Stesura Seveso


Archivio Italiano di Urologia e Andrologia 2022; 94, 4476

REVIEW

No conflict of interest declared.

was considered the standard of treatment justified by two
randomized phase 3 trials (SWOG 8949, EORTC30947)
(1, 2). Both trials showed an overall survival (OS) benefit
of CN followed by interferon-alpha (IFN-a) 2b versus
interferon alone (1-3). Since 2005, systemic therapies (ST),
such as vascular endothelial growth factor receptors
(VEGFR)-tyrosine kinase inhibitors (TKI) and mammalian
target of rapamycin (mTOR) inhibitors, replaced cytokines
as they have been proven superior to cytokines (4, 5). CN
was evaluated, regarding possible advantages on OS in
mRCC patients treated with ST, through multiple retro-
spective studies. The CARMENA trial (6) and the SUR-
TIME trial (7), are the only randomized controlled trials
(RCT) investigating the role of CN in the ST era. These
two studies reduced the enthusiasm on upfront CN and
opened a discussion about which patients treated with ST
could benefit more by CN. Furthermore, new therapeutic
agents such as immune check point inhibitors (ICI), pre-
sented as superior to TKI in recent studies (8-10). These
controversial observations prompted us to conduct a sys-
tematic review in order to examine the role of CN for syn-
chronous mRCC patients in the ST era and beyond
regarding the overall survival (OS), the optimal sequence
between ST and CN and prognostic factors.

METHODS
The systematic review was conducted in accordance with
the PRISMA guidelines (Preferred Reporting Items for
Systematic Reviews and Meta-Analysis) (11). 
Bibliographic search was performed in Medline (PubMed),
ClinicalTrials.gov, and Cochrane Library-Cochrane Central
Register of Controlled Trials (CENTRAL). Studies included
were those indexed from 2005 in an attempt to limit those
conducted in the cytokine era. The last search date was
March 14, 2022. 
The following medical subject heading terms were used
in combination with Boolean operators (AND, OR, NOT):
(“cytoreductive nephrectomy”) AND ("targeted therapy" OR
"systemic therapy" OR “immune oncology [IO]” OR
immunotherapy OR "immune checkpoint inhibitor*" OR
“immunooncology”) NOT (Review[Publication Type])
NOT (Meta-analysis[Publication Type]) NOT (Systematic
review[Publication Type]). 
Two independent reviewers (K.S, T.L) screened all articles
retrieved by the initial search. All disagreements were

Objective: To assess the role of Cytoreductive
Nephrectomy for synchronous metastatic

Renal Cell Carcinoma patients in the Systemic Therapy era and
beyond regarding the Overall Survival, the optimal sequence
between Systemic Therapy and Cytoreductive Nephrectomy and
prognostic factors.
Methods: The systematic review was conducted in accordance
with the PRISMA guidelines. Bibliographic search was per-
formed in Medline (PubMed), ClinicalTrials.gov, and Cochrane
Library-Cochrane Central Register of Controlled Trials (CEN-
TRAL). Studies included were those indexed from 2005 in an
attempt to limit those conducted in the cytokine era. Risk of bias
assessment was performed by two authors (K.S and T.L) using
the Cochrane Collaborative Risk of Bias tool for randomized
 trials, the Cochrane Risk Of Bias In Non-randomized Studies of
Interventions (ROBINS-I) tool for nonrandomized studies.
Results: Cytoreductive nephrectomy was associated with
improved overall survival in all but one of the observational
studies. While in all of these studies the unvariable analysis
showed improved overall survival in favor of the cytoreductive
nephrectomy group in some studies the subgroup analysis
showed no benefit. Regarding the optimal sequence, deferred
cytoreductive nephrectomy demonstrated better results in more
studies than upfront cytoreductive nephrectomy but a advantage
was not clearly certain. In the analysis of possible prognostic
factors for overall survival with cytoreductive nephrectomy,
most common prognostic factors found were age (in 8 studies),
tumor histology (in 7 studies), number of metastasis (in 6 stud-
ies), and T stage.
Conclusions: Cytoreductive nephrectomy can still play an impor-
tant role in wisely selected patients, although the role of cytore-
ductive nephrectomy in the new immunotherapy era needs to be
defined.

KEY WORDS: Cytoreductive nephrectomy; Metastatic renal cell
carcinoma; Systemic therapy; Immune check point inhibitors.

Submitted 4 September 2022; Accepted 2 October 2022 

INTRODUCTION
During the last two decades, the role of cytoreductive
nephrectomy (CN) in the treatment of synchronous
metastatic renal cell carcinoma (mRCC) has been reevalu-
ated many times according to the newly discovered dif-
ferent oncological therapies. In the cytokine era, due to
lack of significant effectiveness of medical therapies, CN

Cytoreductive nephrectomy for synchronous metastatic
renal cell carcinoma. Is there enough evidence?

Stamatios Katsimperis, Lazaros Tzelves, Themistoklis Bellos, Konstantinos Pikramenos, 
Ioannis Manolitsis, Ioannis Tsikopoulos, Iraklis Mitsogiannis

Department of Urology, Athens, Greece.

DOI: 10.4081/aiua.2022.4.476

Summary



477Archivio Italiano di Urologia e Andrologia 2022; 94, 4

Nephrectomy for metastatic renal cell carcinoma

resolved with discussion, and final decision was reached by
consensus with a third reviewer (M.I.). Reference lists were
systematically searched for relevant articles in a snowball
procedure. 
An ethical approval is not required because this study is
a review of the existing international literature.

Study criteria
Clinical trials, cohort studies, and case-control studies were
considered for inclusion (Figure 1). 
Excluded studies met ≥ 1 of the following criteria: (1) irrel-
evant to the subject studies, (2) studies published in a non-
English language, (3) case reports, case series including less
than 10 patients, systematic reviews and meta-analyses, and
(4) editorials, perspectives, and letters to the editors, (5)
studies including only drugs from cytokine era (studies
excluded are summarized in Supplementary Table 1).

Types of participants and exposure
Patients diagnosed with synchronous mRCC, who under-
went CN. Studies with patients undergoing partial
nephrectomy, ablative procedures or nephrectomy for
palliative reasons were not included. Primary research
question was the effect of CN in the OS. Secondary ques-

tions were the optimal sequence between systemic thera-
pies and CN, and possible prognostic factors.

Risk of bias assessment
Risk of bias assessment was performed by two authors (K.S
and T.L) using the Cochrane Collaborative Risk of Bias tool
for randomized trials (12), the Cochrane Risk of Bias in
Non-randomized Studies of Interventions (ROBINS-I) tool
for nonrandomized studies (13) (Table 1). Most common
reasons for the studies evaluating the relationship between
CN and OS to be classified as having moderate or serious
risk of bias were the unmeasured differences between CN
and control groups and the inadequate adjustment for con-
founding factors. The inability to adjust for differences
between groups was also found in the studies assessing the
prognostic factors and the role of sequence between ST and
CN. Moreover, the studies assessing the sequence between
ST and CN also demonstrated selection bias.

RESULTS

Cytoreductive nephrectomy and overall survivor
Thirty studies were included in the analysis of the rela-

Figure 1. 
PRISMA 2020 flow
diagram for new
systematic reviews
which included
searches 
of databases and
registers only.



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478

tionship between CN and OS (14-42, 65) (Table 2). All of
the studies except for one (41), which was a prospective
randomized trial, were retrospective cohort studies. 
Ten of them were from the Surveillance, Epidemiology, and
End Results (SEER) database, 4 from International
Metastatic RCC Database Consortium (IMDC), two from
National Cancer Database (NCDB) and the rest were sin-

gle or multi-center studies. Most common systemic agent
used was sunitinib (Table 1), while there were three stud-
ies (2, 40, 42) comparing CN with the use of ICIs. These
studies are of great importance, as they are the first retro-
spective studies on the role of CN in the immunotherapy
era and demonstrated an OS benefit in patients treated
with ICI plus CN compared to ICI alone (HR 0.23-0.39,

Table 1. 
Risk of bias assessment for non-randomized studies.

First author Confounding Participant Intervention Deviation from Missing Outcome Selected Overall
(year) selection classification inteended treatment data measurement reporrting bias
Day (2016) Moderate Moderate Low Low Moderate Low Low Moderate
de Groot (2016) Moderate Serious Low Low Moderate Low Low Serious
Hanna (2016) Moderate Serious Low Low Moderate Low Low Serious
Heng (2014) Moderate Serious Low Low Low Low Low Serious
Klatte (2018) Moderate Serious Low Low Low Low Low Serious
Patel (2017) Serious Moderate Low Low Moderate Moderate Low Serious
Tatsugami (2015) Moderate Moderate Low Low Moderate Low Low Moderate
You (2011) Moderate Moderate Low Low Low Low Low Moderate
Abern (2014) Serious Moderate Low Low Low Low Low Serious
Conti (2014) Serious Moderate Low Low Low Low Low Serious
Marchioni (2019) Serious Moderate Low Low Low Low Low Serious
Patel (2017) Serious Moderate Low Low Moderate Moderate Low Serious
Aizer (2014) Serious Moderate Low Low Low Moderate Low Serious
Song (2016) Serious Serious Low Low Low Low Low Serious
Abel (2017) Moderate Moderate Low Low Moderate Low Low Moderate
Corcoran (2014) Moderate Moderate Low Low Low Low Low Moderate
Culp (2010) Moderate Moderate Low Low Low Low Low Moderate
Culp (2014) Moderate Moderate Low Low Low Low Low Moderate
Kalogirou (2017) Serious Moderate Low Low Low Low Low Serious
Sakai (2014) Moderate Moderate Low Low Low Low Low Moderate
Sharma (2015) Moderate Moderate Low Low Moderate Low Low Moderate
You (2015) Serious Moderate Low Low Low Low Low Serious
MacLeod (2017) Moderate Moderate Low Low Moderate Low Low Moderate
Stroup (2013) Serious Moderate Low Low Low Low Low Serious
Wood (2009) Serious Moderate Low Low Low Low Low Serious
Luzaggo (2021) Moderate Moderate Low Low Low Low Low Moderate
Singla (2020) Moderate Moderate Low Low Low Low Low Moderate
Palumbo (2020) Moderate Moderate Low Low Low Low Low Moderate
Choi (2018) Moderate Serious Low Low Low Low Low Serious
Janish (2020) Moderate Serious Low Low Moderate Low Moderate Serious
Alnimer (2021) Moderate Moderate Low Low Low Low Low Moderate
Vaishampayan (2019) Serious Moderate Low Low Low Low Low Serious
Graham (2019) Moderate Serious Low Low Low Moderate Low Serious
You (2014) Moderate Moderate Low Low Low Low Low Moderate
Zhao (2019) Serious Moderate Low Low Low Low Low Serious
Poprach (2020) Moderate Moderate Low Low Low Low Low Moderate
Bakouny (2020) Serious Moderate Low Low Low Low Low Serious
Dragomir (2021) Serious Moderate Low Low Low Moderate Low Serious
Ljungberg (2020) Serious Serious Low Low Low Low Low Serious
Mcintosh (2020) Moderate Moderate Low Low Low Low Low Moderate
Rosiello (2019) Serious Serious Low Low Low Low Low Serious
Teishima (2018) Serious Moderate Low Low Low Low Low Serious
Adashek (2021) Moderate Moderate Low Low Low Low Low Moderate
Bhindi (2020) Moderate Moderate Low Low Low Low Low Moderate
De Bruijn (2020) Serious Serious Low Low Low Low Low Serious
Uprety (2018) Moderate Moderate Low Low Low Low Low Moderate

Study Random Allocation Blinding of participants Blinded outcome Incomplete Selective Other Overall
sequence generation concealment and personnel assessment outcome data reporting bias risk of bias

Bex (2017) Low Low Low Low Low Low Moderate Moderate
Mejean (2018) Low Low Low Low Low Low Moderate Moderate

Risk of bias assessment for randomized studies.



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Table 2. 
Studies evaluating the association between CN and OS.

Study Number Systemic agents CN-systemic therapy Median OS (CN vs no CN) Supplementary info
of patients used sequence OS HR (95% CI) for the study

Conti (2014) (14), Retrospective cohort, N (total) = 20104 NR NR 15 vs 4, HR 0.41 Non–clear cell renal cell carcinoma studied
USA (SEER) 1993-2010 N (CN) = 6915 (95% CI 0.37–0.55)

N (no CN) = 13819
Aizer (2014) (15), Retrospective cohort, N (total) = 591 NR NR 14 vs 6, HR 0.45 Cytokines + ST
USA (SEER) 2000-2009 N (CN) = 384 (95% CI 0.39–0.43)

N (no CN) = 207
Abern (2014) (16), Retrospective cohort, N (total) = 7143 NR NR HR 0.33 Median OS in months: NR
USA (SEER) 2005-2009 N (CN) = 2629 (95% CI 0.31–0.36)

N (no CN) = 4514
Vaishampayan (2019) (17), Retrospective cohort, N (total) = 18422 NR NR 18 vs 3, HR 0.39 -
USA (SEER) 2010-2016 N (CN)= 7660 (95% CI 0.30–0.33)

N (no CN) =10762
Zhao (2019) (18), Retrospective cohort, N (total) = 1113 NR NR 26 vs 9, HR 0.40 -
USA (SEER) 2010-2014 N (CN) = 618 (95% CI 0.35–0.47)

N (no CN) = 415
Marchioni (2019) (19), Retrospective cohort, N (total) = 851 NR NR HR 0.38 Median OS in months: NR
USA (SEER) 2001-2014 N (CN) = 575 (95% CI 0.30–0.47) Non-clear Cell Renal Cell Carcinoma studied

N (no CN) = 276
Palumbo (2020) (20), Retrospective cohort, N (total) = 2241 NR NR 28 vs 12, HR 0.49 -
USA (SEER) 2010-2015 N (CN) = 1168 (95% CI 0.41–0.58)

N (no CN) = 1073
Luzzago (2021) (21), Retrospective cohort, N (total) = 1573 NR CN before ST No treatment = 3 
USA (SEER) 2006-2015 N (no-treatment) = 350 ST alone = 7

N (ST alone) = 387 CN = 9
N (CN) = 396 CN+ST = 13
N (CN+ST) = 440 HR = NR Non–clear cell renal cell carcinoma studied

Alnimer (2021) (22), Retrospective cohort, N (total) = 5483 NR NR 24 vs 6, HR 0.33 -
USA (SEER) 2010-2016 N (CN) = 2991 (95% CI 0.28–0.40)

N (no CN) = 2483
Hanna (2016) (23), Retrospective cohort, N (total) = 15390 NR CN before or after ST 17.1 vs 7.7, HR 0.49 -
USA (NCDB) 2006-2013 N (CN) = 5374 (95% CI 0.46–0.52)

N (no CN) = 10016
Singla (2020) (24), Retrospective cohort, N (total) = 391 Upfront CN = 197, No CN = 11.6 Median OS was not reached in the CN group.
USA (NCDB) 2015-2016 N (CN) = 221 ST before CN = 24 HR 0.23 (95% CI 0.15–0.37) Patients were treated with immune 

N (no CN) = 170 checkpoint inhibitors
Choi (2018) (25), Retrospective cohort, N (total) = 294 Sunitinib (52.4%) ST before CN 29 vs 11, HR 0.40 -
Korea (Single center) 2005-2015 N (CN) = 109 Pazopanib (26.2%) (95% CI 0.28–0.58)

N (no CN) = 105 Sorafenib (10.9%) 
Temsirolimus (4.4%)

Janish (2020) (26), Retrospective cohort, N (total) = 262 Sunitinib (66%) CN before ST 27 months for the CN group No difference in OS between the two groups
Germany (Single center) 2000-2016 N (CN) = 104 Sorafenib (20%) P > 0.05

N (no CN) = 158 Pazopanib (10%)
You (2011) (27), Retrospective cohort, N (total) = 78 Sunitinib (81%) CN before ST 21.6 vs 13.9, HR 0.53 -
Korea (Single center) 2006-2009 N (CN) = 45 Sorafenib (19%) (95% CI 0.24–1.15)

N (no CN) = 33
Graham (2019) (28), Retrospective cohort, N (total) = 353 Sunitinib (54%) CN before ST 16.3 vs 8.6, HR 0.62 Metastatic Papillary Renal Cell
international (IMDC) 2005-2017 N (CN) = 244 Temsirolimus (23%) (95% CI 0.45–0.85) Carcinoma studied

N (no CN) = 109 Pazopanib (11%) 
Sorafenib (2.8%)

Klatte (2017) (29), Retrospective cohort, N (total) = 261 Sunitinib (60.5%) CN before ST Unadjusted: -
UK (Single center), 2006-2017 N (CN) = 97 Pazopanib (28.4%) 25.6 vs 12.4, HR 0.46

N (no CN) = 164 cabozantinib or (95% CI 0.34–0.62)
Nivolumab (8.4%) IPTW-adjusted: 20.9 vs 12.6, 
other (34.5%) HR 0.63 (95% CI 0.46–0.84)

You (2014) (30), Retrospective cohort, N (total) = 171 Sunitinib (70%), CN before ST 19.9 vs 11.7 -
Korea (Single center) 2006-2012 N (CN) = 96 Sorafenib(19%), HR: NR

N (no CN) = 75 Pazopanib (4%), 
Temsirolimus (7%)

Tatsugami (2015) (31), Retrospective cohort, N (total) = 330 NR NR 27.4 vs 10.3, HR 0.40 Mixed population of approximately half 
Japan (multicenter) 2001-2015 N (CN) = 254 (95% CI 0.29–0.57) patients receiving Cytokines and half 

N (no CN) = 76 Subgroup analysis for patients receiving Systemic Therapy
receiving only ST: 30.9 vs 15.5, 
HR 0.48 (95% CI 0.28–0.90)



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480

with 95% CI 0.15-0.37 and 0.19-0.83). Regarding the
sequence of CN and ST, CN was administered before ST
in 12 studies (21, 26-30, 32, 33, 35-37), before or after
in 5 (23, 38, 40-42), after in one study (25) while
sequence was not specified in the rest.

CN was associated with improved OS in all but one of the
observational studies (26), with HRs ranging from 0.23 to
1.90 (Table 1). In all of these studies (14-25, 27-42) the
univariable analysis showed improved OS in favor of the
CN group although in some studies subgroup analysis

Day (2016) (32), Retrospective cohort, N (total) = 91 Sunitinib (74%) CN before ST 23 vs 10.9, HR 0.33 -
Australia (multicenter) 2006-2012 N (CN) = 46 Pazopanib (4%) (95% CI 0.20–0.55)

N (no CN) = 45 Everolimus (4%)
Bevacizumab (2%) 
Interferon (2%) 
Temsirolimus (1%)

Choueiri (2011) (33), Retrospective cohort, N (total) = 314 Sunitinib (63%) CN before ST 19.8 vs 9.4, HR 0.68 -
Canada and USA (multicenter) 2004-2008 N (CN) = 201 Sorafenib (30%) (95% CI 0.46–0.99)

N (no CN) = 113 Bevacizumab (7%) 
Heng (2014) (34), Retrospective cohort, N (total) = 1658 CN; no CN NR 20.6 vs 9.6, HR 0.60 -
international (IMDC), years not specified N (CN) = 982 Sunitinib (67%; 79%) (95% CI 0.52–0.69)

N (no CN) = 676 Sorafenib (20%; 8.6%)
Axitinib (0.4%; 0.4%)
Bevacizumab (4%; 1.5%)
Temsirolimus (3.6%; 6.4%)
Pazopanib (2.8%; 2.8%)
Everolimus (1%; 1%)
Other (0.7%; 0.3%)

De Groot (2016) (35), Retrospective population N (total) = 146 Sunitinib CN before ST 17.9 vs 8.8, HR 0.61 -
based matched cohort, The Netherlands 2008-2010 N (CN) = 73 (95% CI 0.41–0.92)

N (no CN) = 73
Poprach (2020) (36), Retrospective cohort, N (total) = 730 Sunitinib (78.8%) CN before ST 27.2 vs 14.2, HR 0.55 -
Czech Republic (National registry) 2007-2018 N (CN) = 458 Pazopanib (21.2%) (95% CI 0.45–0.68)

N (no CN) = 272
Song (2016) (37), Retrospective cohort, N (total) = 74 Sunitinib (44.6%) CN before ST 32.2 vs 23 -
China (single center) 2006-2014 N (CN) = 51 Sorafenib (29.7%) HR: NR

N (no CN) = 23 Famitinib (18.9%)
Pazopanib (6.7%)

Bhindi (2020) (38), Retrospective cohort, N (total) = 1541 Sunitinib CN before or after ST CN+sunitinib vs sunitinib Comparative analyses of upfront CN+ sunitinib
IMDC 2006-2018 N (CN+Sunitinib) = 805 vs sunitinib+dCN 19 vs 10 vs 46 vs sunitinib+ dCN vs sunitinib

N (no CN) = 651 Upfront CN+sunitinib vs sunitinib 
N (Sunitinib+dCN) = 85 HR 0.89 (95% CI 0.71–1.1)

Sunitinib+dCN vs sunitinib
HR 0.89 (95% CI 0.71–1.1)
Sunitinib+dCN vs Upfront CN +sunitinib
HR 0.52 (95% CI 0.39–0.70)

Patel (2017) (39), Retrospective cohort, N (total) = 1062 NR NR HR 1.90 (95% CI 1.61–2.25) OS in months NR
Australia 2001-2009 N (CN) = 289 Includes cytokine era 

N (no CN) = 773
Dragomir (2021) (40), Retrospective cohort, N (total) = 788 Sunitinib (51.1%) CN before CN+ST vs ST 36 vs 18, HR 0.65 One of few studies including patients treated
Canada (multicenter) 2011-2020 N (CN) = 80 Pazopanib (16.8%) or after ST (95% CI 0.52–0.82) with ICI

N (CN+ST) = 383 Ipilimumab/ ST+CN vs ST 48 vs 18, HR 0.41 
N (ST+CN) = 73 Nivolumab (13.8%) (95% CI 0.28–0.60)
N (ST only) = 282 other (18.9%) CN (only) vs ST (only)

24 vs 18, HR 0.75 
(95% CI 0.48–1.17)
CN+ST vs ST+CN 36 vs 48, HR 0.66 
(95% CI 0.42–1.04)

Mejean (2018) (41), Prospective Randomized trial, N (total) = 450 Sunitinib CN before or after ST 13.9 vs 18.4, HR 0.89 17% of patients in the sunitinib-only 
France, Norway, England, Scotland, N (CN) = 226 (95% CI 0.71–1.1) arm received subsequent CN
Sweden 2009-2017 N (no CN) = 224
Bakouny (2020) (42) Retrospective cohort, N (total) = 4054 NR CN before or after ST CN+ ICI vs ICI One of few studies including patients treated 
international (IMDC) 2009-2019 N (TT only) = 1386 53.6 vs 21.4, HR = 0.44 with ICI

N (CN+TT) = 2470 (95% CI 0.30-0.64)
N (CN+ICI) = 143 CN+ TT vs TT 26.5 vs 10.3, HR = 0.48 
N (ICI only) = 282 (95% CI 0.45-0.52)

Uprety (2018) (65), Retrospective cohort, N (total) = 3376 NR NR 18 vs 4
USA (SEER) 2006-2012 N (CN) = 1110

N (no CN) = 2266
CN = Cytoreductive nephrectomy; dCN = Deferred CN; OS = Overall survival; HR = hazard ratio; ST = Systemic therapy; NR = Not reported; CI = Confidence interval; SEER = Surveillance, Epidemiology, and End Results; NCDB = National Cancer Database; 
IMDC = International Metastatic Renal Cell Carcinoma Database Consortium.



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Table 3. 
Studies evaluating the sequencing of CN and ST.

Study Number of patients Comparison Findings
Wood (2009) (43), Retrospective cohort, N (total) = 102 CN followed by TT versus TT followed by CN Unadjusted KM analysis revealed similar median CSS.
USA (single center) 2005-2007 N (CN+TT) = 58 31 vs 27.7 mo, p = 0.697

N (TT+CN) = 44
Stroup (2013) (44), Retrospective cohort, N (total) = 35 CN followed by Sunitinib versus Sunitinib followed by CN Unadjusted KM analysis revealed no difference in OS
USA (multi center) 2005-2009 N (CN+Sunitinib) = 17 p = 0.579

N (Sunitinib+ CN) = 18
Hanna (2016) (23), Retrospective cohort, N (total) = 4223 CN followed by TT versus TT followed by CN Unadjusted KM analysis revealed, 1-, 2-, and 3-year OS rates were: 61.2%,
USA (NCDB) 2006-2013 N (CN+TT) = 3733 37.8%, 26.6% for CN+TT patients versus 73.3%, 48.1%, 35.3%

N (TT+CN) = 490 for TT+CN patients log-rank p < 0.001
Macleod (2017) (45), Retrospective cohort, N (total) = 537 CN followed by TT versus TT followed by CN Median OS of CN+TT vs TT+CN: 17.4 vs 9.2 months
USA (SEER) 2006-2011 N (CN+TT) = 190 HR 0.50 (95% CI 0.38-0.65) In propensity score matching: 5.8

N (TT+CN) = 347 months advantage for immediate CN
Bex (2018) (7), Prospective RCT, N (total) = 99 CN followed by Sunitinib versus Sunitinib followed by CN In the ITT population, no difference in PFR at 28 weeks 
The Netherlands, Canada, UK, Belgium 2010-2016 N (CN+Sunitinib) = 50 (CN+Sunit. 42% vs Sunit.+CN 43% p = 0.61)

N (Sunitinib+ CN) = 49 Median OS of CN+Sunit. vs Sunit.+CN: 15 vs 32.4 months
HR 0.57 (95% CI 0.34-0.95) p = 0.032
In the PPP the OS was greater in deferred CN but not statistically 
significant p = 0.23

Bhindi (2018) (46), Retrospective cohort, N (total) = 15068 CN followed by TT versus TT followed by CN In IPTW analysis, median OS of CN+TT vs TT+CN: 16.5 vs 9.2 months
USA (NCDB) 2006-2013 N (CN+TT) = 6731 HR 0.61 (95% CI 0.59-0.64) p < 0.001

N (TT+CN) = 8337
Bhindi (2020) (38), Retrospective cohort, N (total) = 1541 CN followed by Sunitinib versus Sunitinib followed by CN Median OS of CN+Sunitinib vs Sunitinib+deferred CN: 19 vs 46 months
USA (IMDC) 2006-2018 N (CN+Sunitinib) = 805 HR 0.52 (95% CI 0.39–0.70) p < 0.001

N (no CN) = 651
N (Sunitinib+dCN) = 85

Kapoor (2019) (47), Retrospective cohort, N (total) = 54 CN followed by TT versus TT followed by CN Median OS of CN+TT vs TT+CN: 30.7 vs 36.9 months
Canada (single center) 2009-2016 N (CN+TT) = 32 When stratified by number of metastatic sites (< 3 vs ≥ 3 sites) 

N (TT+CN) = 22 median OS was significantly longer in the upfront TT group 
with ≥ 3 metastasis sites: 33 vs. 12.1 months 
HR 4.65 (95% CI 1.18–18.39) p = 0.03
In intermediate-risk patients, upfront TT group had longer OS:
70.5 vs. 30.7 months 
HR 3.25 (95% CI 1.16–9.08) p = 0.03

De Bruijn (2020) (48), Retrospective analysis, N (total) = 338 CN followed by TT versus TT followed by CN In unselected for risk group
Pooled data from prospective trials 2006-2016 N (CN+TT) = 149 Median OS of CN+TT vs TT+CN: 18.4 vs 24.3 months

N (TT+CN) = 189 HR 0.78 (95% CI 0.59–1.04) p = 0.09
In intermediate-risk group
Median OS of CN+TT vs TT+CN: 22.8 vs 33 months
HR 0.72 (95% CI 0.52–0.99) p = 0.047

Dragomir (2021) (40), Retrospective cohort, N (total) = 788 CN followed by ST versus ST followed by CN Median OS of CN+ST vs ST+CN: 36 vs 48 months
Canada (multicenter) 2011-2020 N (CN) = 80 ST includes TT or immune check point inhibitors HR 0.66 (95% CI 0.42–1.04)

N (CN+ST) = 383
N (ST+CN) = 73
N (ST only) = 282

CN = Cytoreductive nephrectomy; OS = Overall survival; CSS = Cancer specific survival,; HR = Hazard ratio; ST = Systemic therapy; TT = Ttargeted therapy; CI = Confidence interval; KM = Kaplan Meier; ITT = Intention to treat; PPP = Per protocol population; 
SEER = Surveillance, Epidemiology, and End Results; NCDB = National Cancer Database; IMDC = International Metastatic Renal Cell Carcinoma Database Consortium.

showed no benefit (33, 34). Choueiri et al. (33) stratified
patients according to the IMDC prognostic factors and
demonstrated that poor-risk patients had no significant
benefit in OS (HR 0.67 95% CI 0.44-1.01, p = 0.06).
Also, Heng et al. (34), in a similar subgroup analysis
showed absence of OS benefit for poor risk patients (OS
6 vs 5.4 months, p > 0.1).
The CARMENA trial (41), the only prospective trial in
this review, compared sunitinib plus CN versus sunitinib
alone in mRCC patients and showed for the first time the
non-inferiority of systemic therapy compared to upfront
CN plus sunitinib, with OS 18.4 months vs 13.9 months
(HR 0.89 95% CI 0.71-1.1). Results were similar in the
intermediate risk (HR 0.92 95% CI 0.68-1.24) and poor-

risk (HR 0.86 95% CI 0.62-1.17) patients. However, the
study has some serious limitations. In the sunitinib alone
arm, 17% of the patients underwent subsequent CN and
7% of patients in the CN plus sunitinib arm did not
receive surgery. The study also included only poor-risk
Memorial Sloan Kettering Cancer Center (MSKCC) and
intermediate-risk MSKCC patients that have been shown
before not to benefit from CN (33, 34).

Sequencing of cytoreductive nephrectomy 
and systemic therapies
Ten studies were included in the analysis of the sequenc-
ing of CN and ST (Table 3). Nine studies were retrospec-
tive cohorts (23, 38, 40, 43-48), and one was a prospec-



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S. Katsimperis, L. Tzelves, T. Bellos, K. Pikramenos, I. Manolitsis, I. Tsikopoulos, I. Mitsogiannis

482

tive randomized controlled trial (RCT) (7). Out of retro-
spective studies, two were population based (45, 38),
three studies used a national hospital-based database (46,
23, 40), two were from a single institution (43, 47), one
study was multicenter (44) and one study pooled data
from 4 prospective trials (48).
In two studies (45, 46), CN prior to ST found to have an
advantage in OS. Macleod et al. (45) showed that median
OS of immediate CN was 17.4 months vs 9.2 in the
deferred CN group, with HR 0.50 (95% CI 0.38-0.65). An
advantage of 5.8 months for the immediate CN group was
also found in propensity score matching. There was no sur-
vival benefit regarding the sequencing of CN and ST in
three studies (40, 43, 44). Unadjusted Kaplan Meier (KM)
analyses from both Wood et al. and Stroup et al. did not
reveal a benefit in survival in neither the upfront nor the
differed CN group (p = 0.697 and p = 0.579 respectively).
In the only prospective RCT from Bex et al. (7) median OS
in the deferred CN group was greater than in the imme-
diate one in the intention to treat population (32.4 vs 15
months, HR 0.57; 95% CI 0.34-0.95, p = 0.032) but not
in the per protocol population (HR 0.71; 95% CI 0.40-
1.24, p = 0.23). Similar results with advantage of deferred
CN were reported in four more studies (23, 38, 47, 48).
Interestingly, Bhindi et al. (38, 46), in two studies report-
ed contradictory results for the role of deferred CN.
When initial treatment with CN, with or without subse-
quent targeted therapy (TT) was compared to initial treat-
ment with TT, with or without subsequent CN in a sam-
ple population pooled from National Cancer Data Base
(NCDB) (46), Authors found an OS benefit for the first
group (HR 0.61; 95% CI 0.59-0.64, p < 0.001). However,
in a more recent study (38), a retrospective cohort with
data from International mRCC Database Consortium
(IMDC), comparison of CN followed by Sunitinib versus

Sunitinib followed by CN, favored the latter (HR 0.52;
95% CI 0.39-0.70, p < 0.001). Another study of notable
mention comes from Dragomir et al. (40), as it is the only
one that included in the ST arm patients who were also
treated with ICI. This study also favors deferred than ini-
tial CN (HR 0.66; 95% CI 0.42-1.04).

Prognostic factors for OS with CN
Twenty-four studies were included in the analysis of pos-
sible prognostic factors for OS with CN. In Figure 2 inde-
pendent prognostic factors are demonstrated with green
color, those found not to be independent prognostic fac-
tors are demonstrated with red, while those not assessed
are the ones in the white cells. 
Most common prognostic factors found in the analysis
were age (in 8 studies) (15, 18, 23, 27, 30, 39, 52, 53,
57), tumor histology (in 7 studies) (15, 18, 26, 27, 32,
51-53), number of metastasis (in 6 studies) (18, 30, 45,
51, 55, 60), and T stage (in 6 studies) (18, 31, 51-53, 57,
58). Other factors were, sarcomatoid histology, IMDC or
MSKCC classification, systemic symptoms, lym-
phadenopathy, hemoglobin and albumin level, levels of
serum calcium or creatinine or platelets, C-reactive protein
(CRP) level, absolute neutrophil count and neutrophil-
lymphocyte ratio, bone metastasis, lymph node metasta-
sis, visceral metastasis or liver metastasis, tumor grade,
sex, body mass index (BMI), marital status, race, level of
thrombus, if existing, and other comorbidities. From the
factors mentioned above, those associated with poor
overall survival after CN are high T stage and number of
metastasis, sarcomatoid histology, bone metastasis,
lymph node metastasis, visceral metastasis or liver metas-
tasis, thrombus level above the diaphragm, existing
comorbidities, presence of systemic symptoms, poor
IMDC or MSKCC classification, unmarried status, poor

Figure 2. 
Prognostic factors.



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Nephrectomy for metastatic renal cell carcinoma

performance status, hemoglobin level less than the lower
limit of normal, LDH level above the upper limit of nor-
mal and a neutrophile/lymphocyte ratio ≥ 4. Female gen-
der, thrombocytosis, CRP level ≥ 1 ng/ml, good perform-
ance status, and good/intermediate IMDC or MSKCC
classification were considered having an OS benefit.

DISCUSSION
Treatment of synchronous mRCC has faced many
changes in recent years, due to the ongoing development
of new drugs, making the therapeutic choice a complex
task. The two well-known RCTs that were published
regarding the role of CN in mRCC patients, CARMENA
and SURTIME, changed what we thought to be the stan-
dard of care. The role of CN was deeply questioned, and
systemic therapies were found to be more effective.
Results from SURTIME and CARMENA (6, 7) demon-
strated an absence of benefit in immediate CN, while
deferred CN showed an OS benefit in intermediate risk
patients. However, their results should be interpreted
with caution as both CARMENA and SURTIME, are
found to have certain pitfalls. For instance, in CARMENA
there was a significant crossover with 17% of patients in
the sunitinib alone arm undergoing subsequent CN, and
7% of patients in the CN plus sunitinib arm not receiving
surgery. SURTIME on the other hand, suffered from poor
accrual, changing the primary endpoint from progression
free survival (PFS) to progression free rate (PFR). A discor-
dance was also found, between the intention to treat and
per protocol population, OS outcome. For that reason,
the selection of patients who might benefit from CN is of
great importance. In our review, most of the studies eval-
uating the effect of CN in OS showed a benefit of CN (14-
25, 27-42). Although most of these studies are retrospec-
tive and observational, their results cannot be over-
looked. In three studies that used ICIs (2, 40, 42), CN
demonstrated an OS benefit. Given the absence of
prospective studies with patients treated with ICIs, these
results underline the importance of CN in the mRCC
treatment.
Prognostic factors have been described, with age, tumor
histology, number of metastasis and T stage being the
most common. There are also two prognostic models
allowing patient risk stratification: MSKCC and IMDC
risk scores (34, 63). These models stratify patients in
favor, intermediate and poor risk categories, using per-
formance status (PS), time from diagnosis to treatment,
hemoglobin concentration, calcium level and lactate
dehydrogenase level as criteria. According to current evi-
dence, poor MSKCC/IMDC risk patients do not seem to
benefit from upfront CN (33, 34) while other patients
such as those with good risk prognosis and good PS seem
to benefit the most from CN. It should be noted howev-
er, that MSKCC/IMDC prognostic scores were originally
designed to predict OS in patients with mRCC, and not
the OS benefit associated with CN (65). That shows the
need for new validated prognostic models. Among
patients that were found to benefit from CN, the optimal
sequence between CN and TT is not yet well established,
as was also documented in our review. 
Deferred CN demonstrated better results, in more studies

than upfront CN (7, 23, 38, 47, 48) but a certain advan-
tage was not clear.
Despite the new insights into the treatment of mRCC
patients that CARMENA and SURTIME provided, TKIs
are not anymore considered the standard of care as ICIs
have been established as first-line therapy in mRCC
patients. Three randomized trials: The CheckMate-214
(nivolumab plus ipilimumab vs sunitinib), KEYNOTE-
426 (pembrolizumab plus axitinib vs sunitinib), and
JAVELIN Renal 101 (avelumab plus axitinib vs sunitinib)
demonstrated the superiority of ICIs in the treatment of
mRCC whereas sunitinib and other VEGFR-TKI
monotherapies are reserved for those who cannot tolerate
ICI combination or have no access to these drugs(9-11).
What we already know from CARMENA and SURTIME
has to be re-evaluated. Singla et al. (24) in the first retro-
spective analysis of the role of CN in the immunotherapy
era, demonstrated an OS benefit for those patients treat-
ed with ICI plus CN compared to ICI alone (HR 0.23;
95% CI 0.15-0.37). In this regard, further data from high
level of evidence studies are required in order to define
the role of CN in the modern immune oncology (IO) era.
Currently there are two RCTs underway, to guide us to
that. The PROBE trial (NCT04510597) will evaluate the
combination of CN followed by IO or TKI+ IO compared
to no CN. The NORDIC-SUN trial (NCT03977571) will
evaluate the role of deferred CN in patients receiving
combination IO.
We acknowledge that the present study had several limi-
tations. The major limitations were the retrospective
nature of the studies included and the small number of
studies having ICIs as the main agent used. The retro-
spective nature could have resulted in selection bias in
performance of CN. Moreover, many studies come from
an era when systemic therapies were not well established.

CONCLUSIONS
The role of CN on mRCC treatment remains a controver-
sial issue. Data from most recent studies have questioned
the benefit from CN, shifting the first line treatment from
surgical to medical. CN can still play an important role in
wisely selected patients, although the role of CN in the
new immunotherapy era still needs to be defined.

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Correspondence
Stamatios Katsimperis, MD
stamk1992@gmail.com
Lazaros Tzelves, MD
lazarostzelves@gmail.com
Themistoklis Bellos, MD
bellos.themistoklis@yahoo.com
Konstantinos Pikramenos, MD
k.pikramenos@gmail.com
Ioannis Manolitsis, MD
giannismanolit@gmail.com
Ioannis Tsikopoulos, MD
Ioannistsikopoulos@yahoo.com
Iraklis Mitsogiannis, MD
imitsog@med.uoa.gr
Department of Urology, Athens, Greece