EUROPEAN UROLOGY 60 (2011) 11521159

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Platinum Priority Kidney Cancer

Editorial by Simon P. Kim and R. Houston Thompson on pp. 11601162 of this issue

A Stage-for-Stage and Grade-for-Grade Analysis of Cancer-Specific

Mortality Rates in Renal Cell Carcinoma According to Age:
A Competing-Risks Regression Analysis
Maxine Sun a,y,*, Firas Abdollah b,y, Marco Bianchi a,b, Quoc-Dien Trinh a,c, Claudio Jeldres a,d,
Zhe Tian a, Shahrokh F. Shariat e, Hugues Widmer d, Kevin Zorn d, Mani Menon c,
Francesco Montorsi b, Paul Perrotte d, Pierre I. Karakiewicz a,d
a

Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Canada; b Department of Urology, Vita Salute San Raffaele

University, Milan, Italy; c Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI, USA; d Department of Urology, University of Montreal Health
Center, Montreal, Canada; e Department of Urology, Weill Medical College, Cornell University, New York, NY, USA

Article info

Abstract

Article history:
Accepted July 27, 2011
Published online ahead of
print on August 5, 2011

Background: The association of advanced age and cancer control outcomes shows
discordant findings.
Objective: To evaluate the effect of age on cancer control outcomes in a large population-based cohort of patients diagnosed with renal cell carcinoma (RCC) of all stages.
Design, setting, and participants: Using the Surveillance Epidemiology and End Results
database, 36 333 patients with RCC were identied. The population was stratied
according to age: < 50, 5059, 6069, 7079, and 80 yr. The effect of age on cancer
control outcomes was evaluated using competing-risks regression models. Analyses
were repeated stage for stage and grade for grade.
Measurements: Cancer-specic mortality (CSM) was measured.
Results and limitations: Age categories 5059, 6069, 7079, and 80 yr respectively
portended a 1.4-, 1.5-, 1.6-, and 1.9-fold higher risk of CSM than age category <50 yr (all p <
0.001). The effect of advanced age was particularly detrimental in patients with stage I
disease: 1.8-, 2.3-, 3.2-, and 3.8-fold higher CSM risk for the same age groups, respectively
(all p < 0.001). The effect of age on CSM was at its peak in patients with stage I, low-grade
RCC (1.6-, 2.2-, 3.6-, and 4.3-fold, respectively; all p < 0.001) and remained elevated in
stage I, high-grade RCC (2.2-, 2.6-, 2.4-, and 3.0-fold higher, respectively; all p < 0.05).
Conversely, its effect was virtually absent in patients with stage IIIV RCC.
Conclusions: Our data suggest that stage I RCC may behave in a more aggressive fashion
in elderly patients. Further studies are required to conrm the current ndings.
Crown Copyright # 2011 Published by Elsevier B.V. on behalf of European Association of
Urology. All rights reserved.

Keywords:
Renal cell carcinoma
Age
Cancer-specific mortality
Nephrectomy
Competing-risks regression

y
Both authors contributed equally to the manuscript.
* Corresponding author. Cancer Prognostics and Health Outcomes Unit, CHUM, 1058 rue St-Denis,
Montreal, QC, H2X 3J4, Canada. Tel. +1 514 890 8000 ext 35335; Fax: +1 514 227 5103.
E-mail address: mcw.sun@umontreal.ca (M. Sun).

1.

Introduction

The incidence of renal cell carcinoma (RCC) continues to

increase [1]. In the United States, approximately 53 581 new
cases were diagnosed in 2010 [2]. Despite the innovations in
the treatment management of RCC in recent years,

mortality rates have continued to rise [1,3]. It is known

that the majority of newly diagnosed RCC patients are aged
6069 or 7079 yr. Given that the average life expectancy
has steadily increased in the United States [4], it may be
expected that more elderly patients will be diagnosed with
RCC in the upcoming years.

0302-2838/$ see back matter Crown Copyright # 2011 Published by Elsevier B.V. on behalf of European Association of Urology. All rights reserved.

doi:10.1016/j.eururo.2011.07.064

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EUROPEAN UROLOGY 60 (2011) 11521159

As with several other urologic malignancies, age represents an independent prognostic factor of worse survival in
patients with RCC [510]. In a pertinent study, Hollingsworth
et al. [10] examined the Surveillance Epidemiology and End
Results (SEER) database to evaluate cancer-specific mortality
(CSM) in patients according to age groups. Within that study,
only surgically managed localized and regional RCC patients
were included. The authors recorded an increasing risk of
CSM with more advanced age in a univariable analysis. That
being said, the effect of age was not examined with
adjustment for other important tumor characteristics, such
as stage and grade.
The current study has several objectives. First, we
examined RCC patients according to different age decades.
Second, we sought to perform a stage-for-stage and grade-forgrade analysis of CSM rates according to age groups. Finally,
since a large proportion of elderly patients may die of causes
other than cancer, we used competing-risks methodology to
account for this potential confounder in all our analyses.
2.

Materials and methods

2.1.

Data source

collects patient demographics and publishes cancer incidence and

survival data from population-based cancer registries, covering approximately 26% of the US population. Data from 1988 to 2006 from 17 SEER
registries were abstracted.

2.2.

Study population

Individuals with histologically conrmed RCC were identied using the

International Classication of Diseases for Oncology [ICD-O] (C67.0, C.67.9).
Patients <25 yr were removed from the analysis. All autopsy or death
certicate cases were excluded from the current study. Only patients with
the main histologic subtypes (clear cell, papillary, chromophobe) were
included. Patients with missing tumor (T) or node (N) stage information
were removed as well as patients with no information on distant metastasis
status. This method resulted in a total of 36 333 RCC patients of all stages.

2.3.

Description of covariates

Patient age at diagnosis was classied according to decades, similar to a

previous study: <50, 5059, 6069, 7079, and 80 yr [10]. Other patient
characteristics include race (white, black, other) and year of diagnosis
tertiles (19882001, 20022004, 20052006). Treatment type was
categorized as patients who were surgically managed (partial nephrectomy
[PN] vs radical nephrectomy [RN]) or patients for whom surgery was not
recommended. The latter categorization was identied via the absence of a
concomitant code for RN or PN. Several clinical and pathologic
characteristics were available within the SEER database, namely, tumor

The SEER program database, as reported by the US National Cancer

size (continuously coded), histologic subtype (clear cell, papillary,

Institute, was used to identify the study population. The SEER program

chromophobe), and Fuhrman grade (low grade [III], high grade [IIIIV]).

Table 1 Descriptive characteristics of 36 333 patients with renal cell carcinoma, Surveillance Epidemiology and End Results, 19882006
Variable
Gender
Male
Female
Race
White
Black
Other
Surgery type
Radical nephrectomy
Partial nephrectomy
Nonsurgical management
Histologic subtype
Clear cell
Chromophobe
Papillary
Tumor grade
III
IIIIV
T stage
T1
T2
T3
T4
N stage
N0
N12
M stage
M0
M1
AJCC stage
I
II
III
IV

<50 yr (n = 6603)

5059 yr (n = 8922)

6069 yr (n = 9877)

7079 yr (n = 8294)

>80 yr (n = 2637)

4122 (62.5)
2481 (37.6)

5908 (66.2)
3114 (34.9)

6342 (64.2)
3535 (35.8)

4988 (60.1)
3306 (39.9)

1458 (55.3)
1179 (44.7)

5407 (81.9)
741 (11.2)
455 (6.9)

7398 (82.9)
980 (11.0)
544 (6.1)

8398 (85.0)
875 (8.9)
604 (6.1)

7231 (87.2)
573 (6.9)
490 (5.9)

2370 (89.9)
139 (5.3)
128 (4.9)

5257 (79.6)
1287 (19.5)
59 (0.9)

7326 (82.1)
1504 (16.9)
92 (1.0)

8132 (82.3)
1619 (16.4)
126 (1.3)

7064 (85.2)
1071 (12.9)
159 (1.9)

2284 (86.6)
238 (9.0)
115 (4.4)

5841 (88.5)
276 (4.2)
486 (7.4)

7906 (88.6)
256 (2.9)
760 (8.5)

8732 (88.4)
248 (2.5)
897 (9.1)

7335 (88.4)
225 (2.7)
734 (8.8)

2273 (86.2)
102 (3.9)
262 (9.9)

4943 (74.9)
1660 (25.1)

6338 (71.0)
2584 (29.0)

7051 (71.4)
2826 (28.6)

5895 (71.1)
2399 (28.9)

1825 (69.2)
812 (30.8)

4464
1139
943
57

5729
1348
1753
92

6334
1276
2148
119

5339
963
1896
96

1608
313
678
38

p value
<0.001

<0.001

<0.001

<0.001

<0.001

<0.001
(67.6)
(17.2)
(14.3)
(0.9)

(64.2)
(15.1)
(19.6)
(1.0)

(64.1)
(12.9)
(21.7)
(1.2)

(64.4)
(11.6)
(22.9)
(1.2)

(61.0)
(11.9)
(25.7)
(1.4)
0.003

6357 (96.3)
246 (3.7)

8594 (96.3)
328 (3.7)

9484 (96.0)
393 (4.0)

8050 (97.1)
244 (2.9)

2530 (95.9)
107 (4.1)

6443 (97.6)
160 (2.4)

8572 (96.1)
350 (3.9)

9543 (96.6)
334 (3.4)

8100 (97.7)
194 (2.3)

2578 (97.8)
59 (2.2)

4408
1077
752
366

5639
1238
1417
628

6247
1184
1753
693

5258
902
1683
451

1574
295
597
171

<0.001

<0.001
(66.8)
(16.3)
(11.4)
(5.5)

(63.2)
(13.9)
(15.9)
(7.0)

T = tumor; N = node; M = metastasis; AJCC = American Joint Committee on Cancer.

(63.2)
(12.0)
(17.7)
(7.0)

(63.4)
(10.9)
(20.3)
(5.4)

(59.7)
(11.2)
(22.6)
(6.5)

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EUROPEAN UROLOGY 60 (2011) 11521159

The TNM 2002 staging system was used to classify patients according to the
American Joint Cancer Committee (AJCC) stages: I (T1N0M0), II (T2N0M0),
III (T13N01M0), and IV (T4N01M01) [11].
The cause of death was dened according to the SEER-specic cause
of death code (29010). Deaths from RCC were coded as CSM events. All
other deaths were considered as other-cause mortality (OCM).

2.4.

Statistical analysis

Frequencies and proportions were generated for categorical variables.

We relied on the competing-risks regression methodology to assess CSM,
as described by Fine and Gray [12]. The latter accounts for the effect of
OCM and provides the most unbiased estimates of CSM. Age-stratied
cumulative incidence CSM rates were generated for different groups
and compared with the Gray test [13]. Subsequently, univariable and
multivariable competing-risks regression models were used to test the
effect of age (at <50, 5059, 6069, 7079, and 80 yr) on CSM rates.
Covariates included gender, race, year of diagnosis, tumor size, histologic
subtype, AJCC stage, and Fuhrman grade. To assess the magnitude of the
effect related to age, we repeated all multivariable competing-risks
regression models after stratifying according to AJCC stage (stages I, II, III,
and IV) and tumor grade (III vs IIIIV). Finally, to reduce the bias
associated with pathologic staging data, the aforementioned analyses
were repeated within patients who underwent RN. Prior to tting the
competing-risks models, the proportional cause-specic hazards
assumption, the proportionality of the hazards of the cumulative incidence
function assumption, and the linearity assumption were tested [14].
All statistical tests were performed using the R statistical package
(v.2.12.2) or SPSS (Chicago, IL, USA). Finally, all tests were two-sided,
with a signicance level set at p < 0.05.

3.

Results

Overall, 36 333 RCC patients were identified between 1988

and 2006 (Table 1). Several baseline characteristics differed
according to age groups. For example, more females were

aged 80 yr relative to those aged <50 yr (45% vs 38%; odds

ratio [OR]: 1.35; p < 0.001). A lower proportion of black race
was recorded in persons aged 80 yr (5% vs 11%; OR: 0.44; p
< 0.001). Patients of different age groups also differed
according to clinical and pathologic characteristics. In
general, patients aged 80 yr had a more advanced T stage
than patients aged <50 yr (T4: 1.4% vs 0.9%; OR: 1.68;
p = 0.01), a higher proportion of node-positive patients
(4.1% vs 3.7%; OR: 1.1; p = 0.5), and more advanced Fuhrman
grade (IIIIV: 31% vs 25%; OR: 1.33; p < 0.001). Patients aged
5059 yr had a higher rate of distant metastasis than
patients aged <50 yr (3.4% vs 2.9%; OR: 1.6; p < 0.001).
The number of deaths from CSM and OCM for the entire
cohort, stratified according to age group and disease stage,
is illustrated in Table 2. The overall respective 5- and 10-yr
CSM rates, after accounting for OCM, were 8.7% and 12.5%
for patients aged <50, 12.4% and 18.7% for patients aged 50
59, 13.2% and 20.7% for patients aged 6069, 14.8% and
23.9% for patients aged 7079, and 18.0% and 26.2% for
patients aged 80 yr (all p < 0.001, Fig. 1). When cumulative incidence CSM rates were stratified according to AJCC
stage, older age continuously portended to higher CSM rates
than their younger counterparts (data not shown).
The multivariable age-specific hazard ratios (HRs)
predicting CSM in the entire cohort and stratified according
to AJCC stage are depicted in Figure 2A2E. Patients aged
5059, 6069, 7079, and 80 yr demonstrated a higher
rate of CSM than their counterparts aged <50 yr (HR: 1.4,
1.5, 1.6, and 1.9, respectively; all p < 0.001), even after
accounting for OCM (Fig. 2A). The risk of CSM was 1.8-, 2.3-,
3.2-, and 3.8-fold higher, respectively, for the same age
groups within stage I RCC (all p < 0.001; Fig. 2B); 1.4-, 1.4-,
1.6-, and 1.5-fold higher, respectively, for stage II RCC (all

Table 2 Cause-of-death information within the entire population and stratified according to age group and renal cell carcinoma stage
Overall

<50 yr

5059 yr

6069 yr

7079 yr

80 yr

Entire cohort
Patients, no.
Total deaths, no.
Renal cell carcinoma
Other-cause mortality

36 333
8210
3565
4645

6603
750
459
291

8922
1421
844
577

9877
2265
1006
1259

8294
2667
923
1744

2637
1107
333
774

Stage I
Patients, no.
Total deaths, no.
Renal cell carcinoma
Other-cause mortality

23 126
3801
807
2994

4408
255
65
190

5639
527
154
373

6247
1048
220
828

5258
1396
272
1124

1574
575
96
479

Stage II
Patients, no.
Total deaths, no.
Renal cell carcinoma
Other-cause mortality

4696
1058
534
524

1077
142
101
41

1238
216
143
73

1184
280
135
145

902
297
120
177

295
123
35
88

Stage III
Patients, no.
Total deaths, no.
Renal cell carcinoma
Other-cause mortality

6202
2069
1170
899

752
169
134
35

1417
364
266
98

1753
543
322
221

1683
705
335
370

597
288
113
175

Stage IV
Patients, no.
Total deaths, no.
Renal cell carcinoma
Other-cause mortality

2309
1282
1054
228

366
184
159
25

628
314
281
33

693
394
329
65

451
269
196
73

171
121
89
32

EUROPEAN UROLOGY 60 (2011) 11521159

[(Fig._1)TD$IG]

1155

Fig. 1 Cumulative incidence plot depicting cancer-specific mortality (CSM) rates, stratified according to age categories (all Gray test p < 0.001) for (A) the
entire population and for (B) stage I, (C) stage II, (D) stage III, and (E) stage IV renal cell carcinoma.

p < 0.05; Fig. 2C); 1.1-, 1.1-, 1.3-, and 1.4-fold higher for
stage III RCC (all p < 0.05, except for ages 6069 and 50
59 yr; Fig. 2D); and 1.2-, 1.2-, 1.1-, and 1.4-fold higher
respectively, for stage IV RCC (all p < 0.05, except for ages
5059 and 7070 yr; Fig. 2E). Similar findings were
recorded in two subanalyses of patients with T1aN0M0
and T14N0M0 RCC. Specifically, the risk of CSM for the two
groups was 1.5-, 3.0-, 4.8-, and 8.5-fold and 1.4-, 1.5-, 1.8-,
and 2.1-fold higher in patients aged 5059, 6069, 7079,
and 80 yr, respectively (all p < 0.001).
Figure 3A3J illustrates the stage-for-stage and gradefor-grade age-specific HRs predicting CSM. Regardless of
stage, more advanced age portended to higher CSM among
patients with low- and high-grade disease. For example,
relative to patients aged <50 yr, the risk of CSM was 1.4-,
1.6-, 2.1-, and 2.4-fold higher in patients with low-grade
RCC, aged 6069, 7079, and 80 yr, respectively (all
p < 0.001; Fig. 3A). Similarly, in patients with high-grade
RCC, the respective HRs for the same age groups were 1.3,
1.3, 1.4, and 1.5, respectively (all p < 0.001, Fig. 3B). Within
stage I, low-grade RCC (HR: 1.6, 2.2, 3.6, and 4.3) and highgrade RCC (HR: 2.2, 2.6, 2.4, and 3.0), more advanced age
portended to higher CSM rates (all p  0.001; Fig. 3C and
3D). In stage II, more advanced age demonstrated significantly worse survival only in low-grade RCC (Fig. 3E). In all
other stage and grade combinations, age failed to reach
independent predictor status (Fig. 3G3J). In a subanalysis
of patients treated with RN, virtually the same results were
recorded (Fig. 4).

4.

Discussion

Our objective was to examine the effect of age on CSM in

patients with RCC of all stages, regardless of the treatment
modality and after accounting for OCM. To date, the effect
of age has never been studied using this type of appraisal.
Previous age analyses were invariably performed on highly
select patient subsets, in which the inclusion criteria relied
on disease stage or treatment type, or both. These
limitations undermined the generalizability of the findings. Most important, no study assessed the effect of age in
a stage-for-stage and grade-for-grade fashion. In the
current analysis, we attempted to circumvent these
limitations. We included surgically and nonsurgically
managed patients, as well as all disease stages. Finally,
we used multivariable time-to-event modeling that
controlled for other competing events. This consideration
is essential in analyses addressing age, since a large
proportion of elderly patients may succumb to OCM,
which may critically confound the results.
Our results first focused on the entire patient cohort.
Subsequently, the data were stratified according to AJCC
stage and tumor grade. Finally, the stratified analyses were
repeated exclusively on patients treated with RN. The
overall results showed that more advanced patient age
predisposes to higher CSM rates, even after adjusting for all
covariates, including that of OCM. Stage-specific analyses
showed that the most substantial effect of advanced age on
CSM was observed in individuals with stage I RCC.

[(Fig._2)TD$IG]

1156

EUROPEAN UROLOGY 60 (2011) 11521159

Fig. 2 Multivariable competing-risks regression predicting cancerspecific mortality (CSM) in patients with renal cell carcinoma of (A) all
stages, (B) stage I, (C) stage II, (D) stage III, and (E) stage IV, stratified
according to age categories. The x-axes denote the hazard ratios. The yaxes denote the age categories. The referent (ref.) category is patients
aged <50 yr (hazard ratio: 1.0) across all examined subcohorts. The 95%
confidence intervals are represented for each category.

Furthermore, the effect of age was stronger in patients with

low-grade RCC, regardless of stage. In other stages, the
effect was substantially less. That being said, the effect of
advanced age, although statistically significantly associated
with worse survival, may be less pronounced in patients
with stage III or IV RCC given the aggressive nature of the
disease, beyond that of stage and grade, in younger patients,
as was recently examined [15].

[(Fig._3)TD$IG]

Fig. 3 Multivariable competing-risks regression predicting cancerspecific mortality (CSM) in patients with renal cell carcinoma of all
stages, stage I, stage II, stage III, and stage IV, stratified according to low
grade (III) and high grade (IIIIV). The x-axes denote the hazard ratios.
The y-axes denote the age categories. The referent (ref.) category is
patients aged <50 yr (hazard ratio: 1.0) across all examined subcohorts.
The 95% confidence intervals are represented for each category.

Further stage-for-stage and grade-for-grade substratification revealed interesting findings. Specifically, the effect
of advanced age in stage I patients is most prominent among
individuals with low-grade tumors. It may be postulated
that the detrimental effect of advanced age in individuals
with low-grade disease was largely attributable to patients
who were nonsurgically managed. Unfortunately, because

EUROPEAN UROLOGY 60 (2011) 11521159

[(Fig._4)TD$IG]

Fig. 4 Multivariable competing-risks regression predicting cancerspecific mortality (CSM) in patients treated with radical nephrectomy for
renal cell carcinoma of all stages, stage I, stage II, stage III, and stage IV,
stratified according to low grade (III) and high grade (IIIIV). The x-axes
denote the hazard ratios. The y-axes denote the age categories. The
referent (ref.) category is patients aged <50 yr (hazard ratio: 1.0) across
all examined subcohorts. The 95% confidence intervals are represented
for each category.

of the low number of cases within the current cohort, we

were unable to examine the effect of CSM in exclusively
nonsurgically managed patients. Nonetheless, the detrimental effect of more advanced age remained highly
important in surgically managed individuals with stage I
low-grade tumors.
Taken together, these data imply that the effect of more
advanced age on CSM is particularly important in patients
with stage I RCC and/or low-grade tumors. In contrast, the
effect of age becomes secondary to disease characteristics in
patients with tumors of more advanced stage (stage IIIV)
and/or high grade (IIIIV). These findings are particularly

1157

important given the rising incidence of localized RCC and

increasing life expectancy of the population [16].
Several explanations may be proposed as to why the
prognosis of elderly patients with low-stage and low-grade
disease is significantly worse than that of their younger
counterparts. First, the natural history of RCC may be more
aggressive in the elderly. Second, elderly patients may be
subject to a delay in treatment and suboptimal follow-up
after diagnosis, particularly in the context of small renal
masses, for which elderly patients may be more likely to be
investigated or treated in a less timely fashion. Third, health
insurance provider differences between elderly and younger patients may exist. Specifically, younger patients may
be subject to periodic health examinations, whereas retired
individuals may undergo less routine examinations. That
said, given that the SEER database does not contain any
information on tumor characteristics beyond stage and
grade, and given that we did not have the time interval
between diagnosis and treatment or health insurance
information, the explanations proposed remain speculative.
Furthermore, from a practical perspective, the current
data suggest that active surveillance may not always be
suitable in the elderly with stage I RCC, regardless of the grade
of the tumor. This observation contradicts existing North
American guidelines, in which older age is considered as a
condition allowing less aggressive treatment management
[17,18]. In contrast, the most up-to-date European guidelines
do not account for the effect of age on prognosis in patients
with RCC [19]. Currently, the rationale for active surveillance
derives from the hypothesis that surgical intervention for
small renal masses may not confer a survival advantage in
elderly patients. For example, the Cleveland Clinic Foundation demonstrated a lack of survival benefit of both PN (HR:
0.67; 95% CI, 0.421.05) and RN (HR: 0.75; 95% CI, 0.451.26)
relative to active surveillance in patients aged 75 yr
( p = 0.2) [20]. Moreover, the majority of small renal masses
may be benign or low-grade disease with indolent behavior
[21]. However, existing series on active surveillance are
limited by small sample size and short follow-up, and they
originate from single-institution data. Furthermore, the
current study as well as previously published reports showed
that more advanced age represents a strong risk factor for
CSM in patients with localized RCC [22,23]. However, more
advanced age is a predictor for surveillance [20]. Although
existing paradigms suggest that there is overtreatment in
localized RCC, undertreatment represents an equally important consideration. Consequently, at least in some elderly
patients with localized RCC, the potential for curative disease
management should not be denied.
More historical prognostic models for prediction of CSM
do not incorporate age. Specifically, the University of
California, Los Angeles, system opted for the inclusion of
performance status in its model over age [24]. Similarly, the
Mayo Clinic series relies on disease stage, tumor grade, and
necrosis to generate a score to predict outcome [25]. A
postoperative nomogram for prediction of recurrence also
fails to account for age, as well as performance status [26].
However, more contemporary models have revealed
important prognostication for patient age at diagnosis.

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EUROPEAN UROLOGY 60 (2011) 11521159

For example, Karakiewicz et al. [9] developed a highly

accurate preoperative nomogram predicting CSM-free
survival using age, sex, symptoms, tumor size, tumor stage,
and distant metastasis status.
In summary, there is a growing but nonetheless
discordant body of literature focusing on the relationship
between age and CSM in RCC. Some studies have shown an
association between young age and survival. For example,
Sanchez-Ortiz et al. [27] recorded a survival benefit in
patients aged 40 yr relative to those aged 5861 yr. Others
recorded a 5-yr CSM-free survival benefit in younger
patients (3039 yr) versus older patients (7079 yr,
p = 0.01) for localized RCC [5]. Jung et al. [28], as well as
Komai et al. [7], recently corroborated these findings within
two single institutional reports. Conversely, Thomson et al.
[29] and Gillett et al. [30] reported a lack of statistically
significant difference between young and old individuals in
regard to CSM. Similarly, Hollingsworth et al. [10] failed to
detect a significant difference for CSM for individuals with
advanced age using univariable competing-risks analyses.
Our manuscript is not without limitations. First, the SEER
database does not allow the differentiation between sporadic
versus hereditary RCC. This information is important, given
that when RCC is diagnosed in patients aged <50 yr, a
hereditary case may be suspected. Since the natural history of
RCC in von Hippel-Lindau disease is different between
hereditary and sporadic RCC [31], this differentiation may
have provided important insights into the difference in
prognosis according to age. Second, the version of the SEER
database used does not contain information on baseline
comorbidity status or performance status, both of which are
important in the selection of surgical candidates. The lack of
comorbidities represents an important limitation to the
current study. The combination of age and comorbidities
allows the estimation of life expectancy, which is an essential
proxy for determining the survival outcomes of patients with
RCC [16]. The use of competing-risks regression analysis may
have compensated for the lack of baseline comorbidity and
performance status. Nonetheless, the sole adjustment for
OCM remains insufficient. Future studies examining the
effect of age on survival should attempt to incorporate this
information. Third, information on other minimally invasive
treatment approaches (eg, percutaneous radio frequency
ablation, cryoablation, microwave ablation, laser ablation,
and high-intensity focused ultrasound ablation), immunotherapy, and targeted therapy was not available within the
current database. This limitation may have induced a
selection bias. Nonetheless, previous investigators have
shown that thermal ablation was low (3.8%) in the SEER
database [32]. Moreover, older patients were more likely to
receive such treatment relative to their younger counterparts. Consequently, worse survival in elderly patients may
not be entirely explained according to such bias. Fourth, we
were unable to examine the effect of age on patients who
were exclusively nonsurgically managed because of the small
sample size. Existing literature on the role of active
surveillance remains controversial. No study examining
active surveillance and survival with adequate sample size
and sufficient follow-up time exists. Fifth, the lack of

information on adjuvant therapies likely affected survival

data, especially in patients with more advanced disease
stage. Sixth, as in all retrospective observational data, a
coding misattribution with regard to cause of death may have
been operational. However, this misattribution should be
equally applicable to all patients, regardless of their age or
stage of disease. Thus the limitation cannot completely
explain the observed effect, where more advanced age
portended to a worse survival, particularly in patients with
low-stage/low-grade disease. Similarly, lack of central
pathology, other coding misattribution, and entry error
may have been operational. However, all previous studies
examining population-based cohorts were also affected by
this limitation [10,23,33].
5.

Conclusions

The current data show that increasing age is an important

prognostic factor for worse survival outcomes in patients
with low-stage, low-grade RCC, despite adjusting for
available covariates, including OCM. However, given the
lack of information on comorbidities and performance
status, the current study cannot recommend an undiscriminated surgical approach for all elderly patients with a
localized disease. Nonetheless, further studies are necessary
to confirm or refute the current findings.
Author contributions: Maxine Sun 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: Sun, Abdollah, Bianchi, Karakiewicz.
Acquisition of data: Sun, Tian.
Analysis and interpretation of data: Sun, Abdollah, Trinh, Jeldres,
Karakiewicz.
Drafting of the manuscript: Sun, Abdollah, Karakiewicz.
Critical revision of the manuscript for important intellectual content:
Jeldres, Shariat, Widmer, Zorn, Menon, Montorsi, Perrotte, Karakiewicz.
Statistical analysis: Sun, Tian.
Obtaining funding: Perrotte, Karakiewicz.
Administrative, technical, or material support: Perrotte, Karakiewicz.
Supervision: Shariat, Menon, Montorsi, Perrotte, Karakiewicz.
Other (specify): None.
Financial disclosures: I certify that all conicts of interest, including
specic nancial interests and relationships and afliations relevant to
the subject matter or materials discussed in the manuscript (eg,
employment/afliation, grants or funding, consultancies, honoraria,
stock ownership or options, expert testimony, royalties, or patents led,
received, or pending), are the following: Pierre I. Karakiewicz is partially
supported by the University of Montreal Health Centre Urology
Specialists, Fonds de la Recherche en Sante du Quebec, the University
of Montreal Department of Surgery and the University of Montreal
Health Centre (CHUM) Foundation.
Funding/Support and role of the sponsor: None.

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