Advanced patient age is associated with inferior cancer-specific survival after radical nephroureterectomy.

Abstract

To assess the impact of patient age on outcomes after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC).
Data were collected on 1453 patients treated with RNU at 13 centres. Pathological slides were reviewed by dedicated genitourinary pathologists according to standardized criteria. Age at RNU was analysed both as a continuous and categorical variable (<50, n = 85; 50-59.9, n = 229; 60-69.9, n = 416; 70-79.9, n = 523; > or =80 years, n = 200). RESULTS Patients aged <50 years were less likely to have undergone previous ureteroscopy and to have a history of bladder cancer (P < or = 0.026). Advanced age was associated with infiltrative architecture and female gender (P < or = 0.003). Patients aged >70 years were less likely to undergo lymphadenectomy and to receive adjuvant chemotherapy (P < or = 0.026). In multivariable analyses, being older was associated with decreased all-cause (AC) survival (>60 years) and cancer-specific survival (CSS; >80 years) after controlling for the effects of standard pathological features (P < or = 0.006). However, addition of age did not improve the predictive accuracy of a base model that included standard pathological features for prediction of either disease recurrence, AC survival or CSS.
Being older at the time of RNU was associated with decreased survival. This finding could be due to a change in the biological potential of the tumour cell, a decrease in the host's defence mechanisms, or differences in care patterns. Further work is needed to improve our understanding of UTUC outcomes in this growing segment of the population and to develop strategies to improve cancer control in the elderly.

Full text

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2 0 0 9 B J U I N T E R N AT I O N A L | 10 5 , 1 6 7 2 – 1 6 7 7 | doi:10.1111/j.1464-410X.2009.09072.x
Urological Oncology
ASSOCIATION OF AGE WITH OUTCOMES OF UPPER TRACT UROTHELIAL CARCINOMA
SHARIAT
ET AL.
Advanced patient age is associated with
inferior cancer-specific survival after
radical nephroureterectomy
Shahrokh F. Shariat
Pierre I. Karakiewicz
Mesut Remzi
Karim Bensalah
Richard Zigeuner
Vitaly Margulis
1
University of Texas Southwestern, Dallas, TX,
School,
Cornell University, New York, NY,
Sacramento, CA, USA,
Graz, Graz,
Medical University of Vienna, Vienna, Austria,
School of Medicine, Tokyo, Japan,
Rennes, Rennes, France
Accepted for publication 12 August 2009
S.F.S. and G.G. are currently at Memorial Sloan-Kettering Cancer Center in New York, NY, USA
1
, Guilherme Godoy
3
, Jay D. Raman
, Marco Roscigno
10
, Theresa M. Koppie
13
, Cord Langner
14
1
, Yair Lotan
, Hendrik Isbarn
, Eiji Kikuchi
11
, Wassim Kassouf
13
, Christopher G. Wood
1
, Michael Droller
2
, Alon Weizer
, Christian Bolenz
12
, Jeffrey C. Wheat
14
and
2
,
45
,
6789
,
5
,
14
MD Anderson Cancer Center, Houston, TX,
University of Michigan, Ann Arbor, MI,
University of Montreal, McGill University, Montreal, Quebec, Canada,
7
2
Mount Sinai Medical
University of California Davis,
13
Medical University
8
Keio University
4511
312
6
Vita-Salute University, Milan, Italy,
9
Mannheim Medical Center, University of Heidelberg, Germany, and
10
University of
n
70–79.9,

=
85; 50–59.9,
n
n

≥
=
229; 60–69.9,
80 years,
n

=
416;

=
523;
n

=
200).
RESULTS
Patients aged
have undergone previous ureteroscopy and
to have a history of bladder cancer
(
P

≤
0.026). Advanced age was associated
with infiltrative architecture and female
gender (
P

≤
0.003). Patients aged
>
70 years were less likely to undergo
lymphadenectomy and to receive adjuvant
chemotherapy (
P

≤
0.026). In multivariable
analyses, being older was associated with
decreased all-cause (AC) survival (
and cancer-specific survival (CSS;
after controlling for the effects of standard
pathological features (
addition of age did not improve the
predictive accuracy of a base model that
<
50 years were less likely to
>
>
60 years)
80 years)
P

≤
0.006). However,
included standard pathological features for
prediction of either disease recurrence, AC
survival or CSS.
CONCLUSIONS
Being older at the time of RNU was
associated with decreased survival. This
finding could be due to a change in the
biological potential of the tumour cell, a
decrease in the host’s defence mechanisms,
or differences in care patterns. Further work
is needed to improve our understanding of
UTUC outcomes in this growing segment of
the population and to develop strategies to
improve cancer control in the elderly.
KEYWORDS
age, prognosis, urinary tract cancer,
urothelial carcinoma, survival
Study Type – Prognosis (case series)
Level of Evidence4
OBJECTIVE
To assess the impact of patient age on
outcomes after radical nephroureterectomy
(RNU) for upper tract urothelial carcinoma
(UTUC).
PATIENTS AND METHODS
Data were collected on 1453 patients treated
with RNU at 13 centres. Pathological slides
were reviewed by dedicated genitourinary
pathologists according to standardized
criteria. Age at RNU was analysed both as a
continuous and categorical variable (
<
50,
INTRODUCTION
RNU is the gold standard treatment for high-
risk upper tract urothelial carcinoma (UTUC),
and improvements in perioperative care
together with refinements of surgical
technique have made this a safe and feasible
operation for an increasing number of
patients. To our knowledge, the extent to
which advanced chronological age affects the
indications for and outcomes of radical
nephroureterectomy (RNU) has not been
investigated. Moreover, the effectiveness and
relative use of RNU in the subgroup of older
patients remain controversial. Similar to
bladder cancer, patients might be denied the
opportunity to receive the most effective
treatment for their disease, based on
chronological age alone [1]. In this context,
we evaluated the association of patient age
with pathological and long-term oncological
BJUI
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outcomes in a large international cohort of
patients treated with RNU for UTUC.
PATIENTS AND METHODS
This was an Institutional Review Board-
approved study with participating sites
providing necessary institutional data-
sharing agreements before initiation of the
study. The international collaboration resulted
from the joined efforts of all involved
institutions with the main purpose of creating
a comprehensive quality data repository with
the potential to be explored widely to seek
satisfactory answers exploring many different
research questions on the diagnosis,
prognostic factors and management of UTUC.
In all, 13 academic centres worldwide
provided data. A computerized databank was
generated for data transfer. After combining
the data sets, reports were generated for each
variable to identify data inconsistencies
and other data integrity problems. Through
regular communication with all sites,
resolution of identified anomalies was
achieved before analysis. Before final
analysis, the database was frozen and the
final data set was produced for the present
analysis.
The present study comprised 1453 patients
who underwent RNU with ipsilateral bladder
cuff resection between 1987 and 2007.
Regional lymphadenectomy was generally
performed in patients with suspicious lymph
nodes on preoperative imaging or with
adenopathies detected during intraoperative
examination. Extended lymphadenectomy
was not routinely performed. Neoadjuvant
and adjuvant chemotherapy regimens were
administered to 42 (2.9%) and 169 (11.6%)
patients, respectively.
All surgical specimens were processed
according to standard pathological
procedures, and all slides were reviewed
by dedicated genitourinary pathologists
according to prospectively defined identical
criteria. Pathologists were ‘blinded’ to clinical
outcomes. All specimens were histologically
confirmed to be UC. Tumours were staged
according to the American Joint Cancer
Committee/Union Internationale Contre le
Cancer TNM classification. Tumour grading
was assessed according to the 1998 WHO/
International Society of Urologic Pathology
consensus classification [2]. Lymphovascular
invasion was defined as the presence of
tumour cells within an endothelium-lined
space without underlying muscular walls. The
presence of concomitant carcinoma
and the tumour architecture were also
assessed in every representative section.
Tumour necrosis was defined as the presence
of microscopic coagulative necrosis whereas
the presence of necrosis on gross examination
was not included. The extent of tumour
necrosis was assessed in a semi-quantitative
manner at low magnification (reduced from
×
40). Tumour necrosis was recorded as absent
or focally present (0–10% of tumour area) or
extensively present (
>
10% of the tumour
area).
in situ

Patients were generally followed every
3–4 months for the first year after RNU, every
6 months from the second through to the
fifth year, and annually thereafter. Follow-up
consisted of history, physical examination,
routine blood work and serum chemistry
studies, urinary cytology, chest radiography,
cystoscopic evaluation of the urinary bladder,
and radiographic evaluation of the
contralateral upper urinary tract. Elective
bone scans, chest CT, or MRI were performed
when clinically indicated.
Disease recurrence was defined as local
failure in the operative site, regional lymph
nodes, or distant metastasis. Isolated bladder
cancer was not considered as disease
recurrence. Cause of death was determined by
the treating physicians, by chart review
corroborated by death certificates, or by death
certificates alone. Death certificates were
retrieved from the archived death certificates
and reviewed for cause of death. Attribution
of cause of death on the death certificate is
described in two parts. Part I lists death
caused by (i) immediate cause of death (final
disease or condition resulting in death) or by
(ii) underlying cause of death, and part II lists
other significant conditions contributing to
death but not resulting in the underlying
cause given in part I. Information abstracted
from each death certificate included the date
of death, and whether UC was noted in either
part I or II. To reduce bias in attribution
of cause of death, for the present study
purposes, only patients who had UC listed in
part I of the death certificate were considered
to have died of UTUC. All patients who were
coded as dead of cancer had previous disease
recurrence. Perioperative mortality (any death
≤
30 days of surgery or before discharge) was
censored at time of death for cancer-specific
(CS) mortality analyses.
The Fisher’s exact test and the chi-square
test were used to evaluate the differences
between categorical variables. Differences in
age across dichotomous or ranked categories
were assessed using the Mann–Whitney
and the Kruskal–Wallis tests, respectively.
Univariate recurrence and survival
probabilities after RNU were estimated using
the Kaplan–Meier method and compared
using the log-rank statistic. Univariate and
multivariable regression using Cox
proportional hazards ratio models addressed
time to recurrence, all-cause (AC) mortality,
and CS mortality after RNU. In all models,
proportional hazards assumptions were
systematically verified using the Grambsch-
Therneau residual-based test. Predictive
accuracy was quantified with Harrell’s
concordance index [3,4]. Internal validation
was performed using 200 bootstrap re-
samples [3,4]. All reported
sided and statistical significance was set at
0.05. Nominal
P
values are given with no
adjustments made for the calculated values.
U

P
values were two-
RESULTS
ASSOCIATION OF AGE WITH CLINICAL AND
PATHOLOGICAL CHARACTERISTICS
The median (range; interquartile range [IQR])
interpatient age was 69.7 (27–97; 15) years.
At the time of RNU, 85 (5.8%), 229 (15.8%),
416 (28.6%), 523 (36.0%) and 200 (13.8%)
patients were aged
<
50, 50–59.9, 60–69.9,
70–79.9, and
>
80 years, respectively.
The association of age at RNU with
clinicopathological characteristics is shown
in Table 1. Being older was significantly
associated with a history of previous
ureteroscopic intervention, history of bladder
cancer, laparoscopic RNU, infiltrative tumour
architecture, worse Eastern Cooperative
Oncology Group (ECOG) performance status,
Caucasian ethnicity, and female gender (all
P

≤
0.02). Lymphadenectomy was performed
more commonly in younger patients
(
P

≤
0.001). Adjuvant chemotherapy was
given more commonly to younger patients
(
P

≤
0.001). There was no association between
age at time of RNU and preoperative
chemotherapy.
ASSOCIATION BETWEEN AGE AS CONTINUOUS
AND CATEGORICAL VARIABLES AND
DISEASE OUTCOMES
The mean (median; range; IQR) follow-up was
61 (48; 0–250; 61) months for patients alive

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TABLE 1
Association of age at the time of RNU with clinical and pathological characteristics in 1453 patients treated for UTUC
Variable
All
Gender:
Male
Female
pT stage:
Ta
Tis
T1
T2
T3
T4
History of bladder cancer:
Absent
Present
Previous endoscopic procedures:
Negative
Positive
Tumour grade:
Low
High
Lymph nodes status:
pNx
pN0
pN1–2
ECOG performance status:
0
1
2
3
Ethnicity:
White
Black
Pacific Islander/Asian
Lymphovascular invasion:
Absent
Present
Architecture:
Papillary
Infiltrative
Procedure type:
Open
Laparoscopic
Tumour necrosis:
Absent
Present
Tumour location:
Renal pelvis
Ureter
Concomitant carcinoma
Negative
Positive
Adjuvant chemotherapy:
Negative
Positive
No. patients
(%)
1453 (100)
Age (years) as continuous
variable
Median (range)
69.7 (27.0–97.1)
Age (years) stratified in categories,
<
5050–59.9
85 (5.8) 229 (15.8)
n
(%)
≥
200 (13.8)
80
P
–
<
60–69.9
416 (28.6)
70–79.9
523 (36.0)
0.001*
986 (67.9)
467 (32.1)
68.1 (27.5–97.1)
72.3 (27.0–94.3)
61 (71.8)
24 (28.2)
168 (73.4)
61 (26.6)
308 (74.0)
108 (26.0)
334 (63.9)
189 (36.1)
115 (57.5)
85 (42.5)
0.281†
295 (20.3)
28 (1.9)
317 (21.8)
269 (18.5)
475 (32.7)
69 (4.7)
70.2 (31.0–94.3)
67.0 (32.0–86.1)
68.0 (34.1–90.7)
69.2 (30.0–96.9)
70.0 (27.0–97.1)
72.9 (43.0–89.0)
20 (23.5)
1 (1.2)
20 (23.5)
16 (18.8)
26 (30.6)
2 (2.4)
48 (21.0)
5 (2.2)
57 (24.9)
47 (20.5)
62 (27.1)
10 (4.4)
73 (17.5)
12 (2.9)
95 (22.8)
75 (18.0)
145 (34.9)
16 (3.8)
118 (22.6)
7 (1.3)
100 (19.1)
92 (17.6)
179 (34.2)
27 (5.2)
36 (18.0)
3 (1.5)
45 (22.5)
39 (19.5)
63 (31.5)
14 (7.0)
0.003*
1085 (74.7)
368 (25.3)
69.0 (27.0–96.9)
71.0 (40.0–97.1)
74 (87.1)
11 (12.9)
177 (77.3)
52 (22.7)
314 (75.5)
102 (24.5)
379 (72.5)
144 (27.5)
141 (70.5)
59 (29.5)
0.023*
1253 (86.2)
200 (13.8)
69.0 (27.0–97.1)
71.0 (31.0–94.3)
78 (91.8)
7 (8.2)
203 (88.6)
26 (11.4)
361 (86.8)
55 (13.2)
441 (84.3)
82 (15.7)
170 (85.0)
30 (15.0)
0.198*
516 (35.5)
937 (64.5)
69.4 (30.0–96.9)
70.0 (27.0–97.1)
37 (43.5)
48 (56.5)
85 (37.1)
144 (62.9)
142 (34.1)
274 (65.9)
185 (35.4)
338 (64.6)
67 (33.5)
133 (66.5)
<
0.001†
841 (57.9)
472 (32.5)
140 (9.6)
70.9 (27.5–97.1)
68.0 (30.7–96.9)
68.0 (27.0–90.0)
44 (51.8)
29 (34.1)
12 (14.1)
121 (52.0)
89 (38.9)
19 (8.3)
224 (53.8)
147 (35.3)
45 (10.8)
315 (60.2)
162 (31.0)
46 (8.8)
137 (68.5)
45 (22.5)
18 (9.0)
<
0.001†
1001 (68.9)
358 (24.6)
85 (5.8)
9 (0.6)
68.0 (27.0–91.0)
72.0 (30.7–96.9)
74.4 (37.3–90.0)
64.1 (48.6–97.1)
67 (78.8)
15 (17.6)
2 (2.4)
1 (1.2)
177 (77.3)
44 (19.2)
7 (3.1)
1 (0.4)
308 (74.0)
85 (20.4)
20 (4.8)
3 (0.7)
348 (66.5)
137 (26.2)
36 (6.9)
2 (0.4)
101 (50.5)
77 (38.5)
20 (10.0)
2 (1.0)
0.004†
1194 (82.2)
36 (2.5)
223 (15.3)
70.1 (27.0–97.1)
69.5 (30.0–85.0)
67.0 (36.0–89.0)
66 (77.6)
6 (7.1)
13 (15.3)
175 (76.4)
4 (1.7)
50 (21.8)
341 (82.0)
8 (1.9)
67 (16.1)
439 (83.9)
10 (1.9)
74 (14.1)
173 (86.5)
8 (4.0)
19 (9.5)
0.063*
1104 (76)
349 (24)
69.0 (30.0–97.1)
70.6 (27.0–94.0)
64 (75.3)
21 (24.7)
186 (81.2)
43 (18.8)
319 (76.7)
97 (23.3)
383 (73.2)
140 (26.8)
152 (76.0)
48 (24.0)
<
0.001*
1066 (73.4)
387 (26.6)
68.7 (27.0–97.1)
71.4 (34.1–91.0)
72 (84.7)
13 (15.3)
180 (78.6)
49 (21.4)
313 (75.2)
103 (24.8)
358 (68.5)
165 (31.5)
143 (71.5)
57 (28.5)
0.006*
1128 (77.6)
325 (22.4)
69.0 (27.0–97.1)
71.1 (32.0–94.3)
64 (75.3)
21 (24.7)
185 (80.8)
44 (19.2)
341 (82.0)
75 (18.0)
397 (75.9)
126 (24.1)
141 (70.5)
59 (29.5)
0.278*
1089 (74.9)
364 (25.1)
69.5 (27.0–96.9)
70.0 (37.3–97.1)
65 (76.5)
20 (23.5)
179 (78.2)
50 (21.8)
310 (74.5)
106 (25.5)
386 (73.8)
137 (26.2)
149 (74.5)
51 (25.5)
0.107*
958 (65.9)
495 (34.1)
69.0 (27.0–96.9)
70.3 (27.5–97.1)
64 (75.3)
21 (24.7)
158 (69.0)
71 (31.0)
271 (65.1)
145 (34.9)
330 (63.1)
193 (36.9)
135 (67.5)
65 (32.5)
in situ:
0.237*
1035 (71.2)
418 (28.8)
69.1 (27.0–97.1)
70.0 (32.0–93.0)
67 (78.8)
18 (21.2)
171 (74.7)
58 (25.3)
289 (69.5)
127 (30.5)
369 (70.6)
154 (29.4)
139 (69.5)
61 (30.5)
<
0.001*
1249 (86.0)
203 (14.0)
70.0 (27.5–97.1)
66.0 (27.0–93.0)
70 (82.4)
15 (17.6)
193 (84.3)
36 (15.7)
346 (83.2)
70 (16.8)
456 (87.4)
66 (12.6)
184 (92.0)
16 (8.0)
*Mann–Whitney test; †Kruskal–Wallis test.

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at last follow-up. Actuarial recurrence-free
estimates at 2, 5, and 10 years after RNU were
73%, 69%, and 66%, respectively. Actuarial
AC survival estimates at 2, 5, and 10 years
after RNU were 73%, 61%, and 47%,
respectively. Actuarial CS survival (CSS)
estimates at 2, 5, and 10 years after RNU were
79%, 72%, and 69%, respectively.
In univariate analyses, age was significantly
associated with AC and CS mortality, but not
disease recurrence (Table 2). In univariate
Cox regression analyses, being older was
associated with increased risk of AC (Table 2,
P

<
0.001) and CS mortality (Table 2,
P
(Table 2,

<
0.001), but not disease recurrence
P

=
0.054).
In multivariable analyses controlling for the
effects of tumour stage, grade, lymph node
status, and lymphovascular invasion, age was
an independent predictor of both AC (Table 2,
P

<
0.001) and CS mortality (Table 2,
P

=
0.004). Subgroup analysis in patients who
did not undergo lymphadenectomy did not
change the statistical significance of these
associations.
To further investigate the significant
relationship between age at the time of
RNU and AC and CS mortality, similar Cox
regression analyses were performed
controlling for the effects of the same
cofactors as the previous models, but
including age as a categorical variable. In
univariate and multivariable analyses, an
age of
≥
60 years (univariate
multivariable
P

<
0.001) and
(univariate
P

=
0.02 and multivariable
P

<
0.001) were significantly associated with
AC and CS mortality, respectively (Table 3).
P
≥

80 years
<
0.001 and
The predictive accuracy of age as continuous
variable for prediction of disease recurrence,
AC survival, and CSS was 52.3%, 59.2%, and
55.9%, respectively. The predictive accuracies
of age as a categorical variable for prediction
of AC and CS mortality were 57.9%, and
54.3%, respectively (Fig. 1). The addition of
age as categorical variable did not improve
the predictive accuracies of the base model
that comprised pathological stage, grade,
lymphovascular invasion, and lymph node
status for prediction of disease recurrence, AC
and CS mortality.
DISCUSSION
Compared with other cancers, there is little
data on the impact of age on patterns of care
and outcomes of patients with UTUC. In the
present study, 6% of patients treated with
RNU were aged
<50 years and 14% were aged
>80 years. Being older was associated with a
history of previous ureteroscopy, history
of bladder cancer, laparoscopic RNU,
infiltrative tumour architecture, worse ECOG
performance status and female gender.
TABLE 2 Univariate and multivariable Cox regression analyses predicting disease recurrence, AC survival and CSS in 1453 patients treated with RNU for UTUC
Variable
pT stage
T1 vs Ta/Tis
T2 vs Ta/Tis
T3 vs Ta/Tis
T4 vs Ta/Tis
LVI
Tumour grade
Lymph node status
Nx vs N0
Npositive vs N0
Age
Disease recurrence
Univariate
HR
AC survival
Univariate
HR
CSS
Univariate
HR
Multivariable
HR
Multivariable
HR
Multivariable
HR
P
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
0.5
<0.001
0.054
P
<0.001
0.02
<0.001
<0.001
<0.001
0.03
<0.001
<0.001
<0.001
<0.001
0.3
P
<0.001
0.03
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
0.002
<0.001
<0.001
P
<0.001
0.3
<0.001
<0.001
<0.001
0.002
<0.001
<0.001
<0.001
<0.001
<0.001
P
<0.001
0.004
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
0.2
<0.001
<0.001
P
<0.001
0.030
<0.001
<0.001
<0.001
0.01
<0.001
<0.001
<0.001
<0.001
0.004
2.85
6.76
15.28
52.36
3.31
5.15
2.14
4.62
8.66
21.34
1.29
2.50
1.45
2.37
4.19
12.28
2.57
2.37
1.21
1.96
3.13
6.58
1.40
1.56
2.75
7.16
16.31
52.55
3.55
4.72
2.13
5.10;
9.82
21.28
1.38
2.20
1.09
4.97
1.01
1.54
2.29
1.01
1.37
3.46
1.03
1.61
1.77
1.03
1.21
5.03
1.02
1.65
2.21
1.02
LVI, lymphovascular invasion; Nx, lymphadenectomy not performed.
TABLE 3 Univariate and multivariable Cox regression analyses of age as a categorical variable predicting
AC survival and CSS in 1453 patients treated with RNU for UTUC
Variable
Age predicting AC survival
50–59 vs ≤50 years
60–69 vs ≤50 years
70–79 vs ≤50 years
≥80 vs ≤50 years
Age predicting CSS
50–59 vs ≤50 years
60–69 vs ≤50 years
0–79 vs ≤50 years
≥80 vs ≤50 years
Univariate analysis
HR
Multivariable analysis
with age as categorical
variable
HR
P
<0.001
0.9
0.04
0.003
<0.001
0.02
0.6
0.3
0.5
0.03
P
<0.001
0.7
0.06
0.01
<0.001
<0.001
0.5
0.3
0.8
0.04
0.97
1.57
1.93
2.68
0.92
1.52
1.78
2.51
0.85
1.30
1.19
1.69
0.81
1.30
1.09
1.63
All models corrected for pT stage, lymphovascular invasion, tumour grade and lymph node status.

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Elderly patients were less likely to undergo
lymphadenectomy or receive postoperative
chemotherapy for advanced stage disease.
Most importantly, age was an independent
predictor of AC and CS mortality.
Being older was associated with CS mortality,
but not disease recurrence, after controlling
for the effects of standard pathological
features. Reasons for this could be a change
in the biological potential of the tumour
cell or a decrease in the host’s defence
mechanisms with advancing age, or even a
detrimental effect of differences in care
patterns in elderly compared with younger
patients. Indeed, in the present study
advanced age was associated with features of
advanced disease such as higher rate of
infiltrative tumour architecture, which has
been shown to be an ominous independent
predictor of outcomes after UTUC [5]. In
addition, while the rate of pTa disease
decreased, that of pT4 disease increased with
advancing age.
The higher CS mortality of elderly patients
treated with RNU compared with younger
patients may be secondary to suboptimal
use of RNU (patient selection and delay),
lymphadenectomy, and/or postoperative
chemotherapy. It may be that similar to
bladder cancer, there is a reluctance to
perform radical surgery in older patients with
comorbidities resulting in higher tumour
stage when surgery is eventually performed
leading to higher CS mortality [1,6]. Thus, the
association between advanced age and worse
outcomes in the present study may be a
selection bias resulting in treatment with RNU
of elderly patients with relatively more
advanced disease.
An alternative explanation may be that there
is a longer delay between diagnosis and
definitive treatment in elderly patients
resulting in disease progression and worse
survival [7–9]. In support of this, in the
present study older patients were more
likely to undergo multiple ureteroscopic
interventions before the decision to perform a
RNU compared with their younger
counterparts.
Similar to the reported data on bladder UC,
elderly patients with UTUC were less likely to
receive postoperative chemotherapy in the
presence of advanced disease stage [1,10].
This may be partially due to the frailty and
presence of significant comorbidities in these
patients, such as impaired renal function and
cardiac disease. The risk/benefit ratio is
differently weighted in the elderly compared
with younger patients. The compromise
between life years gained vs quality of life
may be different from the perspective of
elderly compared with younger patients.
Similarly, elderly patients were less likely to
undergo lymphadenectomy. We and others
have previously shown that nodal status is a
significant predictor of CS mortality in UTUC
and that pNx is significantly associated with a
worse prognosis than pN0 in the subgroup of
muscle-invasive tumours [11]. Moreover, it
has also been recently shown that the
extension of the lymphadenectomy in
patients with pN0 UTUC seems to be
associated with CS mortality [12].
The host response might also play a critical
role in the differential CS mortality rates
between young and older patients treated
with RNU for UTUC. In bladder UC, Miller et al.
[13] reported that the Charlson Index score
was a strong predictor of increased risk of
extravesical disease and CS mortality.
Unfortunately, we did not have data to
rigorously examine the impact of the
comorbidities in the present cohort. Weizer
et al. [14] reported that Karnofsky
performance status was an independent
predictor of overall survival on patients aged
≥70 years presenting with nonmetastatic
muscle-invasive bladder UC. Moreover, their
study confirmed that most elderly patients
were able to undergo definitive treatment
supporting the point that in elderly patients
with a good performance status, radical
surgery offers the best disease control.
There are several limitations in the
present study. Our results were analysed
retrospectively and did not control for
possible selection bias such as presence of
patient comorbidities. While there was an
association between age and survival
endpoints, this association was not true for
disease recurrence. This could be explained
by the decrease in the host’s defence
mechanisms with advancing age and/or
differences in selection for administration of
adjuvant chemotherapy. We are unable to
comment on the extent to which patient age
factored into the selection of RNU and/or
perioperative chemotherapy among available
treatment options for patients presenting
with high-risk disease. The impact of an age-
based selection bias on treatment outcomes
FIG. 1. Probability estimates of (A) recurrence-free survival and (B) CSS in 1453 patients treated with RNU for
UTUC stratified by age categorized into <50 (85 patients), 50–59.9 (229), 60–69.9 (416), 70–79.9 (523), and
≥80 years (200).
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
–12 0 12 24 36 48 60 72 84 96 108120132144156168180192204216228240252
Time from RNU, months
Probability of CSS
50 to 59.9
70 to 79.9
60 to 69.9
Above 80
Below 49.9

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for UTUC is probably substantial, particularly
given the suspected relative under use of RNU
for elderly patients. The relative under use of
chemotherapy in older patients in the present
series suggests a bias against adjuvant
treatment in our older patients; the individual
reasons for this were not available. A careful
analysis of other factors not addressed in the
present study, such as the time from invasive
UTUC diagnosis to the RNU and the impact of
comorbidities is needed to have a better
understanding of the effect of age on tumour
biology and patient survival. Moreover, we did
not have data on functional status outcomes.
Such data have not been systematically
examined and may add to the perspective of
quality-of-life-adjusted relative survival
benefits.
Another potential limitation is that the
patients were treated by various physicians
and the specimens were evaluated by various
pathologists over a long period. Although the
differences in practice patterns across the
institutions in the present study may affect
the interpretation of our findings, they are
reflective of the real world scenario, making
the conclusions more generalizable. To
minimize the difference in pathological
evaluation of the specimens, all specimens
were reviewed by dedicated genitourinary
pathologists according to strict
morphological criteria to standardize
reproducibility. Furthermore, this is the largest
reported series of patients treated with
RNU for UTUC and it is unlikely that large
prospective randomized trials will be
organized, due to the relative rarity of this
disease [15,16]. The limited predictive
accuracy of our models may suggest that age
and other important related factors, which
could not be explored in the present study,
may play an important role in determining the
outcomes of this patient population.
In conclusion, the present study suggests
that delay in definitive treatment, lack of
lymphadenectomy, and potential under use of
adjuvant chemotherapy are potential
modifiable risk factors that could lead to
improvement of outcomes in elderly patients.
This together with the efficacy of RNU for
disease control suggests that elderly patients
with high-risk UTUC who have an adequate
performance status should be offered RNU
earlier. The limitations of the present study do
not allow us to make recommendations based
on our data; however, our observations are
provocative and deserve further attention to
identify the causes for the worse CS mortality
in elderly patients and to develop strategies to
improve cancer control in this population.
CONFLICT OF INTEREST
None declared. Source of Funding: National
Institute of Health; T32 training grant
(T32CA082088).
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Correspondence: Shahrokh F. Shariat,
Division of Urology; Sidney Kimmel Center
for Prostate and Urologic Cancer, Memorial
Sloan-Kettering Cancer Center, 1275
York Avenue, Box 27, New York, NY 10065,
USA.
e-mail: shariats@mskcc.org;
sfshariat@gmail.com
Abbreviations RNU, radical
nephroureterectomy; (UT)UC, (upper tract)
urothelial carcinoma; AC, all-cause; CS(S),
cancer-specific (survival); IQR, interquartile
range; ECOG, Eastern Cooperative Oncology
Group.