treatment failure (TTF) in favor of deferred CN. On sensitivity
analyses excluding patients with PD and among
patients receiving upfront sunitinib, median OS without
and with deferred CN were 16 (IQR 9-32) and 46 (IQR 25-
67) months, respectively (P<0.001), while median TTF
without and with deferred CN were 8 (IQR 5-16) and 14
(IQR 9-27) months, respectively (P<0.001). On multivariable
analysis adjusted for responses, deferred CN remained
significantly associated with OS (HR 0.58, 95%
CI 0.40-0.84, P=0.004).
Candidates for Cytoreductive Nephrectomy
The evidence thus far including data from CARMENA
and SURTIME has tempered enthusiasm towards initial
CN, particularly in unselected patients, with growing evidence
to support a deferred CN approach in those with
intermediate risk mRCC who require systemic therapies
for VEGF-TKIs. It is worthwhile to note that in CARMENA,
there was an element of deferred CN in the sunitinib
alone arm whereby 38 patients (17%) underwent
secondary CN for acute symptoms or near-complete response
at a median of 11.1 months from randomization
to CN (9). In an update and post hoc analysis of CARMENA,
40 patients in the sunitinib-only arm had a secondary
nephrectomy with a median OS of 48.5 months
(95% CI 27.9-64.4) vs. 15.7 months (95% CI 13.3-20.5)
in patients who did not have nephrectomy.15 Although
this finding was likely a reflection of patient selection
bias towards those with more favorable disease course,
this updated analysis of CARMENA reclassified patients
based on IMDC risk groups instead of MSKCC risk
groups15 and highlights: 1) the role for CN after sunitinib
with an OS achieved in intermediate-risk patients that
should not be underestimated and 2) the importance of
selection given that the secondary nephrectomy rate was
even higher (25%-30%) among patients who survived
long enough.
Deferred CN is a favorable approach for other reasons
as well. As described in SURTIME, a deferred CN approach
allows a greater proportion of patients who are
otherwise in need of systemic therapy to receive such
therapy as all patients in the ITT deferred CN arm received
systemic therapy compared to 87% in immediate
CN arm.8 Safety was reassuring as the surgical complication
rate was similar in patients who underwent CN after
3 months of pretreatment with sunitinib compared with
those who underwent immediate surgery. A deferred CN
route also allows a selecting out of patients with aggressive
biology or inherent resistance to VEGF-TKIs, i.e., individuals
who would have been unlikely to benefit from
CN in the first place. For example, an exploratory landmark
analysis in SURTIME at week 16 of OS according to
treatment arm and progression status suggested that patients
who had PD in the deferred CN arm before
planned surgery or 16 weeks of immediate CN had similar
poor survival prognosis.8 In the deferred CN group,
8 of 48 (16.7%) experienced PD by 3 cycles of sunitinib.
At the 4-week post-CN restaging assessment, 9 of 46 patients
(20%, 95% CI 9-33%) had PD in the immediate
CN arm vs. 8 of 34 patients (24%, 95% CI 11-41%) in the
deferred CN arm.8
With this evidence in mind, it may be practical and
58 Kidney Cancer Journal
logical to initiate all patients with mRCC in need of
VEGF-TKIs on a delayed CN pathway to select for the
best candidates for CN and avoid unnecessary surgery in
those who are unlikely to benefit from CN. However, as
many groups have contended, the optimal selection of
candidates for CN is difficult to generalize to all mRCC
patients.16,17 There are still mRCC patients in need of
immediate CN even if CN was not initially planned (e.g.,
palliation for symptoms). Others have argued that upfront
CN still may have a role in those with good performance
status and limited metastatic burden amenable
to surveillance or metastectomy.16 Many agree that initial
treatment with systemic therapy is preferred in those
with MSKCC/IMDC poor risk disease, poor performance
status, and/or large-volume metastatic burden.16,17 It has
been noted that current risk stratification criteria for
mRCC invariably classify all CN candidates into intermediate
or poor-risk categories, and given that those
who would benefit from CN are likely to have 3 or less
adverse prognostic factors, we are essentially focusing our
debate on optimal selection of CN candidates within the
MSKCC or IMDC intermediate-risk disease category.17 In
the context for guiding the selection of CN in mRCC at
presentation, there is certainly a clinical need to redefine
low-risk patients.
Lastly, it should be noted that these landmark studies
of CN in mRCC were conducted in the era of VEGF-TKIs.
The current treatment landscape of mRCC has again
shifted in the past 2 years with the advent of immune
checkpoint inhibitors (ICIs) whereby dual ICI combinations
(ie, nivolumab and ipilimumab) and VEGF-TKI and
ICI combinations (ie, axitinib with pembrolizumab or
avelumab) have become Food and Drug Administration
(FDA) approved for the first-line treatment of mRCC.18-
20 With immunotherapy-based regimens now widely
recognized as the preferred first-line standards for mRCC,
it would be prudent to investigate the role of CN in this
population.
Role of CN in the Immunotherapy Era
Data is still fairly limited on the role of CN in the current
immunotherapy era. A retrospective analysis of the National
Cancer Data Base (NCDB) involving patients with
predominantly clear cell mRCC who received modern
immunotherapy between 2015 and 2016 was recently
conducted to analyze survival after CN in this population.
21A total of 96,329 cases were screened but those
preceding 2015 were excluded given that the first ICI approval
was granted in 2015. The final cohort consisted
of 391 mRCC patients (183 diagnosed in 2015, 208 diagnosed
in 2016), including 221 (56.5%) who received
CN plus immunotherapy and 170 (43.5%) who received
immunotherapy only. After a median follow-up of 14.7
months in 183 patients with outcomes data, there were
75 deaths (41%) overall. Patients who received CN had
younger age and a larger median primary tumor size, but
baseline demographics and Charlson/Deyo comorbidity
scores were otherwise similar across groups. In the immunotherapy
only group, the frequency of clinically
positive nodes and hepatic metastasis was higher, but the
rate of bone, brain, and pulmonary metastases was comparable
between groups with no significant difference in