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available at www.sciencedirect.com
journal homepage: euoncology.europeanurology.com

Deferred Cytoreductive Nephrectomy Following Presurgical

Vascular Endothelial Growth Factor Receptor–targeted Therapy in
Patients with Primary Metastatic Clear Cell Renal Cell Carcinoma:
A Pooled Analysis of Prospective Trial Data

Roderick de Bruijn a, Akhila Wimalasingham b, Bernadett Szabados b, Grant D. Stewart c,

Sarah J. Welsh d, Teele Kuusk e, Christian Blank f, John Haanen f, Tobias Klatte g,h,
Michael Staehler i, Thomas Powles b, Axel Bex a,e,*
a
Department of Urology, Netherlands Cancer Institute, Amsterdam, The Netherlands; b Barts Cancer Institute, Queen Mary University of London, London, UK;
c d
Department of Urology, University of Edinburgh, Edinburgh, UK; Department of Urology, Cambridge University Hospitals NHS Foundation Trust,
e
Cambridge, UK; Specialist Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, UCL Division of Surgical and Interventional Science, London,
UK; f Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands; g Department of Urology, Royal Bournemouth Hospital,
Bournemouth, UK; h Department of Urology, Medical University of Vienna, Vienna, Austria; i Department of Urology, Ludwig Maximilian University, Munich,
Germany

Article info Abstract

Article history: Background: Cancer du Rein Métastatique Nephrectomie et Antiangiogéniques (CARMENA)

concluded that sunitinib alone is not inferior to cytoreductive nephrectomy (CN) followed by
Received 14 October 2019Re- vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) in patients with
ceived in revised form metastatic renal cell carcinoma. It remains uncertain whether deferred CN is beneficial in this setting.
29 November 2019Accepted De- Objective: The aim of this study was to compare outcome in patients treated with presurgical
VEGFR-TKI followed by CN (deferred CN) with that in patients receiving CN followed by VEGFR-TKI
cember 24, 2019 (upfront CN).
Design, setting, and participants: Pooled data from prospective trials in which a strategy of
Associate Editor: deferred CN in the absence of disease progression was investigated were compared with a retro-
Gianluca Giannarini spective dataset of upfront CN.
Outcome measurements and statistical analysis: Overall survival (OS) in the Memorial
Sloan-Kettering Cancer Center (MSKCC) intermediate-risk group.
Keywords: Results and limitations: Patients were treated between 2006 and 2016. In the MSKCC inter-
Renal cell carcinoma mediate-risk group, 144 patients with a strategy of deferred CN after systemic therapy were
Cytoreductive nephrectomy compared with 131 patients treated with upfront CN. OS in the deferred cohort was 33.0 mo
(95% confidence interval [CI] 25.0–51.0) compared with 22.8 mo (95% CI 17.9–30.6) after upfront CN
Vascular endothelial growth (hazard ratio 0.72 [95% CI 0.52–0.996], p = 0.047). This study is limited by retrospective comparison of
factor receptor tyrosine kinase data, subgroup analysis, and a lack of intention-to-treat data for the upfront CN cohort.

inhibitor Conclusions: InMSKCCintermediate-riskpatients,astrategyofdeferredCNintheabsenceofprogression

yieldsOS,whichcomparesfavourablywithupfrontCNandpublishedtrialdatafromCARMENA.Thiswarrantsa
formalindividualpatientdataanalysisofCARMENA,SURTIME,andsingle-armprospectivestudiestodefinethe
role andtimingofdeferredCN in intermediate-riskpatients.
Patient summary: In this study, we report outcomes in patients with metastatic renal cell cancer
treated with targeted therapy followed by nephrectomy, which compared favourably with nephrec-
tomy followed by targeted therapy and results from published studies.
© 2020 Published by Elsevier B.V. on behalf of European Association of Urology.

* Corresponding author. Specialist Centre for Kidney Cancer, Royal Free London NHS Foundation
Trust, UCL Division of Surgical and Interventional Science, Pond Street, London NW3 2QG, UK.
E-mail address: a.bex@ucl.ac.uk (A. Bex).

https://doi.org/10.1016/j.euo.2019.12.004
2588-9311/© 2020 Published by Elsevier B.V. on behalf of European Association of Urology.

Please cite this article in press as: de Bruijn R, et al. Deferred Cytoreductive Nephrectomy Following Presurgical Vascular
Endothelial Growth Factor Receptor–targeted Therapy in Patients with Primary Metastatic Clear Cell Renal Cell Carcinoma: A
Pooled Analysis of Prospective Trial Data. Eur Urol Oncol (2020), https://doi.org/10.1016/j.euo.2019.12.004
EUO-296; No. of Pages 6
2 E U R O P E A N U R O L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
1. Introduction
In the cytokine era, a survival benefit was found in patients
with primary metastatic renal cell carcinoma (mRCC)
treated with cytoreductive nephrectomy (CN) in two
randomised studies comparing CN plus interferon-alpha
versus interferon-alpha alone [1,2]. Since 2006, systemic
first-line therapy has changed profoundly with the intro-
duction of tyrosine kinase inhibitors (TKIs) sunitinib and
pazopanib, targeting the vascular endothelial growth factor
receptor (VEGFR). However, upfront CN remained in the
treatment algorithm by default based on retrospective data
[3–5].
Cancer du Rein Métastatique Nephrectomie et Anti-
angiogéniques (CARMENA), a randomised controlled
phase 3 noninferiority trial, investigated whether CN is
still necessary in the VEGFR-TKI era in patients who
require systemic therapy [6]. CARMENA showed that
sunitinib alone was not inferior to CN followed by
sunitinib with regard to overall survival (OS) [7]. Prior
to the publication of CARMENA, previous single-arm and
randomised phase II studies have investigated the role of
deferred CN after treatment with VEGFR-TKI [8–10]. These
studies have focused on a period of 8–12 wk of systemic
therapy followed by CN in patients without systemic
progression. Results demonstrated that the subgroup of
Memorial Sloan-Kettering Cancer Center (MSKCC) poor-
risk patients had poor survival irrespective of deferred
CN, while other patients with intermediate-risk disease
who did not progress and had a deferred CN showed
impressive outcomes. The most significant data are from
the SURTIME randomised phase 2 trial [11]. SURTIME,
initially planned as a phase 3 trial, explored three cycles
of sunitinib prior to CN as an alternative approach to
upfront CN followed by sunitinib in patients who require
systemic therapy. The study revealed exceptionally long
median OS in the deferred CN arm. Unfortunately, the
trial was underpowered and results were mainly explor-
atory. Of note, in CARMENA, 17% of the patients in the
sunitinib-only arm required a secondary CN due to
symptoms related to the primary tumour or a near
complete response. These data indicate that there remain
arguments about performing deferred CN in some
individuals after VEGFR-TKI [6,12,13].
However, the results of SURTIME do not allow a definite
conclusion of superior OS with deferred CN compared with
upfront CN. We therefore compared the outcome of MSKCC
intermediate-risk patients included in several prospective
trials, in which sunitinib or pazopanib was followed by
deferred CN in the absence of disease progression, with a
retrospective dataset of upfront CN followed by VEGFR-TKI
and published trial data from CARMENA.
2. Patients and methods
2.1. Study design and patient population
This is a retrospective analysis of MSKCC intermediate-risk
patients comparing presurgical VEGFR-TKI treatment fol-
Please cite this article in press as: de Bruijn R, et al. Deferred Cytoreductive Nephrectomy Following Presurgical Vascular
Endothelial Growth Factor Receptor–targeted Therapy in Patients with Primary Metastatic Clear Cell Renal Cell Carcinoma: A
Pooled Analysis of Prospective Trial Data. Eur Urol Oncol (2020), https://doi.org/10.1016/j.euo.2019.12.004
lowed by deferred CN in the absence of systemic progressive
disease (PD) with upfront CN followed by VEGFR-TKI
therapy in patients with primary mRCC and published trial
data from CARMENA. MSKCC poor-risk patients were not
compared due to low numbers. Patients were treated
between 2006 and 2016.
The deferred CN cohort included patients treated with
presurgical sunitinib or pazopanib from three single-arm
prospective phase II studies with an almost identical design
and appropriate institutional review board approval (Sup-
plementary Table 1), and from the experimental arm in
SURTIME from a single centre (NCT01099423, n = 20).
Treatment-naïve mRCC patients received VEGFR-TKI 12–
18 wk prior to planned CN, which was cancelled in case of
systemic PD during systemic therapy [8–11]. Patient data
and OS were compared with those of a multi-institutional
European upfront CN cohort planned to receive VEGFR-TKI
after surgery and postoperative recovery. Patients were
from four centres (The Netherlands Cancer Institute,
Amsterdam, Netherlands; Ludwig-Maximilians University,
Munich, Germany; Medical University of Vienna, Austria;
and Western General Hospital, Edinburgh, UK) and treated
in the era of VEGFR-TKI between 2006 and 2016. From this
CN cohort, patients not requiring immediate postoperative
VEGFR-TKI and those with non–clear cell renal cell
carcinoma were excluded. Finally, median OS for MSKCC
intermediate-risk patients was compared with the respec-
tive publicly available data for the upfront CN and sunitinib-
alone arm from CARMENA [6]. A comparison of MSKCC
poor-risk patients was limited due to low numbers in the
upfront CN cohort (Table 1, Supplementary Table 2, and
Supplementary Fig. 1).
For each patient, age, gender, MSKCC criteria, clinical
tumour stage (cT stage) if available, pathological tumour
stage (pT stage), histology type, number of metastatic
sites, type of systemic treatment, and reasons for not
performing surgery were registered. MSKCC criteria were
evaluated based on the five risk factors: low Karnofsky
performance status (<80), high lactate dehydrogenase
(>1.5 times the upper limit of normal), low serum
haemoglobin (<12 g/dl), high corrected serum calcium
(>10 mg/dl), and time from initial diagnosis to systemic
therapy of <1 yr [14].
2.2. Statistical analysis
OS was calculated from the date of diagnosis to death from
any cause and reported as median and 95% confidence
intervals (CIs). The Kaplan-Meier method was used to
estimate survival functions, which were compared using
the log-rank test, in addition to a multivariable Cox-
regression analysis. Analyses were weighted using the
propensity score–based inverse probability of treatment
method to adjust for group imbalances in age, gender, T
stage, MSKCC group, and number of metastatic sites. SPSS
software (SPSS for Windows, version 25) and R 3.5.1 (The R
Foundation for Statistical Computing, Vienna, Austria) were
used for statistical analysis. The level of significance for all
comparisons was chosen at p  0.05.
EUO-296; No. of Pages 6

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Table 1 – Characteristics of patients treated with presurgical VEGFR-TKI followed by cytoreductive nephrectomy (deferred CN, n = 189) and
those receiving upfront cytoreductive nephrectomy followed by VEGFR-TKI (upfront CN, n = 149).

Unweighted cohorta Weighted cohortb

Deferred Upfront Std difference Deferred Upfront Std difference

cytoreductive cytoreductive cytoreductive cytoreductive
nephrectomy nephrectomy nephrectomy nephrectomy

Age (yr), mean (SD) 61.6 (9.9) 62.9 (10.8) 0.122 62.1 (9.8) 62.5 (10.8) 0.035
Gender 0.134 0.007
Male 142 (75.1) 103 (69.1) 74.2 73.9
Female 47 (24.9) 46 (30.9) 25.8 26.1
MSKCC (n = 335) 0.280 0.001
Intermediate risk 144 (77.4) 131 (87.9) 84.8 84.8
Poor risk 42 (22.6) 18 (12.1) 15.2 15.2
Number of metastatic sites 0.373 0.029
1 49 (25.9) 63 (42.3) 32.8 32.7
2 83 (43.9) 50 (33.6) 39.0 39.7
3 52 (27.5) 30 (20.1) 24.8 24.6
4 5 (2.6) 6 (4.0) 3.4 2.9
T stage (n = 336) 0.602 0.011
T1 21 (11.2) 22 (14.8) 14.4 14.5
T2 66 (35.3) 19 (12.8) 16.4 16.0
T3 78 (41.7) 96 (64.4) 58.9 59.3
T4 22 (11.8) 12 (8.1) 10.3 10.1
Surgery – –
Surgery performed 123 (65) 149 (100)
Surgery not performed 66 (35) –
Reasons for not performing surgery – –
Progression of disease 22 (12) –
Patients choice 10 (5) –
Unfit for surgery 11 (6) –
Unknown 23 (12)
Presurgical treatment –
Sunitinib 85 (45) –
Pazopanib 104 (55) –
1st-line treatment –
None 10 (7)
Sunitinib 85 (45) 113 (76)
Pazopanib 104 (55) 20 (13)
Sorafenib – 6 (4)

CN = cytoreductive nephrectomy; MSKCC = Memorial Sloan-Kettering Cancer Center; SD = standard deviation; Std = standard; VEGFR-TKI = vascular endothelial
growth factor receptor tyrosine kinase inhibitor.
Comparisons in baseline characteristics at diagnosis between groups before and after weighting were performed using the standardised difference approach. In
this quantitative method, significant imbalances in covariates are present if the standardised difference is 0.1.
a
Data are presented as number (percentage) of patients unless otherwise indicated.
b
Data are presented as percentage of patients unless otherwise indicated.

3. Results For intermediate-risk patients, OS in the deferred CN

Patient characteristics are summarised in Table 1 (and
Supplementary Table 2 for both MSKCC intermediate- and
poor-risk subgroups).
The pooled deferred CN cohort included 189 patients, of
whom 57% received sunitinib and 43% pazopanib, and 144
(76%) patients were at MSKCC intermediate risk and 42
(22%) at poor risk. From 244 patients with upfront CN, a
cohort of 149 patients was used for comparison after
excluding favourable-risk and non–clear cell mRCC. Of
those, 131 patients (88%) were at intermediate risk, while 18
(12%) were considered to be at poor risk. The majority (76%)
of patients received sunitinib.
For the deferred CN cohort unselected for risk group, the
median OS was 24.3 mo (95% CI 20.8–34.8), while for
unselected patients receiving upfront CN, median OS was
18.4 mo (95% CI 14.4–26.9, p = 0.09; Fig. 1A).
cohort was 33.0 mo (95% CI 25.0–51.0) compared with
22.8 mo (95% CI 17.9–30.6) after upfront CN, with a
weighted hazard ratio for death of 0.72 (95% CI 0.52–
0.996, p = 0.047; Fig. 1B). The result was confirmed in a
sensitivity analysis with a multivariable Cox model
(Supplementary Table 3). Review of publicly available data
from CARMENA for MSKCC intermediate risk in the upfront
CN arm and the sunitinib-only arm revealed median OS of
19.0 mo (12.0–28.0) and 23.4 mo (17.0–32.0), respectively
[6]. There was no statistically significant OS difference in
poor-risk patients (hazard ratio 1.33, 95% CI 0.74–2.38,
p = 0.3; Supplementary Fig. 1).
Overall, 66 (35%) patients in the deferred CN cohort did
not undergo CN (24% in the intermediate-risk and 52% in the
poor-risk group; Table 1 and Supplementary Table 2)
In the upfront CN cohort, following nephrectomy,
34 MSKCC intermediate-risk patients (25.9%) had short

Please cite this article in press as: de Bruijn R, et al. Deferred Cytoreductive Nephrectomy Following Presurgical Vascular
Endothelial Growth Factor Receptor–targeted Therapy in Patients with Primary Metastatic Clear Cell Renal Cell Carcinoma: A
Pooled Analysis of Prospective Trial Data. Eur Urol Oncol (2020), https://doi.org/10.1016/j.euo.2019.12.004
EUO-296; No. of Pages 6

4 E U R O P E A N U R O L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X

Fig. 1 – Inverse probability of treatment weighting-adjusted Kaplan-Meier estimates of overall survival for (A) all patients and (B) patients with MSKCC
intermediate-risk disease. The curves were weighted using the propensity score–based inverse probability of treatment method to adjust for group
imbalances. CN = cytoreductive nephrectomy; HR = hazard ratio; MSKCC = Memorial Sloan-Kettering Cancer Center.

cancer-specific survival of <6 mo. Ten patients (7%) never
went on to receive VEGFR-TKI, eight due to rapid PD.
4. Discussion
In this retrospective analysis of MSKCC intermediate-risk
patients, OS achieved with a strategy of VEGFR-TKI therapy
with planned deferred CN in the absence of PD compares
favourably with upfront CN. This is reminiscent of survival
data observed in SURTIME, which included predominantly
MSKCC intermediate-risk patients [11].
In contrast to CARMENA, SURTIME investigated upfront
CN followed by sunitinib versus sunitinib followed by CN in
the absence of distant metastatic disease progression
[6]. Owing to poor accrual, the design was changed and
as a consequence most results are exploratory. SURTIME did
not find a difference in median progression-free survival nor
the progression-free rate, but reported an OS signal in the
deferred nephrectomy arm. In addition, sunitinib prior to
planned CN appeared to select out patients with rapid
progression due to inherent resistance to sunitinib. Surgery
after sunitinib was found to be safe [15].
SURTIME therefore raises the question of whether
patients with MSKCC intermediate-risk mRCC who start
on systemic therapy with VEGFR-TKI benefit from a
planned deferred CN in the absence of disease progres-
sion. The survival benefit in SURTIME for patients with
deferred CN was 17.4 mo and represents a clinically
meaningful OS trend favouring this approach. In this
retrospective pooled analysis, we again observed an OS
benefit for deferred CN compared with upfront CN.
Likewise, although not statistically significant, patients
with MSKCC intermediate risk in CARMENA receiving
sunitinib alone had OS in excess of several months
compared with the CN arm. This is of importance because
the experimental arm of sunitinib alone in CARMENA
allowed secondary CN if deemed appropriate. In a recent
update and post hoc analysis of CARMENA, 40 patients
had a secondary nephrectomy in the sunitinib-only arm,
with median OS of 48.5 mo (95% CI 27.9–64.4) versus
15.7 mo (95% CI 13.3–20.5) in patients who did not have
surgery [16]. While this is clearly a reflection of patient
selection bias towards a more favourable course of the
disease in those undergoing secondary CN, it suggests
that the impact of secondary CN on the OS achieved in
the intermediate-risk patients of the sunitinib-alone
arm should not be underestimated. Unfortunately,
detailed patient characteristics for this subgroup are
not available.
The interpretation of data in our retrospective analysis
requires caution. Contrary to an intention-to-treat (ITT)
analysis performed in CARMENA, the analysis of the upfront
CN cohort in our study did not capture patients who were
planned to undergo surgery but never received it. It would
therefore be more appropriate to compare the OS of the
MSKCC intermediate-risk presurgical cohort, which was
collected from the ITT populations of the prospective trials,
with the OS of the intermediate MSKCC ITT subgroups that
received upfront CN or sunitinib alone in CARMENA
(125 patients of 226 [56%] in the CN arm and 131 of
224 [59%] in the sunitinib-alone arm, respectively)
[6]. Without access to individual patient data from
CARMENA, our pooled and retrospective comparison with
results from CARMENA fails to demonstrate statistically
significant OS differences between deferred CN, VEGFR-TKI
alone with optional secondary CN, or upfront CN, but trends
in favour of deferred CN in MSKCC intermediate risk are
apparent.

Please cite this article in press as: de Bruijn R, et al. Deferred Cytoreductive Nephrectomy Following Presurgical Vascular
Endothelial Growth Factor Receptor–targeted Therapy in Patients with Primary Metastatic Clear Cell Renal Cell Carcinoma: A
Pooled Analysis of Prospective Trial Data. Eur Urol Oncol (2020), https://doi.org/10.1016/j.euo.2019.12.004
EUO-296; No. of Pages 6
E U R O P E A N U RO L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
The median OS in the unselected upfront CN cohort in our
study was 18.4 mo, which is relatively long compared with
the 13.9 mo (11.8–18.3) median OS in the unselected CN arm
in CARMENA. This discrepancy can be explained by a higher
rate of poor-risk patients in CARMENA as well as the influence
of the aforementioned ITT analysis. In our retrospective
upfront CN cohort, only 12% of patients had MSKCC poor risk.
This contrasts with CARMENA, in which 44% of patients
randomised for upfront CN were considered to be at a poor
risk [6]. This suggests that investigators may have been biased
towards inclusion of poorer surgical candidates into a trial
that offered a 50% chance of not receiving CN [17].
In summary, this study is limited by retrospective
comparison of data, which may include uncontrolled bias,
subgroup analysis of prospective and retrospective datasets,
and a lack of ITT data for the retrospective upfront CN
cohort. Nevertheless, data are matched by risk scores and
can be compared with the respective ITT subgroups from
CARMENA. This comparison suggests that a formal indi-
vidual patient data meta-analysis should be performed
based on the data from CARMENA, SURTIME, and the single-
arm prospective studies of deferred CN to investigate the
role of this approach. Uncertainties include the timing of
and indication for surgery, with CN performed as either a
planned approach in the absence of progression following a
predefined systemic treatment period or only a secondary
procedure whenever appropriate in the course of the
disease treated with systemic therapy alone.
Finally, European and American guidelines on mRCC
were recently updated, recommending immunotherapy as
first-line treatment in clear cell carcinoma [18]. This new
treatment era will hopefully result in longer survival of
mRCC patients [19]. As the role of CN in patients treated
with immune checkpoint inhibitors is yet undefined,
understanding the role and especially the sequence of CN
in the targeted therapy era is still relevant.
5. Conclusions
In MSKCC intermediate-risk patients, deferred CN in the
absence of progression yields favourable OS results when
compared with retrospective patient cohorts of upfront CN
and the respective subgroups of CARMENA. A formal
individual patient data analysis from CARMENA, SURTIME,
and the single-arm prospective studies of deferred CN
should be performed to investigate the role and timing of
deferred CN in intermediate-risk patients.
Author contributions: Axel Bex had full access to all the data in the study
and takes responsibility for the integrity of the data and the accuracy of
the data analysis.
Study concept and design: de Bruijn, Bex.
Acquisition of data: Wimalasingham, Szabados, Stewart, Welsh, Kuusk,
Blank, Haanen, Klatte, Staehler, Powles, Bex.
Analysis and interpretation of data: de Bruijn, Bex, Klatte, Wimalasing-
ham.
Drafting of the manuscript: de Bruijn, Bex.
Critical revision of the manuscript for important intellectual content: Klatte,
Stewart.
Please cite this article in press as: de Bruijn R, et al. Deferred Cytoreductive Nephrectomy Following Presurgical Vascular
Endothelial Growth Factor Receptor–targeted Therapy in Patients with Primary Metastatic Clear Cell Renal Cell Carcinoma: A
Pooled Analysis of Prospective Trial Data. Eur Urol Oncol (2020), https://doi.org/10.1016/j.euo.2019.12.004
5
Statistical analysis: de Bruijn, Szabados, Klatte.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: None.
Other: None.
Financial disclosures: Axel Bex certifies that all conflicts of interest,
including specific financial interests and relationships and affiliations
relevant to the subject matter or materials discussed in the manuscript
(eg, employment/affiliation, grants or funding, consultancies, honoraria,
stock ownership or options, expert testimony, royalties, or patents filed,
received, or pending), are the following: A. Bex: participation in advisory
boards of Pfizer, BMS, Roche, Eisai, and Ipsen. T. Powles: research funds—
Pfizer, Novartis, Roche, and AZ; honoraria—Pfizer, Novartis, Roche, BMS,
MSD, Ipsen, and Eisei. C. Blank: advisory board for Pfizer, BMS, and Roche.
J. Haanen: advisory role for Pfizer. All other authors have declared no
conflicts of interest.
Funding/Support and role of the sponsor: None.
Appendix A. Supplementary data
Supplementary material related to this article can be
found, in the online version, at doi:https://doi.org/10.1016/j.
euo.2019.12.004.
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Please cite this article in press as: de Bruijn R, et al. Deferred Cytoreductive Nephrectomy Following Presurgical Vascular
Endothelial Growth Factor Receptor–targeted Therapy in Patients with Primary Metastatic Clear Cell Renal Cell Carcinoma: A
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