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Ana Molina, M.D., David Nanus, M.D., and Jim Hu, M.D., recently published an editorial in the Journal of Clinical Oncology analyzing the use of surgery for advanced kidney cancer. Read the original here.

Ana Molina, M.D. Until the last decade, there was much debate on the standard of care treatment for patients with metastatic renal cell carcinoma (mRCC), commonly referred to as advanced kidney cancer. Some physicians believed that the best treatment was to surgically remove the kidney, a process called cytoreductive nephrectomy (CN), folowed by cytokine therapies, such as interleukin-2 or interferon-alfa (IFN-α-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-α-2a versus IFN-α-2a alone demonstrated a significant improvement in survival of patients with mRCC that CN became the new standard. A combined analysis of these two trials yielded a median survival of 13.6 months for nephrectomy plus IFN-α-2a compared with 7.8 months for IFN-α-2a alone, 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 as sorafenib, sunitinib, and pazopanib) had undergone nephrectomy (and relapsed) or had a CN before enrollment. The improvements in disease-free and overall survival observed in these studies were in patients among whom the primary tumors had been removed in the vast majority of cases. But the great success of medical therapy called 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. 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%.

Hanna et al 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.

Nevertheless, the overall rate of CN observed in the study by Hanna et al is significantly lower than that reported from centers of excellence (approximately 58% to 85%). One potential reason for lower utilization of CN beyond academic centers could be a result of the absence of referral to urologic surgeons, and this is not identifiable through NCDB data. Moreover, the volume of RCCs treated at a particular center may be associated with higher use of CN, and this also was not examined in the data. In addition, the unavoidable selection bias that accompanies retrospective studies may also contribute to a perception of CN underutilization.

It is unclear that examining data from the NCDB as described by Hanna et al underrepresents CN utilization. The NCDB captures analytical patient data. If a patient presents to an institution with metastatic disease and undergoes biopsy that confirms stage IV kidney cancer, but then goes to another institution for a CN, the nephrectomy may not be captured in the first institution’s data. It would thus be coded 0 in the surgery field at that institution and in the NCDB. This would decrease the number of patients recorded who actually underwent CN before systemic therapy. Another reflection of potentially missing data would be the number of patients who presented with stage IV kidney cancer and underwent CN, but who never received systemic therapy per NCDB data.

Despite these limitations, the data do suggest that the number of patients with mRCC who undergo CN is lower in the general population than indicated. This fact is alarming when considering the other analysis performed on these data, which examined the difference in overall survival between patients who did and did not undergo CN. Survival data were available in nearly 13,000 patients, with a median survival of 17.1 months (95% CI, 16.3 to 18.0 months) for patients who underwent CN compared with 7.7 months (95% CI, 7.4 to 7.9 months) for patients who did not. These data are remarkably similar to the difference in median survival between patients with mRCC treated in the cytokine area who were randomly assigned to receive CN or no surgery. Of note, the 3-year survival rates were 27.7% (95% CI, 26.3% to 29.1%) and 9.8% (95% CI, 9.1% to 10.5%) for CN and non-CN patients, respectively; in a multivariable analysis, CN patients had a lower risk of any death after adjusting for all other covariates that may affect survival.

Until the CARMENA and SURTIME studies are completed and reported, per National Comprehensive Cancer Network and European Society for Medical Oncology guidelines, CN remains the recommendation for patients with mRCC with a good performance status, and should be considered for all patients who present with mRCC. The study by Hanna et al confirms prior reports that with the incorporation of effective VEGF-targeted therapies, CN is underutilized. Moreover, this underutilization appears to directly contribute to inferior survival among patients who present with mRCC.

Perhaps most alarming is the racial disparity in access to recommended therapy: Black and Medicare/Medicaid/uninsured patients are less likely to undergo CN. African Americans diagnosed with RCC have a poorer prognosis than white patients, and this inferior survival is more pronounced in black patients who do not undergo CN. In a recent study of black and white patients with RCC in an equal-access health care system, no statistically significant racial difference in overall survival was detected. However, among patients who did not undergo surgery, black patients experienced poorer survival. 

These observations, together with those reported by Hanna et al and others, should serve as a wakeup call to both medical oncologists and urologists to seriously consider CN for every patient who presents with mRCC.