Controversies and Consensus Surrounding
Initial Cytoreductive Nephrectomy vs Targeted Therapy:
What Is the Optimal Approach?
ew topics have generated as much controversy and debate
as determining the optimal approach for cytoreductive
nephrectomy in the targeted therapy era.
Although the paradigm has been a moving target, with many
reports taking opposing viewpoints, new population-based
studies are closing in on a consensus. The debate is not going
away soon, but clear guidelines are emerging.
Compared to the era of cytokine therapy, when the benefits
of initial cytoreductive nephrectomy (CN) for metastatic
renal cell carcinoma (mRCC) were well established,
the advent of targeted therapy has not only ushered in a
new treatment paradigm, it has created a conundrum surrounding
the role of CN, its timing, and related survival
benefits. Here is the conundrum: In the targeted therapy
era, recent reports have indicated declining utilization
rates of CN; and yet, the most up-to-date guidelines from
the National Comprehensive Cancer Network support
the role of CN with targeted therapy (TT) in the appropriate
clinical setting.1
Questions and quandaries about CN have been
around for a long time so this is nothing new. However,
as Molina et al posted in an analysis in the Journal of Clinical
Oncology,2 the current trajectory and confusion about
the role of CN is alarming when one considers differences
in overall survival between patients who did and did not
undergo such surgery. For clinicians in the 1990s, a debate
raged about the benefit of CN for patients who were
subsequently treated with cytokine therapies, such as interleukin
2 or interferon-alfa (IFN-alpha-2a). But the debate
was virtually laid to rest when two randomized trials
comparing CN plus IFN-alpha-2a vs IFN-alpha-2a alone
demonstrated a significant improvement in survival of
patients with mRCC, thereby offering compelling evidence
54 Kidney Cancer Journal
that CN should be the new standard in this setting.
In the cytokine era, 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.
Why is that not true today, despite the evidence? For
example, consider survival data for 13,000 patients from
the National Cancer Data Base (NCDB)3 that showed a
median survival of 17.1 months for patients who underwent
CN compared with 7.7 months for patients who did
not. These results are markedly similar to what was found
in the pivotal study by Flanigan et al4 at the tail end of
the cytokine era when median survival differences were
compared for patients randomly assigned to receive CN.
CN Questioned in Era of Targeted Therapy
As phase 2 and phase 3 studies of targeted therapies (such
as sunitinib and pazopanib, and sorafenib) suggested
translational impact and radically changed the treatment
paradigm, the success of these efforts began to undermine
the rationale for upfront CN. Questions about the conventional
wisdom of going to CN initially arose, namely:
• Does CN extend survival in the era of VEGF-targeted
therapies?
• Should CN be performed before or after targeted therapy?
The era of targeted therapies has brought with it a
wide range of other questions as well, and although these
are beyond the scope of this paper, they reflect a more
nuanced approach to the management of mRCC, including
strategies that evaluate far more closely than was
the case in the cytokine era various risk factors and a basis
for stratification (favorable to intermediate to poor risk)
that influences clinical decision making. As is the case
with the rationale for using different approaches of targeted
therapy, a somewhat similar line of thinking can
be applied to the use of CN. And many recent reports
highlight the extent to which these risk factors should be
considered in delineating the role of CN.
Michael L. Blute, MD
Walter S. Kerr, Jr, Professor of Surgery, Urology
Harvard Medical School
Chief, Department of Urology
Massachusetts General Hospital
Boston, Massachusetts
F
Keywords: cytoreductive nephrectomy, initial, targeted therapy, CARMENA
trial, SURTIME, IMDC risk criteria, NCCN guidelines, TKI.
Corresponding Author: Michael L. Blute, Sr, MD, Chief, Department of
Urology, Massachusetts General Hospital, 165 Cambridge Street, 7th Floor,
Boston, MA 02114 Email: MBLUTE@mgh.harvard.edu
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