83 96
1.
Introduction
Urothelial bladder
cancer
(UBC)
is
the
fifth most
common
cancer
in
Western
societies,
accounting
for
10
000,
69
000,
and
180
000
new
cases
per
year
in
the
UK,
USA,
and
EU,
respectively
[1].
The
global
incidence
of
UBC
is
rising,
reflecting
patterns
of
cigarette
smoking
and
occupational
carcinogen
exposure
[2],
the
most
common
aetiological
factors
[1].
There
has
been
little
improvement
in
the
outcome
for
UBC
patients
since
the
1980s,
reflecting
complex
diagnostic
pathways
and
treatment
regimens
and
a
lack
of
therapeutic
advances
[3].
Given
these
constraints,
much
attention
has
been
paid
to
reducing delays
in presentation
[4], diagnosis,
and
treatment
[5].
For
UBC
the
relationship
between
time
to
diagnosis
and
treatment,
and
disease-specific
survival
is
complex
[6–9]; many
tumours
are
indolent,
for which
a
delay
in
diagnosis
does
not
alter
survival
[10],
and
outcomes
for
aggressive
UBCs
are
multifactorial
[6–9].
In
addition
to
delays
in health
care
pathways,
disease
biology
(reflected
by
stage,
grade,
and
tumour
characteristics
[11,12] )and
patient-specific
factors
are
important.
The
latter
reflect
aetiological
exposure
to
agents
(eg,
smoking
is
more
common
in
males)
[9,13,14] ,gender-specific mis-
diagnoses
(eg,
females
are more
likely
to
be
incorrectly
diagnosed
with
infection
[15] ) [1,16,17] ,and
potential
differences
in
the
molecular
pathogenesis
of
male
and
female
UBC
[18] .To
obtain
a
clearer
understanding
of
factors
affecting
outcomes
in
UBC,
we
have
followed
a
large
cohort
of
prospectively
recruited patients
since 1991
[9]. This popula-
tion
represents
85%
of
new
cases
of
UBC
arising
over
an
18-mo
period within
the West Midlands
region
of
the
UK
[9]. Here we
report
long-term outcomes and
investigate
the
influence
of
gender,
carcinogen
exposure,
and
pathway
delays
for
this
cohort.
2.
Patients
and methods
2.1.
Patients
Patients
newly
diagnosed
with
UBC
within
the West
Midlands
(UK)
were prospectively
recruited between
January 1, 1991 and
June 30, 1992
[9]. Data
regarding
exposures,
date
of
symptom
onset,
first
referral
by
general practitioner
(GP), first hospital appointment, and first
treatment
(date
of
transurethral
resection
of
bladder
tumour
[TURBT])
were
collected
at
recruitment.
Data
were
checked
to
ensure
that
TNM
classification correlated with histopathology and bimanual examination
findings.
Discrepancies
were
resolved
by
the
investigators
and
the
operating
consultant.
All
patients were
notified
to
the West Midlands’
cancer
registry, who
provided
death
information
at
the
censor
date
of
December 31, 2010. Ethics
committee
approval was
received before
the
study was opened. Ex-smokers were defined as
those who had abstained
for
>
12 mo.
Occupational
exposure was
identified
by
three
assessors
(
>
90%
consensus)
using
International
Agency
for
Research
on
Cancer
contemporary
evidence
to
assign no
risk, possible
risk,
and definite
risk
of
working
in
an
occupation
implicated
in
the
pathogenesis
of
UBC
(Supplementary
Table
1)
[19].
2.2.
Pathway measures
Pathway
times were
defined
as
follows:
Time 1:
from date
of
onset
of
symptoms
to date
of
first GP
referral
to
secondary
care.
Time 2:
from date of
first GP
referral
to
secondary
care
to date of
first
hospital
attendance
for
urological
assessment.
Time 3:
from date of
first hospital attendance
to date of
first
treatment
by
TURBT.
Hospital delay was
calculated
as
the
sum
of
times 2
and 3,
and
total
delay
as
the
sum
of
all
three
time
periods.
2.3.
Statistical methods
All
statistical
analyses were
performed
using
Stata
11.2
(StataCorp
LP,
College
Station,
TX,
USA)
and
R
version
2.13.2
(The
R
Foundation
for
Statistical
Computing,
http://www.R-project.org).
Associations
between
patient or
tumour
features
and median delay
times were
analysed using
the Pearson
x
2
test
for
categorical data
and
the Mann-Whitney
U
test
for
continuous data.Survivalwascalculated fromthedate offirst TURBTtothe
date
of
death
or
the
censor
date
of December
31,
2010,
using
all-cause
mortality.
Survival
curves
for
each
stage
(Ta, T1, T2–4) were
constructed
using
the Kaplan-Meier method, and outcomes were
compared between
groups using
the
log-rank
test. We estimated
relative survival
to calculate
the
crude
probability
of
death
in
the
general
population
compared
to
patients diagnosed with pTa
tumours according
to
the user-written Stata
command
strs
, matched
for
age
at
diagnosis,
sex,
and
year
of
diagnosis
[20].
Probabilities
were
calculated
according
to
the
Ederer
II method.
Survival was
compared
in
terms
of demographic
and
tumour
character-
istics
and
delay
times. A
stratified
survival
analysis was
used
to
test
for
differences within
delay
times
adjusted
for
tumour
stage
and
to
test
for
smoking status adjusted for delay times. Cox proportional-hazardsmodels
using
a
complete
case
approach
were
applied
to
investigate
the
independent
effect
of
age,
sex,
smoking
status,
haematuria,
and
tumour
stage,
grade,
type,
size,
and number. We
tested
the proportional hazards
assumption
of
the
models
by
examining
the
Schoenfeld
and
scaled
Schoenfeld
residuals;
in
each
test,
the
proportional
hazards
assumption
wasmet.
In addition, we evaluated the model fit using Cox-Snell residuals,
which
confirmed
that
the models
fit
the
data well.
This
yielded
a
base
model
that was used
to
adjust
the
effects
of
each delay.
To assess competing risks of death, we first used a nonparametric
test
to
assess
the
equality
between
groups
by
calculating
the
cumulative
incidence
function
(CIF)
as
described
by
Scrucca
et
al
[21].
Specific CIFs
were
compared
using
the Gray
test
[22](Supplementary methods).
3.
Results
3.1.
Cohort
description
In
total,
1537
patients
were
enrolled
into
the
study
and
reliable
long-term
survival
data
were
available
for
1478
participants
(96.2%;
Table 1 ).
The
cohort
was
typical
for
UBC, with
a male/female
ratio
of
3:1
and
a median
age
at
diagnosis
of
69
yr
(interquartile
range
[IQR]
62–76
yr)
for
male
and
71
yr
(IQR
64–78
yr)
for
female
patients. A
large
proportion
of
patients
(973,
77%) were
current
or
former
cigarette
smokers,
and
330
(27%)
patients were
classified
as
having
possible
or
definite
exposure
to
occupational
carcinogens.
As
detailed
previously,
patients were
treated
by
contemporaneous
standard
practice
(which
did
not
E U R O P E A N
U R O L O G Y
F O C U S
1
( 2 0 1 5
)
8 2 – 8 9
83