we suspect. The study also alludes to but does not directly
address the issue of timing of CN in the targeted therapy
era (See the report in this section on the results from CARMENA
presented at the 2018 ASCO sessions). In the study
by Hanna et al,3 patients who underwent CN after targeted
therapy had better OS compared with those who
underwent CN before targeted therapy. However, these
results with regard to timing should be regarded cautiously
because there were limited data on how clinicians
opted to administer targeted therapy—before or after CN.
Still another issue addressed by Hanna et al is of overriding
importance—namely, the impact of risk stratification
criteria. As they report, careful patient selection
remains critical in determining if patients will benefit
from CN:
• Patients with poor survival outcomes or those with
rapidly progressing disease are less likely to benefit
from CN. This confirms a much earlier report in 2011
by Choueiri et al25 who found that patients with poor
risk features (according to the IMDC criteria) did not
benefit from CN.
• The National Comprehensive Cancer Network (NCCN)
has formalized guidelines on the likelihood of CN
benefit. Those likely to benefit include patients with
lung-only metastases, good prognostic features, and
good performance status.
Timing: Initial CN or Deferred?
What Is the Optimal Sequence?
The debate over the optimal sequence of CN has continued
unremittingly in the last few years, and results emerging
in 2018, however, have begun to
more clearly delineate at least some aspects
of the discussion as efforts remain
underway to produce a consensus. Results
from the 2017 European Society of
Medical Oncology26 and two reports in
201827,28 contribute substantially to an
improved understanding regarding the
benefits of CN.
Treating primary tumors by administering
targeted therapy with sunitinib
prior to cytoreductive nephrectomy
(CN) did not improve the progressionfree
rate at 28 weeks over a sequence of
“Although more level 1
evidence for the use of initial
CN in the era of targeted therapy
is still needed, a consensus
is taking shape from large
analyses of population-based
data. Initial CN is underutilized,
particularly in non-academic
centers where this underuse
contributes to inferior survival
among patients who present
with mRCC.”
immediate CN followed by sunitinib in
patients with synchronous metastatic
renal cell carcinoma (mRCC), according
to findings presented by Axel Bex, MD, Surgical Oncology
Urology, The Netherlands Cancer Institute in Amsterdam,
Netherlands and colleagues.26 They investigated
whether the outcome after sequential cytoreductive
nephrectomy (CN) followed by targeted therapy with
sunitinib could be improved with the opposite sequence.
They randomized 99 patients with mRCC to immediate
CN followed by sunitinib (n=50) versus three cycles of
sunitinib followed by CN plus sunitinib (n=49). The study
(EORTC 30073 SURTIME NCT01099423) included patients
58 Kidney Cancer Journal
with histologically confirmed clear-cell subtype,
and a resectable asymptomatic primary tumor plus 3 or
fewer surgical risk factors. Due to poor accrual (and that
is a fundamental flow in this study), it was decided to report
the progression-free rate (PFR) at week 28 as the primary
endpoint, which required 98 patients, instead of
median progression-free survival, which required 380
events to detect a 3-month increase.
At a median follow-up of 3.3 years, 46 of 50 patients
underwent CN in the immediate CN arm and 40 of these
patients had received post-CN sunitinib. In the deferred
CN arm, 48 of 49 patients had been treated with sunitinib
prior to CN; of these patients, 40 underwent CN and
26 also received post-CN sunitinib. No significant difference
between the treatment sequence was observed in
PFR, which was 42.0% (95% confidence interval CI 28.2,
56.8) versus 42.9% (95% CI 28.8, 57.8) in the immediate
and deferred arms, respectively (P > 0.99)
One of the conundrums to emerge in the targeted
therapy era is our lack of level 1 evidence for CN. The evidence
has been equivocal and the need for consensus
has become imperative. While one study compared the
sequence of CN and targeted therapy among patients
who received both therapies,3 in clinical practice not all
patients undergoing initial CN will receive subsequent
targeted therapy; and not all patients undergoing targeted
therapy will undergo subsequent CN.28 Other variations
on this theme have also been observed, further suggesting
how practice patterns can diverge. In retrospective
studies, for example, approximately one-third of patients
did not receive targeted therapy after initial CN, according
to the analysis by Bindhi et al. To
what extent is targeted therapy administered
in a timely fashion? Several reports
indicate that approximately 40% received
targeted therapy in a timely manner
(defined as within 60 days of CN). If
this picture seems confusing as to consistency
of approaches, then consider
that in single-arm trials, 30-40% of patients
initially treated with a tyrosine kinase
inhibitor prior to planned CN
actually underwent sub- sequent surgery.
For proponents of initial CN followed
by targeted therapy, two current studies
offer supporting if not compelling evidence.
A population-based cohort in patients
over age 665 from the Surveillance,
Epidemiology, and End Results registries served as the
starting point for an analysis by Macleod et al.27 Strategies
were categorized by initial treatment and linked with
Medicare claims from 2006 to 2011. Results were accrued
from 537 patients’ 190 had initial CN followed by targeted
therapy and 347 had initial targeted therapy. Median
OS in the initial CN group was 17.4 months
compared with 9.2 months for initial targeted therapy.31
The second study to focus on similar questions identified
patients in the NCDB diagnosed from 2006-2013