Drs. Ana Molina, Jim Hu and David Nanus address key issues in an editorial published this week in the Journal of Clinical Oncology
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), while others argued that surgery did more harm than good.
In 2001 and 2004, two randomized clinical trials compared the two approaches (cytokine therapy alone vs. surgery plus cytokine therapy) in a controlled, side-by-side fashion and demonstrated a survival benefit for patients who had surgery followed by cytokine therapy. Cytokines are man-made versions of naturally occurring proteins that can enhance the immune response to cancer. This research found that patients that underwent surgery in addition to being given the cytokine interferon medication showed an average survival of 13.6 months, compared with 7.8 months for those who only received the interferon treatment, demonstrating a 31% reduced risk of death. Based on this study, urologists and oncologists continued to recommend surgery, seeing major improvements in disease-free and overall survival in patients who had their primary kidney tumors surgically removed.
Over the past ten years, there have been critical advancements in the treatment of kidney cancer and targeted therapies (i.e. vascular endothelial-growth factor inhibitors) have replaced cytokine therapy as the standard of care. Targeted therapies block the growth and spread of cancer by interfering with specific molecular targets associated with cancer. The role of surgery has become unclear since the introduction of targeted therapy. Of note, nearly 90% of patients enrolled in the early studies examining targeted therapies had undergone nephrectomy.
Retrospective studies suggest that surgery improves outcomes and reduces the risk of death from cancer by more than 50%. Despite possible improved outcomes, we have seen a decline in the use of surgery. A recent study sought to evaluate current utilization rates of surgery and examined the survival benefit of surgery compared with no surgery. They noted that currently only three out of 10 patients receiving targeted therapy undergo surgery. In addition, socioeconomic and racial disparities were associated with these declines. Younger, white people with private insurance and earlier stage cancer are more likely to have their tumors removed. These declines are also more significant at community hospitals than academic centers. This is important to point out because research also shows that African Americans with metastatic kidney cancer have a poorer prognosis than white patients, and inferior survival is more pronounced in black patients who do not undergo surgery.
Two large, phase 3 randomized clinical trials (CARMENA and SURTIME) will provide answers about the role of surgery in the era of targeted therapy. The CARMENA study is enrolling patients in France and comparing the outcomes of surgery followed by targeted therapy versus targeted therapy alone. The European SURTIME study is comparing the impact of patients undergoing immediate surgery and then receiving targeted therapy with patients first receiving targeted therapy and then deferred surgery. Until these two studies are completed and the results are available, we recommend that all medical oncologists and urologists carefully evaluate each patient and consider surgery when feasible.