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INTRODUCTION
Approximately 400,000 new cases of renal cell carcinoma (RCC) are diagnosed worldwide each year, with a
[1]
resultant 175,000 deaths . Of these, approximately 15%-20% of patients will present with synchronous
metastatic disease, that is, patients diagnosed with a primary kidney tumor and a corresponding distant
[2]
metastatic site . Until recently, patients diagnosed with synchronous metastatic renal cell carcinoma
(mRCC) who were fit for surgery were offered upfront cytoreductive nephrectomy as standard-of-care
treatment. This was based on two widely cited randomized controlled trials comparing cytoreductive
nephrectomy plus interferon alfa to interferon alfa alone . Both of these trials were published in 2001 and
[3,4]
demonstrated survival-benefit for patients undergoing upfront cytoreductive nephrectomy in the setting of
synchronous metastatic disease. Flanigan et al. showed a 3-month survival advantage among patients
[3]
undergoing nephrectomy followed by interferon therapy compared to interferon alone, while
Mickisch et al. demonstrated a delayed time to progression and improved overall survival as well. These
[4]
studies served as the backbone of treatment algorithms for patients with synchronous mRCC for nearly two
decades.

Over time, however, the treatment landscape of systemic therapy for patients with mRCC changed
considerably, particularly with the introduction of therapies targeting RCC molecular tumorigenesis
pathways in 2005 . With this significant shift away from interferon and IL-2-based systemic therapies
[5]
toward drugs targeting RCC carcinogenesis, particularly the vascular endothelial growth factor (VEGF)
receptor tyrosine kinase inhibitors (TKIs) as well as the anti-VEGF monoclonal antibody bevacizumab, the
role of upfront cytoreductive nephrectomy was once again questioned. Indeed, there was a lack of level 1
evidence comparing immediate cytoreductive nephrectomy to targeted therapies alone. Further, given that
most patients presenting with synchronous metastatic disease have locally advanced primary tumors,
recovery from surgery often takes several weeks, if not more. This postoperative recovery potentially delays
the initiation of systemic therapy, with the potential to negatively impact the outcome. It was the impetus
for the newly published randomized trials comparing cytoreductive nephrectomy to TKI monotherapy.
This review will address the controversies regarding cytoreductive nephrectomy and analyze the best
available data to guide treatment decisions.

EARLY CYTOREDUCTIVE NEPHRECTOMY TRIALS
Any review addressing the role of cytoreductive nephrectomy in patients with synchronous mRCC would
be remiss without mentioning the first trials randomizing patients to cytoreductive nephrectomy vs.
systemic monotherapy. While these trials are mostly considered historical at this point, they laid the
groundwork for cytoreductive nephrectomy in the treatment algorithm of patients with mRCC for nearly
two decades.

[4]
In 2001, Mickisch et al. published the first randomized trial of cytoreductive nephrectomy in The Lancet
(EORTC 30947), randomizing 85 patients with synchronous mRCC to radical nephrectomy plus interferon
alfa immunotherapy vs. interferon alone. The primary endpoints were time to progression and overall
survival. The study showed a modest but statistically significant improvement in time to progression for the
study group compared to the control group (5 months vs. 3 months), as well as an improved overall survival
for patients undergoing nephrectomy (17 months vs. 7 months).

Later in 2001, Flanigan et al. published the concurrently performed randomized SWOG trial of
[3]
nephrectomy followed by interferon-alfa compared with interferon-alfa alone in The New England Journal
of Medicine. SWOG 8949 randomized 246 patients with mRCC to either radical nephrectomy followed by
therapy with interferon-alfa-2b or to receive interferon-alfa-2b therapy alone. The study’s primary endpoint