












































This is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited.  
© 2021 The Authors. Société Internationale d'Urologie Journal, published by the Société Internationale d'Urologie, Canada.

Can Incomplete Metastasectomy  
Impact Renal Cell Carcinoma Outcomes?  
A Propensity Score Matching Analysis From  
a Prospective Multicenter Collaboration
Alice Dragomir,*1 Charles Hesswani,*1 Gautier Marcq,1 Alan I. So,2 Christian Kollmannsberger,2  
Naveen S. Basappa,3 Adrian Fairey,3 Anil Kapoor,4 Aly-Khan A. Lalani,4 Antonio Finelli,5 Lori A. Wood,6  
Daniel Y.C. Heng,7 Georg Bjarnason,8 Rodney H. Breau,9 Luke T. Lavallée,9 Denis Soulières,10  
Darrel Drachenberg,11 Frédéric Pouliot,12 Simon Tanguay 1 
*Co-first authors
1 McGill University, Montreal, Canada 2 Department of Urologic Sciences, University of British Columbia, Vancouver, Canada 3 Cross Cancer Institute, University of 
Alberta, Edmonton, Canada 4 Juravinski Cancer Centre, McMaster University, Hamilton, Canada 5 Princess Margaret Cancer Centre, University of Toronto, Toronto, 
Canada 6 Queen Elizabeth II Health Sciences Centre, Halifax, Canada 7 Tom Baker Cancer Centre, University of Calgary, Calgary, Canada 8 Odette Cancer Centre, 
Sunnybrook Health Sciences Centre, Toronto, Canada 9 Ottawa Hospital Cancer Center, Ottawa, Canada 10 Centre Hospitalier de l’Université de Montréal, Montreal, 
Canada 11 University of Manitoba, Winnipeg, Canada 12 Centre Hospitalier Universitaire de Québec, Université Laval, Quebec, Canada

Abstract

Objectives To evaluate the role of incomplete metastasectomy (IM) for patients with metastatic renal cell carcinoma 
(mRCC) on overall survival (OS) and time to introduction of first-line systemic therapy.

Methods Patients diagnosed with mRCC between January 2011 and April 2019 in 16 centers were selected from 
the Canadian Kidney Cancer information system database. We included mRCC patients who had prior nephrectomy 
and had received an IM (resection of at least 1 metastasis) or no metastasectomy (NM). A propensity score matching 
was performed to minimize selection bias. Cox proportional hazards analysis was used to assess the impact of the 
metastasectomy while adjusting for potential confounders. OS was assessed by Kaplan-Meier analysis.

Results A total of 138 patients with mRCC underwent IM, while 1221 patients did not. On multivariate analysis, 
IM did not improve OS (hazard ratio [HR] 0.96, 95% CI 0.63 to 1.45, P = 0.836) However, subgroup analyses revealed 
IM improved OS compared with NM when lungs were the only site involved (median time to OS not reached versus 
66 months, respectively; P = 0.014). Additionally, lung metastasectomy delayed the systemic therapy compared with 
NM (median 41 and 13 months, respectively, P = 0.014). IM of endocrine organs (thyroid, pancreas, adrenals) or bone 
metastases did not impact OS.

Conclusion The role of IM for mRCC is limited. Incomplete resection of lung metastases was associated with 
improved OS and delayed time to introduction of systemic therapy when lungs were the sole location of metastatic 
disease. Despite case-matching, unknown unadjusted confounders may explain the relationship between IM and 
survival in this analysis.

Key Words Competing Interests Article Information

Kidney neoplasms, incomplete 
metastasectomy, neoplasm metastasis,  
clear-cell metastatic renal cell carcinoma, 
systemic therapy

None declared. Received on September 27, 2020 
Accepted on January 2, 2021

Soc Int Urol J. 2021;2(2):82–95

DOI: https://doi.10.48083/ WQFR32352

Correction: This article was amended  
on March 19, 2021, to correct errors in 
author names.

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Introduction

In 2020, kidney cancer was estimated to be the sixth 
most common neoplasm in Canadian men and the 
eighth most common in Canadian women[1]. Renal 
cell carcinoma (RCC) is metastatic at diagnosis in 15% 
of cases, and metastasis will occur after diagnosis in 
up to 30% of patients[2]. Despite the advent of systemic 
therapies and immunotherapies, drug resistance 
remains a major therapeutic challenge in treating 
metastatic RCC. Since current systemic therapy does 
not offer complete response in most patients with 
metastatic disease, surgical resection of metastases 
can be used to improve survival. Most studies have 
compared complete metastasectomy (CM) w it h 
incomplete or no metastasectomy, and demonstrated 
a significant improvement in overall survival (OS)
[3,4]. A recent systematic review pooling 8 studies 
and 2267 patients demonstrated an improved OS in 
patients undergoing CM when compared with those 
who had incomplete metastasectomy (IM) or no 
metastasectomy (NM) (OS 36.5 to 142 months for CM 
and 8.5 to 27 months for IM/NM)[5]. Similarly, a recent 
single institution retrospective cohort study comparing 
patients undergoing CM with those who had IM/NM 
demonstrated a significantly improved OS (at 2 years 
81% versus 53%, P < 0.001)[6].

Few studies have compared the outcomes of IM 
patients with those of NM patients. The few available 
studies have been discorda nt a nd/or published 
before the era of tyrosine k inase inhibitors and 
immunotherapy[7–9]. All were single-center studies 
with limited power to allow extrapolation and clear 
recommendations for daily practice. Multicenter 
studies comparing IM with NM are lacking. The present 
study was conducted to assess OS and time to first-line 
systemic therapy of IM in patients with metastatic RCC 
(mRCC) when compared to patients who did not receive 
metastasectomy in a large prospective multicenter 
database using propensity score matching.

Methods
Patient demographics and clinical and pathological 
data were collected from the Canadian Kidney Cancer 
information system (CKCis) database, a prospective 
multicenter collaboration of 16 institutions in 6 
Canadian provinces. Baseline information was obtained 
from patient surveys and the medical record and 
included age, sex, date of RCC and mRCC diagnosis, 
date of nephrectomy, comorbidities, and the location 
and number of metastases. CM was defined as surgical 
resection of all visible metastases, while IM was defined 
as resection of some, but not all, of the radiographically 
visible metastases. IM was performed without curative 
intent. If this information was missing, the no evidence 
of disease status of the patient post-metastasectomy 
was used to classify patients between the IM and the 
CM groups. Complete versus incomplete resection was 
specified by patient’s medical records. If the patient 
underwent subsequent metastasectomy at different 
dates, the CM versus IM status was defined on the first 
metastasectomy. The indication for the metastasectomy 
and the reason for incomplete surgical resection were 
not available. Research Ethics Board approval was 
obtained at each individual participating center.

Medical records of patients diagnosed with mRCC 
who underwent radical or partial nephrectomy between 
January 2011 and April 2019 were reviewed. Patients 
receiving a CM were excluded and were reported 
separately[10]. Histopathological evaluation of the 
nephrectomy specimen was used to diagnose RCC. 
The date of diagnosis of a first metastasis confirmed 
by imaging was labeled as the index date. The analysis 
ranged from the index date to the end of follow-up, 
defined as the earliest date between the last patient visit, 
the date of death, or the end of study period (April 31, 
2019).

Clinical characteristics including sex, age, number 
and location of metastases, metastasectomy sites, 
pathological stage, clear cell histology, synchronicity, 
comorbid it ies (d iabetes mel litus, hy per tension, 
dyslipidemia, cardiovascular disease, smoking status, 
and obesit y), Charlson comorbidit y index score 
(excluding the solid tumors) and time from RCC 
diagnosis until metastasis were identified at the index 
date. “Endocrine” metastasis was defined as a metastasis 
at one of the following sites: adrenal glands, pancreas, 
and thyroid. The use of systemic therapy and radiation 
therapy was assessed at the index date and during 
follow-up. A propensity score method was used to 
determinate the predicted probability of receiving an 
IM based on clinical characteristics evaluated at index 
date including age (< 65 years versus ≥ 65), sites and 
number of metastasis (1 versus ≥ 2), synchronous disease 

Abbreviations 
CM complete metastasectomy
HR hazard ratio
IM incomplete metastasectomy
IQR interquartile range
mRCC metastatic renal cell carcinoma
NM no metastasectomy
OS overall survival
RCC renal cell carcinoma

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(yes versus no) and clear cell histology (yes versus no). 
For each patient, a propensity score and its quintiles 
were obtained. In order to reduce selection bias, patients 
receiving IM were matched with patients who had 
not received a metastasectomy. Up to 4 patients were 
randomly selected for each patient with IM. The date of 
IM or the date of selection was defined as the matching 
date. The matching was performed for (1) the propensity 
score quintiles (ie, probability of receiving an IM), (2) the 
status of the systemic treatment at the time of matching 
(yes versus no), (3) time between the first metastasis and 
the RCC diagnosis (< 3 months, 3 months to < 6 months, 
6 months to < 1 year, 1 year to < 2 years, and ≥ 2 years), 
and (4) an equivalent duration of follow-up between 
index date and the matching date.

Clinical and demographic characteristics between 
IM group and NM group were performed using t test for 
continuous variables and chi-square test for categorical 
variables. Individual propensity scores of IM were 
obtained using a multivariate logistic regression model 
based on variables enumerated in the section above. 
Overall survival was calculated from matching date 
to death from any cause. Kaplan-Meier curve analysis 
was performed to estimate OS since matching date in 
the matched cohort, with log-rank test to compare the 
IM and NM groups. Similarly, the time to introduction 
of systemic therapy during follow-up was assessed in 
IM and NM groups. The Cox proportional hazards 
regression model was used in the matched cohort to 
evaluate the association between IM and overall survival 
by adjusting for different covariables that were not used 
for matching. These included sex, age 65 and older (yes 
versus no), sites and number of sites of metastasis and 
clear cell carcinoma versus other histology. The use of 
systemic treatment and the use of radiation therapy were 
also included as time-dependent factors. A second Cox 
model was performed by adding an additional factor, the 
Charlson comorbidity index (0 or 1 versus > 1).

To assess differences between IM and NM by 
metastatic sites we performed several stratified analyses. 
Kaplan-Meier curve analyses were performed (1) to 
estimate OS since matching date and (2) to estimate time 
to introduction of systemic therapy during follow-up, 
in the matched cohort, with log-rank test to compare 
the IM and NM groups by metastatic site (lung, lymph 
nodes, bones, and endocrine). Patients with brain and 
liver metastasis were included in the multiple sites 
analysis but were not considered from the individual 
sites analyses because of the low number of patients 
in these groups. Finally, Kaplan-Meier curve was 
performed to assess the OS among patients receiving IM 
by metastasectomy sites. All statistical tests were 2-sided, 
with a P < 0.05 considered significant. All analyses were 
performed using SASS (version 9; SAS Institute, Cary, 
North Carolina).

Results
During the study period, the CKCis cohort included 

8936 patients diagnosed with RCC (Figure 1); 6223 
patients did not develop metastasis and were therefore 
excluded from the analysis.

Patients without prior nephrectomy (336 patients) 
or who had received a CM (266 patients) were also 
excluded from the cohort. Our final cohort consisted 
of 1367 patients: 146 of these patients underwent an 
IM, and 1221 patients did not undergo any form of 
metastasectomy (Figure 1).

T he demog r aph ic s a nd c l i n ic opat holog ic a l 
characteristics of the cohort before propensity score 
matching were summarized in Supplementary Table S1. 
One hundred thirty-eight patients who underwent an 
IM were matched with 522 patients with NM based on 
usage of systemic therapy before selection or date of 
IM, delay between primary tumor diagnosis and first 
metastasis, and propensity score quintiles (Table  1). 

8,936 patients with con�rmed 
RCC histology

6,223 did not have 
metastatic disease

2,713 RCC patients with 
a diagnosis of metastasis

760 patients diagnosed
before Jan 1, 2011

1,953 prospective
mRCC

417 patients had 
a metastasectomy

151 incomplete metastasectomy

266 complete metastasectomy 

Study cohort: 1,367 patients having had prior nephrectomy
146 patients with incomplete metastasectomy

1,221 patients with no metastasectomy

1,536 mRCC patients 
did not undergo
metastasectomy

Figure 1: Flowchart Diagram. RCC: renal cell carcinoma. mRCC: metastatic 
renal cell carcinoma 

FIGURE 1. 
Flowchart 

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TABLE 1.

Patient demographics, matched cohort

Incomplete 
metastasectomy 

No metastasectomy 
(matched with incomplete)

P Value

No. patients 138 522

Median age at diagnosis (IQR) 63.5 (56–69) 65 (57–72) 0.1496 a

Over 65 years old at mRCC diagnosis,% 43.5 51.2 0.109

Male, % 79.0 73.6 0.193

Female, % 21.0 26.4

Median follow-up, months (IQR) 26 (16–54) 26 (12–42) 0.058 a

Time between primary tumor to metastasis, median 
(IQR) (months)

14.9 (0–60) 14.3 (1–48) 0.376 a

Over 1 year from primary tumor to metastasis, % 59.2 52.9 0.981

Time between the index dateb and the time of 
matchingc date, median (IQR) (months)

Propensity score quintiles

First 72.5 74.1

0.558Second 24.6 24.3

Third 2.9 1.5

Pathological T-stage at diagnosis, %

T1 25.4 31.7

0.002

T2 16.7 15.5

T3 45.7 48.9

T4 5.8 2.5

Tx 6.5 1.4

Clear cell RCC (yes vs no), % 84.8 82.8 0.579

Synchronous metastasis (yes vs no), % 39.9 40.2 0.936

Metachronous metastasis (yes vs no), % 60.1 59.8

Had a nephrectomy (yes vs no), % 100 100 –

Number of organ sites with metastasis

1 71.0 82.4 0.003

≥ 2 29.0 17.6

First-line systemic treatment  
prior to matching datec (%)

16.7 15.7 0.784

a Wilcoxon two-sample test for medians. b Index date: the date of the first metastasis. c Matching date: the date of incomplete metastasectomy or  
the date of selection. d Patients with multiple locations were counted in all specific locations. e Fisher exact text.

continued on page 86

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All the variables used in the matching were balanced 
after matching the IM group and their respective 
NM patients. After matching, several other features 
remained or were balanced between the 2 groups, such 
as age over 65 years, sex, more than 1 year from primary 
tumor diagnosis and usage of systemic therapy during 
follow-up (Table  1). A significant difference persisted 
among the pathological stages at diagnosis between each 
group. The IM group had a higher percentage of pT2, 
pT4 and pTx, while the NM group had increased pT1 and 
pT3 disease (P = 0.002). More patients received radiation 
treatment in the IM group than in the NM group (56.0 
versus 42%, P = 0.036). The number of organs involved 

by metastasis was also significantly different. In the 
IM group, 71% of patients had a single organ with 
metastases compared with 82.4% of patients in the 
NM group (P =  0.003). More patients in the IM group 
had hypertension (P < 0.001), diabetes mellitus (P< 
0.001), dyslipidemia (P = 0.031), and history of smoking 
(P < 0.001). One-third (33.3%) of patients in the IM had a 
Charlson comorbidity index score over 1 compared with 
50.7% of patients in the NM group (P = 0.004) (Table 1).

The median OS was similar between the IM group 
and their matched NM group (58 months IQR 22 to 
“not reached” [NR]) versus 47 months IQR (18 to NR); 
P = 0.878), respectively (Figure 2A). At 12 months, 81.2% 

TABLE 1.

Patient demographics, matched cohort

Incomplete 
metastasectomy 

No metastasectomy 
(matched with incomplete)

P Value

Sites of metastasis,d %

Lung 41.3 44.6 0.483

Bones 26.8 26.6 0.965

Liver 8.7 6.1 0.283

Brain 5.1 2.3 0.083

Endocrine 15.9 0.04

Systemic treatment during follow-up, %

First-line (ref: yes) 71.1 63.4 0.068

Second-line (ref: yes) 33.0 31.7 0.763

Radiation treatment at index date and  
during follow-up (ref: yes), %

56.0 42.0 0.004

Comorbidities, %

Hypertension (ref: yes) 55.1 35.6 <0.0001

Diabetes (ref: yes) 29.0 13.4 <0.0001

Hypercholesterolemia (ref: yes) 23.9 13.6 0.003

Coronary artery disease 8.0 9.0 0.703

Cardiovascular disease 11.6 8.1 0.190

Smoker (ref: yes) 4.4 0 <0.0001e

Obesity (ref: yes) 3.6 3.3 0.831e

Charlson Score index, % (n = 624)

0 or 1 66.7 49.3
         0.0004

More than 1 33.3 50.7

a Wilcoxon two-sample test for medians. b Index date: the date of the first metastasis. c Matching date: the date of incomplete metastasectomy or  
the date of selection. d Patients with multiple locations were counted in all specific locations. e Fisher exact text.

, Cont’d

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of patients were still alive in the IM group, and 86.2% 
in its matched NM group. The 5-year OS was 48.7% 
versus 42.5%, respectively (Figure 2A). Regarding the 
time to introduction of systemic therapy, no significant 
difference was observed between the IM and the NM 
group (P = 0.327) (Figure 2B).

The multivariate analysis revealed that performing 
an IM was not associated with a survival advantage 
compared with NM (hazard ratio [HR] 0.96, 95% CI 
0.63 to 1.45, P  =  0.836) (Table 2). Clear cell histology 
was not found to be an independent factor associated 
with a decreased risk of mortality compared with other 
histology (HR 0.63, 95% CI 0.38 to 1.041, P  =  0.071). 
When including the Charlson comorbidity index in the 

multivariate analysis, the risk of mortality related to an 
IM remained similar (HR 1.05, 95% CI 0.0.69 to 0.1.60) 
(data not shown). Having a Charlson comorbidity score 
of 0 or 1 versus more than 1, was not associated with a 
reduced risk of death (HR 0.89, 95%CI 0.56 to 1.41).

Stratified analyses by site of metastasis revealed 
that IM in patients with only lung metastases, led 
to improved OS (median OS not reached versus 66 
months in the NM group) (2-year OS 82% versus 68%, 
5-year OS 82% versus 50%, respectively) (P  =  0.026) 
(Figure  3A). IM of bone or endocrine lesions did not 
show a significant difference in survival compared 
with NM (P = 0.849 and P = 0.388, respectively), while 
IM of lymph nodes showed a decreased OS compared 
with NM (median OS 14 months versus NR) (2-year OS 
44.4% versus 73.8%) (Figure 3A). IM of liver and brain 
lesions was not assessed because of the low number of 
events at these sites. Furthermore, analysis performed 
for the time to systemic treatment initiation revealed 
that only IM in patients with lung metastasis resulted 
in a delayed initiation of systemic therapy (median of 
41 months (95% CI 14 to 57) compared with 13 months 
(95% CI 7 to 35) in NM patients) (P = 0.026) (Figure 3B). 
No significant difference was found for bone, lymph 
node or endocrine metastasectomy (P = 0.063, P = 0.149 
and P = 0.701, respectively) (Figure 3B).

While there was no difference in OS observed between 
the IM and NM groups all organ sites combined, the OS 
differed among IM sites (Supplementary Figure 1A). 
Among patients with an IM, those with lung lesions had 
better survival (2-year OS of 86%; 5-year OS of 86%) 
(median not reached) when compared with patients who 
had bone, lymph node, and endocrine metastasis (2-year 
OS 62%, 44% and 76.8%; 5-year OS 35%, NA and 57.6%, 
respectively) (medians 41 months (IQR 11 to 65), 14 
months (IQR 8 to NR), and 61 months (IQR 46 to NR), 
respectively) (P = 0.004) (Supplementary Figure 1A).

Subgroup analysis of IM patients with a single 
organ site involved by metastasis yielded a significant 
difference between groups (P = 0.003) The IM of lung 
lesions had the higher delay to first-line systemic therapy 
initiation when compared to bone, lymph node, and 
endocrine metastasectomy (Supplementary Figure 1B). 
The median time to systemic therapy initiation was  
39 months (IQR 14 to 57) compared with 5 months (IQR  
3 to 19), 8 months (IQR 3 to NA), and 15 months (IQR  
6 to 57), respectively.

Discussion
The role of IM on overall survival in mRCC patients, 
as part of a multimodal treatment approach, is limited. 
IM continues to be performed, however, mainly for 
palliative reasons. Also, IM and stereotactic body 
radiation therapy are being increasingly used for 

FIGURE 2.FIGURE 2A.

Overall survival for patients with IM vs NM all organ 
sites combined (matched cohort)

FIGURE 2B.

Overall survival for patients with IM vs NM all organ 
sites combined (matched cohort)

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oligoprogression. In our cohort, 10.7% of patients 
underwent an IM, a rate comparable to those found in 
other studies (range 9% to 19%)[7,11–13]. The median 
age of patients at the time of metastasis is also similar 
to that in other studies (61 to 65 years old)[14,15]. In 
addition, our analysis consisted of primarily clear 
cell histology (84.8%), which is similar to the findings 
of previous studies (80% to 93.8%)[7,16,17]. After 
matching, most clinicopathologic characteristics were 
similar between the 2 groups, with the exception of 
pathological T-stage, number of organ sites involved 
by metastasis, and comorbidities. More patients had 2 
and more organ sites involved by metastasis in the IM 
than the NM. Additionally, patients having undergone 
IM had more comorbidities than NM patients; however, 
Charlson score favored the IM group. This finding may 
reflect the existence of poorly controlled or more severe 

comorbidities in the NM group, resulting in healthier 
patients being selected for surgery. However, when 
adjusting for the Charlson comorbidity index, the HR 
of IM versus NM remained the same, and this was not 
found to be an independent factor associated to the 
survival in this population.

Our survival analysis showed that there was no 
significant difference in OS among patients who had 
undergone IM compared with those who had not 
(P = 0.8). Our results are comparable to those of other 
studies in which IM had no OS advantage over NM. 
As stated before, You et al. reported comparable OS 
medians of 29.6 versus 23.5 months ([95% CI 15.4 
to 43.8 months], and [95% CI 18.9 to 28.1 months], 
respectively) for IM and NM, respectively[12]. In 
addition, Yu and colleagues also reported in a single-
center retrospective study of patients undergoing IM, 

TABLE 2.

Cox regression model incomplete metastasectomy versus no metastasectomy

Variables
Univariate
HR (95%CI)

P Value Multivariate
HR (95%CI)

P Value

N (metastasectomy vs. no metastasectomy) 138 vs. 522 – 138 vs. 522 –

Had a metastasectomy 1.03 (0.71–1.51) 0.868 0.96 (0.63–1.45) 0.836

Male (ref: female) 0.90 (0.62–1.31) 0.580 0.92 (0.62–1.38) 0.686

Systemic therapy during follow-up  
(time-dependent variable) (ref: yes)

0.87 (0.57–1.35) 0.545 0.91 (0.56–1.46) 0.685

Age (ref: ≥ 65 years) 1.42 (1.01–2.00) 0.044 1.39  (0.96–2.02) 0.079

Clear cell renal cell carcinoma (ref: yes) 0.62 (0.39–0.97) 0.038 0.63 (0.38–1.04) 0.071

Bones metastasis (ref: yes) 1.76 (0.88–3.54) 0.110 1.58  (0.67–3.77) 0.299

Liver metastasis (ref: yes) 1.18 (0.60–2.32) 0.634 1.59 (0.70–3.62) 0.2699

Lung metastasis (ref: yes) 1.12 (0.73–1.71) 0.616 1.52 (0.84–2.73) 0.165

Brain metastasis (ref: yes) 0.98 (0.22–4.36) 0.977 0.84 (0.15–4.68) 0.8399

Lymph node metastasis (ref: yes) 1.41 (0.75–2.65) 0.281 1.72 (0.86–3.41) 0.0.124

Endocrine metastasis (ref: yes) 1.24 (0.61–2.50) 0.554 1.40 (0.66–2.98) 0.381

More than 1 location of tumor (ref: 1 location) 1.22 (0.80–1.84) 0.359 0.79 (0.39–1.60) 0.513

Radiation therapy (time-dependent variable) (ref: yes) 1.51 (1.01–2.25) 0.05 1.49 (0.96–2.3) 0.076

Ref: reference.

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similar OS among IM and NM with median OS of 16 
months versus 22 months (95% CI 9.5 to 22.5 and 17.6 to 
26.4, respectively)[7]. In contrast, our recent study using 
the CKCis database found a significant improvement in 
OS all-sites combined when CM was compared to NM 
(median OS 82 months [95% CI 80 to NR] versus 66 
months [95% CI 60 to NR], respectively [P = 0.001])[10]. 
Although no difference in survival was shown among 
all metastasectomy sites combined, the risk of death 
among different IM sites is not similar. Patients with 
lung and endocrine IM experienced longer survival rates 
than those with bone and lymph node IM. However, 
in our subgroup analyses comparing each site to their 
matched NM, only lung IM was associated with better 
OS. In fact, lung IM had a 5-year OS of 82% compared 
with 50.4% without surgical resection. These results are 
similar to what was previously reported in the literature 
for CM (range 75% to 83.3%)[18,19]. Site-specific 
survival analyses were not conducted in previous 

studies evaluating IM[7,8,12]. From what is reported in 
the literature, lymph nodes, both regional and distant, 
represent 15% of sites of metastatic recurrences of 
RCC[20]. In our study, survival was worsened in patients 
with incomplete lymphadenectomy when compared 
with patients without surgical resection (P  =  0.024). 
Yet this finding should be interpreted with caution, as 
this analysis is likely underpowered to assess the role 
of IM on lymph node metastasis since only 9 patients 
received an incomplete resection of lymph nodes, and 
no multivariate analysis was possible. Additionally, 
lymphadenectomy is often done in conjunction with 
organ metastasectomy. Our study confirmed that there 
is no benefit for OS when single or multiple metastatic 
sites are incompletely resected. Therefore, the role of 
lymphadenectomy is limited and should not be part 
of a multi-site IM. Analysis of liver and brain IM was 
inadequate because of the small number of cases present 
in our registry (8.7% and 5.1%, respectively). As for 

FIGURE 3A.

Overall survival for patients with IM vs NM all organ sites combined (matched cohort)

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endocrine IM, our results confirmed the absence of 
survival benefits (P = 0.388). Kavolius et al. previously 
demonstrated that among patients undergoing CM, 
those with isolated endocrine disease (pancreas, adrenal, 
ovary, thyroid, and salivary gland) exhibited the most 
favorable prognosis with a 5-year OS of 63%[9]. However, 
the benefit was only in patients who received a CM and 
not in those who had an IM or NM.

This study is the first to demonstrate significantly 
delayed mean time to introduction of first-line systemic 
therapy (28 months delay in this study) compared with 
NM. Therefore, when lung lesions represent the only site 
of metastasis, there may be a benefit of partial resection 
of metastasis on survival and time to systemic therapy. 
Given that lungs are the most common organ site for 
metastasis in renal cell carcinoma, one can speculate 
that the indication for metastasectomy included a higher 
proportion of patients with oligoprogression when 

compared with other sites[21]. Metastasectomy at other 
organ sites, such as bone or brain metastasectomy, may 
have been performed at a higher proportion for palliative 
measures such as for pathological fractures or seizures. 
Unfortunately, it is impossible to confirm this hypothesis 
through the CKCis database, which constitutes a 
limitation of our study. While stereotactic body radiation 
therapy is mainly used in the contemporary era, surgery 
may represent one treatment modality for such lesions. 
It is important to note that patients undergoing IM had 
a higher burden of metastasis and more comorbidities 
than patients without surgical resection, and despite this, 
a survival benefit was still evident in subgroup analyses. 
Incomplete metastasectomy could not be categorized 
according to the extent of metastasis resected due to the 
unavailability of this information.

The main limitation of our study arises from its 
retrospective nature. Also a selection bias may have 

FIGURE 3B.

Time to first line systemic treatment for patients with IM vs NM by metastatic location (matched cohort)

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occurred with respect to the patient’s characteristics. 
Indeed, patients with a worse general condition may 
have been deemed unfit for surgery and were selected 
in the NM group. We performed a propensity score 
analysis along with matching analysis to address 
this limitation. Propensity score estimation was 
carried for variables such as age, sites and number of 
metastases, disease synchronicity, and histology, and 
each patient undergoing incomplete surgical resection 
was matched with up to 4 patients among those who 
did not have a metastasectomy for variables deemed 
associated with treatment choice, including prior use 
of systemic therapy. This analysis allowed us to balance 
these clinicopathologic variables and drastically limit 
selection bias. With the exception of the number organs 
involved by metastasis, all were balanced in the final 
cohort. Interestingly, patients in the IM group had a 
higher percentage of patients with 2 or more organ sites 
involved than did the NM group. Additionally, patients 
in the IM group had a higher rate of hypertension, 
diabetes, and hypercholesterolemia, and were more 
likely to be smokers. Therefore, despite having more 
comorbidities and a higher disease burden, a significant 
improvement in OS and delay to introduction of systemic 
therapy was obtained for lung IM. Unfortunately, 
no multivariate analysis was possible because of the 
limited number of patients in the analysis stratified by 
metastasis location. Our results show potential benefits 
of IM for lung metastasis only, compared with NM; 
however, our multivariate analysis found that having a 
lung metastasis was not a predictive factor for OS when 
compared with other metastasis location. Furthermore, 
a better survival was observed for patients receiving IM 
for lung metastasis only in comparison with IM for other 
single metastasis locations such as endocrine, lymph 
nodes, and bones. Again, the small number of patients 
in each group made impossible a multivariate analysis 

or another alternative method, ie, matching strategy. 
Another limitation is the lack of quality of life (QoL) 
assessment post-metastasectomy. IM may negatively 
affect patient’s QoL, especially when performed in a non-
palliative setting. Future comparative trials for different 
modalities for metastasectomy such as stereotactic body 
radiation therapy versus surgery versus cryotherapy may 
shed more light on not only potential survival benefits 
of one modality compared with the other, but also on 
improvement in patients’ QoL. Lastly, the patients’ list 
of medications was unavailable. Some medications, 
such as metformin or angiotensin converting enzyme 
inhibitors, may alter survival in metastatic renal cell 
carcinoma patients[22,23].

One of the main strengths of our analysis is the 
multicenter prospective registry: our study included 138 
patients treated in 16 different hospitals across the country, 
making this study one of the largest studies on IM.

Conclusion
Our study indicates that the benefit of IM on OS for 
mRCC patients is limited. Incomplete resection of 
lung metastasis shows a potential improvement in OS 
and delayed time to introduction of systemic therapy 
when lungs are the sole location of metastatic disease. 
Outside this indication, IM is not associated with a 
survival benefit, but may have a role in select patients 
for symptom relief or palliation. In addition, survival 
of patients receiving IM varies depending on the 
metastasectomy site, with the highest value observed 
for singular lung metastasis. Although groups were 
matched by propensity score on important measured 
covariates, some unmeasured confounders may have 
existed and may have impacted the survival benefit of 
lung IM in this analysis. Future randomized controlled 
trials are required to shed more light onto the role of IM.

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continued on page 94

SUPPLEMENTARY TABLE S1. 

Patient characteristics, unmatched cohort

Variable Incomplete Metastasectomy No Metastasectomy P Value

No. patients 146 1221

Median age at diagnosis (IQR) 63.5 (56–69) 64 (56–72) 0.002a

Over 65 years old at diagnosis (yes vs no), % 42.5 48.7 0.152

Male, % 78.8 73.5
0.167

Female, % 21.2 26.5

Median follow-up, months (IQR) 26.5 (16–54) 19 (9–36) <0.0001a 

Time from primary tumor to metastasis,  
median, months (IQR)a

13.0 (0–56) 4.8 (0–22) <0.0001a 

Over 1 year from primary tumor to metastasis, % 50.7 33.3 <0.001

Pathological T-stage, %

T1 24.7 16.5

0.0004

T2 15.8 12.7

T3 48.0 62.4

T4 5.5 6.6

Tx 6.2 1.9

Clear cell RCC (ref: yes), % 83.6 81.1 0.467

Synchronous metastasis (ref: yes), % 39.0 44.9
0.179

Metachronous metastasis (ref: yes), % 61.0 55.1

Had a nephrectomy (ref: yes), % 100 100 –

Location of metastasectomyb, % 

Lung 19.9 – –

Bone 29.5 – –

Liver 2.7 – –

Brain 14.4 – –

Lymph node 10.3 – –

Endocrine 13.0 – –

Number of organs with metastasis, %

a Wilcoxon rank-sum test. b Patients with multiple locations were counted in all specific locations; the total can exceed 100%. c Fisher exact text.

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SUPPLEMENTARY TABLE S1. 

Patient characteristics, unmatched cohort

Variable Incomplete Metastasectomy No Metastasectomy P Value

1 72.6 68.4 0.299

≥ 2 27.4 31.6

Metastasis locationb, %

Lung 39.0 54.7 0.0003

Bones 27.4 15.7 0.0004

Liver 8.2 9.8 0.554c

Brain 7.5 1.5 <0.0001c

Lymph nodes 16.4 27.9 0.003

Endocrine 15.1 13.3 0.55c

Systemic treatment during follow-up, %

First-line 71.2 73.5 0.565

Second-line 33.7 30.1 0.456

Radiation therapy at index date and during follow-up, % 57.5 36.3 <0.0001

Number of metastasectomy, %

1 82.2 –
0.587

≥ 2 17.8 –

Comorbidities, %

Hypertension (ref: yes) 54.1 52.0 0.631

Diabetes (ref: yes) 28.1 21.5 0.069

Hypercholesterolemia (ref: yes) 24.0 19.7 0.219

Coronary artery disease (ref: yes) 7.5 10.7 0.243

Cardiovascular disease (ref: yes) 11.0 9.3 0.506

Smoker (ref: yes) 4.8 4.1 0.689c

Obesity (ref: yes) 3.4 3.8 0.836c

Charlson Score Index, % N = 1374

0 or 1 67.7 50.2
0.0001

More than 1 32.3 49.8

Propensity score quintiles

First 69.2 87.5

<0.0001
Second 25.3 11.6

Third 5.5 0.9

Fourth – –

a Wilcoxon rank-sum test. b Patients with multiple locations were counted in all specific locations; the total can exceed 100%. c Fisher exact text.

, Cont’d

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1.0 

0.8 

0.6 

0.4 

0.2 

0.0 

0 

Glandular
LN

bones
lung

22
9

24
31 23

15
5

17

18
12
2

10

15
9
0

9

11
7

7

8
5

3

3
2

2

1
0

0

+ Censored
Logrank p = 0.0263

Su
rv

iv
al

 P
ro

ba
bi

lit
y

20 40 60 60 

metastasectomy site

time (months)

Endocrine LN bones lung

1.0 

0.8 

0.6 

0.4 

0.2 

0.0 

0 

Glandular
LN

bones
lung

22
9

24
31 23

7
3

12

12
3
2

6

12
2
0

4

6
1

4

3
1

3

2
0

0

0

+ Censored

Su
rv

iv
al

 P
ro

ba
bi

lit
y

20 40 60 60 

metastasectomy site

           time to 1st targeted treatment (months)

Endocrine LN bones lung

Logrank p = 0.0032

SUPPLEMENTARY FIGURE 1A.

Overall survival for patients with IM by  
metastasectomy site

SUPPLEMENTARY FIGURE 1B.

Time to first line systemic treatment for patients  
with IM by metastasectomy

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