Cytoreductive nephrectomy (CN), or the removal of the primary
kidney tumor in the setting of metastatic disease, plays a critical
role in the treatment of metastatic renal cell carcinoma (mRCC). The
benefits of CN, are multifactorial including alleviating symptoms
but also eliminating cells potentially prone to future metastasis,
and potentially extending a patient's survival. As innovations in
mRCC treatment continue to emerge, the importance and timing
of CN in patient care remains the subject of ongoing debate in the
scientific community. With advancements in modern therapies and
the introduction of immune checkpoint inhibitors (ICI), the optimal
integration of CN in mRCC management becomes even more
important to investigate. This manuscript reviews the key literature
related to CN and critically evaluates data that investigated CN
efficacy. Furthermore, this article summarizes data to help identify
ideal candidates for CN, and explores options for integrating CN
within the contemporary systemic therapy landscape.
Renal cell carcinoma will affect
about 82,000 people in the U.S.
in 2023. Unfortunately, around
30% of the individuals who present with
RCC will have metastatic disease either
within their regional lymph nodes or at
distant sites at the time of their presentation 1,2.
While the majority of patients
with metastatic RCC are not curable,
there has been a consistent improvement
in the overall survival of patients
who develop mRCC over the last two
decades 3. Much of this improvement has
come from a deeper understanding of
RCC tumor biology, and the host immune
response within the tumor microenvironment4.
One of the most important
advancements in mRCC management
has been the development of immune
checkpoint inhibitor therapy 5-9, which
has led to a substantial improvement in
survival for mRCC patients compared
to single agent tyrosine kinase inhibitor
(TKI) therapies. As a result, standard
first line therapies for mRCC are combinations
of ICI/ICI or ICI/TKI therapies.
While there have been
significant improvements in the
survival of patients with mRCC due
to advancements in systemic therapy,
surgery continues to remain a critical
component of the management of a
subset of patients with mRCC. CN
has been used throughout the history
of mRCC management, but became
standard of care in 2001 based on the
results of two randomized trials 10-12.
Cytoreductive nephrectomy is defined
as the removal of the primary renal
mass in the setting of synchronous
metastatic disease 13. This can either
occur prior to the receipt of any systemic
therapy (termed “upfront” CN) or after
systemic therapy has been delivered
(termed “deferred” CN). There are
multiple reasons that CN is performed:
1) to remove tumor that harbors cells
capable of metastasizing or are resistant
to therapy, 2) to palliate symptoms such
as pain, gross hematuria, early satiety,
which thereby improves the patient
quality of life, and 3) to extend patient
survival. Despite these indications, the
role of CN has become controversial due
to publication of a randomized trial in
2018 that demonstrated non-inferior
outcomes for CN combined with
sunitinib compared to sunitinib alone14.
This clinical trial was controversial
and had significant limitations, which
reduced the impact of the findings in the
context of modern mRCC management.
The goal of this review is to concisely
summarize the historical context of
CN leading up to the current era of ICI
therapy, including a critical analysis
of the controversies surrounding CN
and how CN can best be incorporated
into the management of patients with
mRCC.
CYTOREDUCTIVE
NEPHRECTOMY – A BRIEF
HISTORY
Prior to the implementation of effective
systemic therapies, CN was used
sparingly and was considered more for
symptomatic purposes. Spontaneous
regression of metastatic disease after
patients received CN was reported but
exceptionally rare15. Cytoreductive
nephrectomy became a standard of
care after the publication of two clinical
trials in 2001: SWOG 8949 and EORTC
3094710,12. The two trials had similar
study designs and randomized patients
to either IFN-α alone or upfront CN
followed by IFN-α. A combined analysis
of these trials demonstrated an overall
survival benefit favoring the CN arm
(13.6 months vs 7.8 months, P=0.001)11.
While these data are older, and IFN-α is
significantly less effective than modern
ICI therapy, the data from these trials
provide a unique view of the benefit of
CN. When these trials were conducted,
there were no approved second line
systemic therapy options available.
Therefore, the survival data from these
trials is less influenced by subsequent
therapies that patients might have
pursued outside the trial setting. This
offers a clearer understanding of the
impact of CN on overall survival, devoid
of the effects created by different second
line therapies on patient survival. These
data demonstrate a significant benefit
for appropriately selected patients
undergoing CN.
The cytokine era of systemic
therapy (prior to 2006) consisted of
IFN-α and IL-2, both of which had
limited efficacy and high toxicity16.After
the cytokine era of systemic therapy,
TKI therapy became standard of care
starting with sorafenib and sunitinib
therapy, after two phase III trials in 2007
demonstrated benefit of these agents
over IFN-α 17,18. In 2015, nivolumab
(an anti-PD1 antibody that activates
exhausted CD8+ T cells) became the
first FDA approved ICI therapy for the
treatment of mRCC, bringing about the
ICI therapy era of mRCC management19.
Since that time, multiple phase III
trials have demonstrated the ability of
ICI therapy to extend patient survival
in the setting of mRCC. For example,
the phase III trial CheckMate 214
published extended follow-up showing
a median overall survival of 56 months
for patients treated with nivolumab plus
ipilimumab, and the KEYNOTE-426
trial demonstrated a median overall
survival of 46 months among patients
treated with pembrolizumab plus
axitinib20,21. These results are nearly
two fold higher than the median overall
survival of patients receiving sunitinib,
which was 26 months upon the trial's
final analysis22. Thus, there has been
a clear improvement in the survival
of patients with mRCC being treated
in clinical trials with modern ICI
therapies.
It is important to note that all of
the phase III trials investigating modern
systemic therapies for mRCC included
a large proportion of patients that had
received a prior nephrectomy (either
prior to metastatic progression or at the
time of synchronous metastatic disease)
(TABLE 1). Thus, the survival benefits
of all modern systemic therapies for
mRCC have to be interpreted knowing
that most patients had their primary
tumors removed prior to systemic
therapy administration. In truth,
randomized clinical trial data for
systemic therapies in mRCC do not exist
in the absence of surgery, which is a key
reason that surgery is considered part
of the multidisciplinary care of mRCC.
CONTROVERSIES REGARDING
CYTOREDUCTIVE
NEPHRECTOMY
The most recent catalyst for CN
controversy was publication of the
results of the CARMENA (Cancer du
Rein Metastatique Nephrectomie et
Antiangiogéniques) clinical trial14,
randomized 1:1 mRCC patients treated
with upfront CN followed by sunitinib
versus sunitinib alone. This was
designed as a non-inferiority trial with
overall survival as the primary endpoint
and statistically powered to include 576
patients. The trial was published in 2018
and demonstrated non-inferior survival
outcomes in the systemic therapy alone
arm vs CN plus systemic therapy arm
(18.4 vs 13.9 months, respectively).
The results and trial design sparked
immediate debate in the literature and
at scientific conferences.
Despite providing the first
randomized clinical trial data in two
decades, the CARMENA study had
significant limitations. First, the trial
enrolled extremely slowly and did not
reach its accrual goal. Two planned
interim analyses (after 152 and 304
deaths) were performed and both
concluded that the trial should cont inue.
However, immediately after the second
interim analysis, the sponsor closed the
trial because of poor accrual. At the
time of publicat ion, the tr ial was able
to enroll 450 patients across 79 centers
over 8 years, significantly short of
enrollment goal of 576 patients. In both
study cohorts, there was significant
cont amination from not receiving the
primary treatment or receiving other
seconda ry treatments, which could bias
the outcomes.
The trial was analyzed according
to the intention-to -treat principle, but
patients were frequently managed
differently than their designated trial
ar m protocol. Seven percent of patients
in the surgic alarm did not receive a
CN and 18% of patients did not receive
subsequent sunitinib therapy and 5% did
not get sunitinib. In both groups, about
half of patients received additional l ines
of systemic therapies after sunitinib.
One of the strongest crit icisms of t his
study was the enrich ment of the study
c ohort for poor risk patients with
high volume metastatic disease. In
CARMENA, the median pat ient had 2
sites of metastatic disease w ith 14 cm
of overall tumor burden with 8.8 cm
primary tumors. Nearly half (44%) of
patients enrolled in the CN arm had poor
risk disea se according to the Memor ial
Sloa n Ketter ing Cancer Center (MSKCC)
mRCC risk classi ficat ion. Multiple pr ior
retrospective studies have demonstrated
that poor risk patients with high volume
disease outside of the kidney are least
likely to derive a survival benefit from CN
and should be counseled against upfront
surgery. Evaluat ion of the CARMENA
patients and known predictors of poor
outc omes af ter C N demonstrate a highrisk
patient population enrolled in the
study to receive CN. The MD Anderson
Cancer Center investigators published
preoperative predictors of worse overall
survival after CN23. These pr edictors
included node positive disea se (N+),
bone metastases, and high stage disease
(clinical T4 disease). The CARMENA
patients included 35% with N+ disease
and 36% with bone metastases.
Additionally, 70% within t he surgery
arm had cT3-T4 disea se compared
to only 51% within the sunitinib only
arm. The select ion of high-risk patients
for inclusion in this trial is further
supported by the fact that the median
overa ll sur vival in the sunitinib ar m is
much lower than the median survival
in the sunitinib arm from other modern
phase III randomized
trials (TABLE 2). A
post hoc analysis of
the CARMENA trial
demonstrated that
patients with one
IMDC risk factor had
significantly longer OS
in comparison to those
with two or more IMDC
risk factors 24. Lastly,
it should be noted that
systemic therapy options
evolved considerably
during the eightyear
study and when
the trial results were
published, sunitinib
was no longer used for
first line therapy for
mRCC patients, further
limiting the applicability
of the results to modern
clinical practice. Strong
conclusions from the
CARMENA trial should
be that appropriate
patient selection is
critical for successful
outcomes25.
A n o t h e r
question that was
attempted to be
investigated with a
randomized clinical trial
is optimal timing of CN
(before or after systemic therapy). The
SURTIME trial (Immediate Surgery
or Surgery After Sunitinib Malate
in Treating Patients with Metastatic
Kidney Cancer) investigated the
timing of CN and sunitinib therapy26.
Patients were randomized to either
upfront CN followed by sunitinib or
sunitinib therapy followed by deferred
CN. Like CARMENA, SURTIME
had difficulty enrolling patients and
only 99 patients were recruited to
the trial before it was closed. In the
intention to treat population, the 28-
week progression free rate (PFR) was
42% compared to 43% in the upfront
versus deferred CN patients (P=0.61)
and the median overall survival was
15 months versus 32.4 months in the
upfront versus deferred CN patients
(P=0.03) 26. The trial indicated no
significant improvement in the 28-week
PFR with a possible survival benefit for
deferred CN but results are difficult to
interpret with small patient numbers.
As a response to poor enrollment, 28-
week PFR became a revised primary
endpoint. Additionally, within the
deferred CN arm, 29% of patients did
not undergo surgery while 92% of
patients in the upfront CN received
surgery. The trial was not powered to
detect an overall survival benefit and
the survival analysis was exploratory.
A per-protocol analysis ultimately did
not demonstrate a significant overall
survival difference between the two
arms. Lastly, sunitinib as first line
therapy is no longer clinically applicable
to modern management of mRCC. In
summary, the SURTIME trial suggested
minimal difference in endpoints with
different timing of CN but did not
definitively answer the question.
The CARMENA and SURTIME
trials fueled significant controversy
regarding the utility and timing of CN
in the management of patients with
mRCC. Following the publication of
these trials, the European Association
of Urology (EAU) guidelines regarding
CN were modified and recommended
poor risk patients (based on MSKCC
risk criteria) should not undergo CN
and intermediate and poor risk patients
should receive systemic therapy first
before CN is considered27. The findings
of these clinical trials, however, need
to be balanced with the large number
of observational data that suggest
a continued survival benefit for
patients receiving CN (TABLE 3) 328-
38. The conflicting evidence between
randomized trials and observational
studies likely resides in surgical
selection bias. The appropriate
selection of patients for CN is critical to
successful outcomes, and this concept
is reflected in many modern guideline
recommendations (TABLE 4).
PATIENT SELECTION
FOR CYTOREDUCTIVE
NEPHRECTOMY – CHOOSING
WISELY
There are no standardized selection
factors for identifying ideal patients
for CN. Multiple different prognostic
and predictive variables have
been identified, all of which have
been investigated in observational
studies. In general, variables that
predict survival outcomes following
CN fall into three major categories:
institutional associated variables,
patient associated variables, and tumor
associated variables. Within each of
these categories, multiple variables
have been identified that help to select
ideal candidates for CN (FIGURE 1).
Tumor Characteristics
Certain characteristics of the primary
and metastatic tumors are significantly
associated with outcomes following
CN. Patients are thought to be more
likely to benefit from CN if the primary
tumor accounts for the majority of total
tumor burden within the patient 39, 40.
One study demonstrated that when
assessing both metastatic and primary
tumors, if the volume of the primary
tumor comprises more than 90% of the
total tumor burden, patients are likely
to experience improved cancer-specific
survival following CN 40.
Also, primary tumors with
a tumor thrombus pose a unique
challenge in the metastatic setting.
Tumors that invade the inferior vena
cava can progress rapidly toward the
right atrium and cause significant
symptoms such as leg swelling, fatigue,
weight loss, liver failure and ultimately
death. Up to 50% of patients with tumor
thrombi can have metastatic disease.
Abel et al. demonstrated that compared
to tumor thrombi that only invade
the renal vein (i.e., level 0), tumor
thrombi that have advanced above the
diaphragm (level IV) have significantly
reduced overall survival (median 22 vs
9 months, respectively)41. Conversely,
tumor thrombi that are still below the
diaphragm but above the renal vein did
not have significantly worse survival
than level 0 thrombi (20 vs 22 months,
respectively) 41. Thus, patients with
tumor thrombi invading the IVC should
still be considered for CN by experienced
surgeons.
The number and location of
metastases should also be considered
when identifying CN candidates. A
greater number of different metastatic
sites is associated with inferior outcomes
following CN and certain locations
portend more aggressive disease42-45.
Patients with lung, pancreas, thyroid, or
adrenal metastases tend to have a more
indolent pattern of progression and may
be better suited for upfront CN, while
patients with liver or brain metastases
tend to have worse overall survival
and more rapid disease progression
and may benefit from upfront systemic
therapy followed by deferred CN in
those who respond or demonstrate
disease stability42-45. Metastasectomy
should also be considered particularly
for patients with oligometastatic
disease in surgically resectable
locations. Patients undergoing
complete metastasectomy with
CN (either at the same time
or in a delayed fashion) have
superior cancer-specific survival;
however, patients undergoing
metastasectomy typically are
highly selected for excellent
performance status and more
indolent tumor biology46,47. If
surgical extirpation is not an
option, metastasis directed
therapy can be achieved in
some circumstances using
either ablative technology48. or
stereotactic body radiotherapy
(SBRT). A phase 2 trial by Tang
et al. recently reported treating
30 patients with ≤5 metastatic
tumors with SBRT to all metastatic
sites. Median progression-free
survival was 22.7 months and
authors concluded that SBRT may
delay systemic therapy initiation
or facilitate breaks from systemic
therapy among patients with
oligometastatic RCC49.
Additional tumor related
characteristics that should be
considered when deciding on
CN are tumor associated symptoms,
tumor histology, and sarcomatoid
dedifferentiation. Patients may
present with a symptomatic primary
tumor with pain, gross hematuria, or
paraneoplastic syndromes. In these
situations, CN should be considered
for appropriate surgical candidates to
palliate symptoms and improve patient
quality of life. Regarding non-clear
cell histology, outcomes following CN
are less well defined, but in general
similar principles apply to patient
selection and observational studies
have demonstrated a survival benefit
for patients receiving CN even with
non-clear cell histologies50-51. Tumors
harboring sarcomatoid dedifferentiation
are particularly aggressive. Prior to
ICI therapy, patients with metastatic
sarcomatoid RCC often had rapid disease
progression and short median overall
survival, and observational studies
of CN for patients with metastatic
sarcomatoid disease showed worse
survival compared to patients without
sarcomatoid disease52. Sarcomatoid
disease appears uniquely responsive to
ICI therapy, however, and patients with
sarcomatoid disease have experienced
impressive responses with ICI therapy
compared to older systemic therapy
agents. The KEYNOTE-426 trial
evaluating pembrolizumab+axitinib
and the CheckMate 214 trial
evaluating nivolumab+ipilimumab
both demonstrated improved disease
response among sarcomatoid tumors
compared to the sunitinib control
arm5,6. Thus, patients with sarcomatoid
dedifferentiation and mRCC should
be considered for upfront ICI/ICI or
ICI+TKI therapy and later treated with
surgery if there has been significant
response to systemic therapy and a
residual primary tumor. One challenge
with sarcomatoid dedifferentiation is
that clinicians frequently do not know
if the tumor harbors sarcomatoid
dedifferentiation at presentation or prior
to offering surgery as it is not reliably
detected on imaging or biopsy and is
mainly determined after nephrectomy
has been performed.
Among patients with borderline
unfavorable tumor characteristics,
some propose using upfront systemic
therapy as a “litmus test” to determine
whether or not the patient will progress
even in the setting of systemic therapy.
If a patient progresses, they are unlikely
to benefit from surgical intervention.
However, if a patient has a durable
response to therapy, they may be more
likely to benefit from surgery. In these
situations, CN can be considered in the
deferred setting. This is particularly
relevant in the ICI therapy era, where
significant responses to ICI/ICI and
ICI/TKI therapy have been observed.
Patient Characteristics
One of the fundamental challenges
faced by clinicians is determining the
fitness of patients preoperatively and
estimating a patient’s individual risk of
morbidity and mortality for a complex
operation such as CN. Various measures
of performance status have been used
to estimate these risks including the
Eastern cooperative group performance
status scale53, Karnofsky performance
status54, and Charlson comorbidity
index55. While each of these measures
can give a general idea of the patient
level of fitness and comorbidity, none
were specifically designed to measure
a patient’s risk of morbidity from CN
or their subsequent survival following
CN. In general, patients with poor
performance status are felt to be higherrisk
candidates for CN and favored to
receive initial systemic therapy. Patient
performance status is dynamic, however,
and may improve after receiving
systemic therapy making them eligible
for CN after initial systemic therapy.
This demonstrates the importance of
a multidisciplinary approach to mRCC
patient management when determining
surgical eligibility, which should be
considered not only during the initial
evaluation of the patient but throughout
a patient’s disease course.
Other serum-based markers
have been identified as predictive of
patient outcomes. The presence of
preoperative anemia, hypercalcemia,
and hypoalbuminemia have been
associated with worse survival
following CN56,57. Markers of systemic
inflammation such as the elevated
neutrophil lymphocyte ratio and
elevated C-reactive protein have
also been associated with worse
survival outcomes following CN58-
60. While each of these variables may
incrementally better inform selection of
patients for CN, none has been routinely
incorporated into patient selection
and most require further external
validation. Additionally, the majority of
these markers were evaluated in the TKI
therapy era, and require further study
in the setting of modern ICI therapy.
Prognostic scores
Various prognostic scores have also
been developed that incorporate many
of the previously described variables.
Two frequently used prognostic scoring
systems are the Memorial Sloan
Kettering Cancer Center (MSKCC) risk
criteria and the International Metastatic
RCC Database Consortium risk criteria61,62. The MSKCC and IMDC risk criteria
are similarly designed but incorporate
different prognostic variables that
predict survival outcomes for patients
with mRCC. Currently, the IMDC risk
criteria are more frequently utilized
as they were more recently developed
in the TKI therapy era. Each variable
in the IMDC risk criteria is assigned
1 point and the variables included
are neutrophilia, thrombocytopenia,
anemia, hypercalcemia, Karnofsky
performance status <80, and time from
diagnosis to systemic therapy of <1 year.
Patients with mRCC are categorized into
favorable (0 risk factors), intermediate
(1-2 risk factors) and poor (≥3 risk
factors) risk groups. The EAU guidelines
recommend that intermediate and poor
risk patients should receive systemic
therapy first and poor risk patients do
not benefit from CN63 The limitation of
using these risk stratifications to make
decisions regarding CN is that they were
not designed specifically to address
survival outcomes following CN.
Also, the risk classifications are often
dynamic and may change during the
disease course. A patient may initially
present with poor risk disease (due
to lab abnormalities such as anemia,
hypercalcemia, and neutrophilia) but
these may improve after receipt of
systemic therapy or CN64,65.
In order to address these
limitations, prognostic scoring systems
have been developed specifically in CN
patient populations to help identify
appropriate candidates for CN23,66 Updating their prior prognostic
classification system66, the MD
Anderson Cancer Center group recently
evaluated a modern cohort of CN
patients and identified 9 predictors of
worse overall survival following CN23.
The advantage of this study is that
it incorporates variables that can be
obtained preoperatively to risk stratify
patients and was designed specifically
in a CN patient population. Similarly,
a study using the European registry for
metastatic RCC (REMARCC) developed
a scoring system to predict overall
survival following upfront CN. The
study incorporated BMI, metastatic
location (lung, liver, bone), number
of metastatic sites, and performance
status into their model for predicting
survival67. Both studies require further
external validation and given the time
periods within which patients were
included, it is unlikely that many
patients received ICI therapy during
the course of their mRCC treatment,
highlighting the need for prospective
registries of mRCC patients receiving
CN to identify predictors of favorable
outcomes.
The medical system impact on
cytoreductive nephrectomy
Another critical aspect of outcomes
following CN is the system in which
the patient is treated. Management
of patients with mRCC is nuanced
and complex, requiring coordination
between multiple disciplines. Patients
with mRCC interact with oncologists
(including urologic, medical and
radiation), pathologists, radiologists,
interventional radiologists,
anesthesiologists, nursing staff (in
the clinic, infusion centers, inpatient
units, research coordinators, and
operating room), medical technologists
(in the operating room and clinics),
phlebotomists, billing and insurance
staff, fellows, residents, and medical
students to name only a few. Coordination
of these components requires a
system designed to and experienced in
delivering care to patients with mRCC.
Poor access to centers such as these may
limit the ability for a patient to receive
CN and negatively impact the survival
outcomes of patients following CN.
Cytoreductive nephrectomy has been
shown to be more frequently performed
at academic institutions and among the
privately insured30. Higher hospital
volume is also independently associated
with improved mortality following
CN68. Thus, patient access to systems
that routinely manage mRCC and a
thoughtful multidisciplinary discussion
of these complex cases is critical for
favorable outcomes.
CYTOREDUCTIVE
NEPHRECTOMY IN THE ERA
OF IMMUNE CHECKPOINT
INHIBITORS
Since nivolumab approval
in 2015, there has been rapid
incorporation of ICI therapy into the
management of mRCC, and ICI/ICI
or ICI/TKI combinations are now first
line therapy69. The improvements in
response rates to modern systemic
therapy again begs the question if
there is still a role for CN. Given ICI
therapy’s relatively recent approval,
very few studies have addressed the
impact of CN on survival outcomes in
the setting of ICI therapy and those that
have are often small sample sizes with
limited follow-up70-73. Cytoreductive
nephrectomy following ICI therapy does
appear safe and feasible. One of the
largest multi-institutional studies by
Shapiro et al. demonstrated that among
75 patients undergoing deferred CN
following ICI therapy, the high-grade
complication rate was only 3% with no
90-day mortalities. Additionally, 48%
of patients were able to enter a period
of surveillance following their CN,
delaying further systemic therapy 71.
Thus, patients being treated with CN at
experienced centers face low morbidity
rates even compared to historic CN
series57.
Regarding survival outcomes, a
recent study by Bakouny et al used the
IMDC database to evaluate the impact of
upfront CN (N=234) vs no CN (N=203)
on survival outcomes among patients
treated with ICI therapy. Multivariable
analysis demonstrated upfront CN was
associated with significantly improved
overall survival compared to no CN
among patients treated with ICI therapy
(HR 0.61, 95% CI 0.41-0.9, P=0.013)74.
These studies again appear to confirm
that among appropriately selected
patients, CN is safe and associated with
improved survival.
CYTOREDUCTIVE
NEPHRECTOMY FUTURE
DIRECTIONS
As we gain a deeper
understanding of RCC tumor biology,
we may begin to better select patients
for CN based on tumor biology. The
TRACERx studies have demonstrated
that tumors harboring BAP1 mutations
are associated with rapid tumor
progression and low intratumoral
genomic heterogeneity. These patients
may not derive a survival benefit from
CN compared to tumors harboring
primarily PBRM1 mutations without
BAP1 mutations, which are associated
with slow progression and high
intratumoral genomic heterogeneity
(FIGURE 2)75. The Memorial Sloan
Kettering group also demonstrated that
BAP1 mutations negatively affected OS
among patients undergoing CN, while
SETD2 and KDM5C mutations were
associated with reduced risk of death76.
Additional explorations into the tumor
and immune microenvironments may
help identify predictive biomarkers
associated with patient survival
following CN4.
Clinical trials investigating CN
are currently being conducted. Active
trials include PROBE (NCT04510597),
NORDIC-SUN (NCT03977571), and
Cyto-KIK (NCT04322955). While these
trials will provide insight on the role
of CN in the deferred setting, there are
currently no large trials investigating
the use of upfront CN, which is utilized
in healthy patients with minimal
metastatic disease. Prior studies
including CARMENA and SURTIME
have demonstrated the difficulties
accruing to CN specific trials, thus
other mechanisms for studying CN
in a robust and generalizable manner
are necessary to supplement clinical
trials. An additional robust method for
studying CN in the future will be multiinstitutional
prospective registries to
investigate CN outcomes, particularly
in the upfront setting. While not
randomized, prospective registry data
can still provide important insight into
CN practice patterns, perioperative
morbidity, and survival outcomes,
particularly in the rapidly changing
treatment landscape of mRCC.
An additional unexplored
area of research is the study of patient
reported outcomes and quality of life
following CN using validated HRQoL
instruments used in most studies of
systemic therapy. One of the primary
proposed benefits of CN is that it
improves patient symptoms and quality
of life, but evidence to support this
hypothesis is absent. Additionally, it
is critical to involve multidisciplinary
care across the patient’s journey of
treatment. Future studies to address
these issues must be conducted.
CONCLUSION
Cytoreductive nephrectomy remains
a critically important component of
the multidisciplinary approach to
management of patients with mRCC. A
large body of evidence supports the use
of CN in appropriately selected patients.
Patients with good performance status
and limited metastatic burden are ideal
candidates for CN. The use and timing
of CN will continue to evolve as our
understanding of RCC tumor biology
advances and systemic therapies
continue to improve.
ACKNOWLEDGMENTS
Figures were constructed using
biorender.com.
FUNDING
The authors report no funding.
AUTHOR CONTRIBUTIONS
Conception: D.D.S., E.J.A. and
P.E.S., Writing: D.D.S., E.J.A. and
P.E.S., Critical review and editing of
manuscript: D.D.S., E.J.A., P.E.S.,
V.A.M., B.J.M., J.C., S.F.M., J.A.K.,
Figure design: D.D.S.
CONFLICTS OF INTEREST
None
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# Corresponding Author: Daniel D. Shapiro, MD.
University of Wisconsin School of Medicine and Public Health.
Email: ddshapiro@wisc.edu.