advocated that removal of the primary renal tumor resulted in more frequent and durable responses in patients with metastatic lesions who were subsequently treated with cytokine therapies, such as interleukin-2 or interferon-alfa (IFN-a-2a). However, others argued that the surgical morbidity and mortality, as well as the delay in initiating systemic therapy resulting in disease progression, did more harm than good. It was not until two randomized trials comparing CN plus IFN-a-2a versus IFN-a-2a alone demonstrated a significant improvement in survival of patients with mRCC that CN became the new standard. A combined analysisofthese twotrialsyieldedamediansurvivalof13.6months for nephrectomy plus IFN-a-2a compared with 7.8 months for IFN-a-2a alone, 1 representing a 31% risk reduction in death. Based on these studies, urologists and oncologists would evaluate every patient who presented with mRCC to determine whether they were an appropriate surgical candidate for CN before systemic therapy. Consequently, it was no surprise that nearly 90% of patients enrolled in the early phase II and III studies of vascular endothelial growth factor (VEGF) –targeted therapies (such assorafenib, sunitinib,andpazopanib)hadundergonenephrectomy (andrelapsed)orhadaCNbeforeenrollment.Theimprovementsin disease-free and overall survival observed in these studies were in patients among whom the primary tumors had been removed in the vast majorityof cases. But the great success of medical therapycalled into question the need for surgery: Does CN extend survival in the era of VEGF-targeted therapies, and if so, should it be performed before or after targeted therapy? Two prospective randomized trials, the Clinical Trial to Assess the Importance of Nephrectomy (CARMENA; NCT0093033) and the European Organisation for Research and Treatment of Cancer’s Immediate Surgery or Surgery After Sunitinib Malate in Treating Patients with Metastatic Kidney Cancer (SURTIME; NCT01099423) trial, should answer these questions; however, we have already observed a decline in the number of CNs over the past 10 years, concurrent with the use of effective systemic medical therapy. 2-4 This decline is despite the fact that a number of retrospective reports suggest that CN improves outcomes, and a recent meta-analysis concluded that CN reduces the risk of death in mRCC by . 50%. 5-10 In the article accompanying this editorial, Hanna et al 11 queried the National Cancer Data Base (NCDB) on the utilization of CN and whether CN had an impact on survival in patients who received targeted therapy. Approximately one-third (35%) of the 15,390 patients treated with targeted therapy between 2006 and 2013 underwent CN. The authors found that CN was significantly associated with white race, younger age, private insurance, lower tumor stage, the absence of lymph node metastases, and treatment at an academic versus a community center. Contrary to prior reports of declining rates of CN utilization during this time, the utilization of CN remained stable over this time period in this cohort.