2016 Article 2832
2016 Article 2832
2016 Article 2832
Abstract
Background: Urothelial carcinoma of the urinary bladder (UCB) is the 4th most common cancer type in men in
developed countries, and tumor recurrence or progression occurs in more than half of the patients. Previous
studies report contradictory trends in incidence and survival over the past decades. This article describes the trends
of UCB incidence and survival from 1981 to 2014, including both invasive and non-invasive UCB using data from
the Cancer Registry of Norway.
Methods: In Norway, 33,761 patients were diagnosed with UCB between 1981 and 2014. Incidence and 5-year
relative survival were calculated, stratified by sex, morphology, stage, age and diagnostic period. Age-period-cohort
models were used to distinguish period- and cohort effects. Temporal trends were summarized by calculating the
average absolute annual change in incidence and relative survival allowing for breaks in this trend by incorporating
a joinpoint analysis. Excess mortality rate ratios (EMRR) quantify the relative risks by using a proportional excess
hazard model.
Results: The incidence of UCB in men increased from 18.5 (1981-85) to 21.1 (1991-95) per 100 000 person-years
and was rather stable thereafter (1996–2014). The incidence rates of UCB were lower in women increasing linearly
from 4.7 to 6.2 over the past 34 years (p = 5.9 · 10-7). These trends could be explained by an increase of the
incidence rates of non-invasive tumors. Furthermore, the observed pattern seemed to represent a birth cohort
effect. Five-year relative survival increased annually with 0.004 in men (p = 1.3 · 10-6) and 0.003 in women (p = 4.5 ·
10-6). There is a significant increase over the past 34 years in survival of UCB in both genders for local tumors but
not for advanced stages.
Conclusions: Increasing and stable incidence trends mirror little improvement in primary and secondary prevention
of UCB for more than three decades. Survival proportions increased only marginally. Thus, any changes in treatment
and follow-up care did not lead to notable improvement with respect to survival of the patients. High estimates of
preventable cases together with large recurrence rates of this particular cancer type, demand more research on
prevention guidelines, diagnostic tools and treatment for UCB.
Keywords: Urothelial carcinoma of the urinary bladder, Bladder cancer, Incidence, Relative survival, Trends,
Registry data, Epidemiology
* Correspondence: b.k.andreassen@kreftregisteret.no
1
Department of Research, Cancer Registry of Norway, Institute for
Population-based Research, Oslo, Norway
Full list of author information is available at the end of the article
© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Andreassen et al. BMC Cancer (2016) 16:799 Page 2 of 11
Background treatment as well. This makes UCB one of the most ex-
Despite large global differences in the incidence of pensive cancers to treat on a per-patient basis [14] in
urothelial carcinoma of the urinary bladder (UCB), this addition to being bothersome for the patients.
cancer type remains the second most common genito- Incidence and survival trends for UCB in different
urinary malignancy after prostate cancer in men world- countries based on cancer registry data have been de-
wide. Globally, about 330 000 new UCB cases were scribed previously [15–17]. However, inclusion and ex-
diagnosed and 123 000 UCB patients died from the dis- clusion criteria differ with respect to diagnose groups
ease in 2012. UCB is most frequent in Europe, Northern and periods as well as classification and registration
America, Western Asia and Northern Africa and least practices. Furthermore, to our knowledge, none of the
common in Eastern, Western and Middle Africa, Central articles addressing UCB trends used a nationwide regis-
America and the non-western regions of Asia [1]. try. We will describe the trends of UCB incidence and
Within Europe, UCB is the fourth most common cancer survival over time in Norway for all patients diagnosed
type in men with an age-standardized incidence rate with urothelial carcinoma of the urinary bladder be-
(world) of 17.7 per 100 000 person-years [1]. The corre- tween 1981 and 2014, including both invasive and non-
sponding rate in Norway is 20.8 per 100 000 person- invasive UCB (including dysplasia) using data from the
years based on the diagnosis period from 2009 to 2013 Cancer Registry of Norway.
[2]. UCB incidence in women is much lower with 3.5
cases per 100 000 person-years in Europe and 6.4 in Methods
Norway. International variation in UCB incidence have Material
recently been described in detail [3], also including The Cancer Registry of Norway has since 1953, compul-
trends over time. sory by law, registered virtually all new cancer diagnoses
Several risk factors have been identified for UCB, to- in Norway. The registry receives information from three
bacco smoking being the most predominant one. The independent sources (clinicians, pathology laboratories,
population attributable risk for ever smoking has lately and from the Cause of Death Registry), which ensures
been estimated to be approximately 50 % in both men completeness and high quality data [18]. Patients are
and women in the US [4] and nearly 40 % in the UK [5]. identified through the unique national personal identifi-
Men are more likely to get UCB with a male to female cation number assigned to all newborns and residents in
ratio of 3.2 in Norway [2]. UCB is also related to occupa- Norway since 1960. The present study comprises all new
tional exposure to certain chemicals like aromatic cases of histologically verified invasive and non-invasive
amines, chlorinated hydrocarbons and polycyclic aro- urothelial carcinoma of the urinary bladder in the
matic hydrocarbons [6, 7]. Patients previously irradiated Norwegian population diagnosed between 1981 and
for pelvic and abdominal malignancies are also at in- 2014. UCB cases were selected based on morphological
creased risk, as is also shown for intake of certain drugs codes for the transitional cell type as presented in
used in previous cancer treatment [8] as well as diabetes Table 1. UCB patients diagnosed before 1981 were ex-
medication [9]. UCB rarely occurs before the age of 40, cluded due to registration changes in the seventies
and has a median age of diagnosis at 75 in the UK [10]. mainly for non-invasive tumors. Thus, in total, 33,761
In Norway, 95 % of all UCB cases are of the transi- UCB patients were included in this study (Table 1).
tional cell type, and about 60 % are primarily diagnosed Participants were followed until death, migration or
without invasion into subepithelial connective tissue end of follow up on the 31st of March 2016. The
(tumor stage T1) or muscle (T2-4). These non-invasive total follow-up time was 230 783 person-years with a
tumors (papillary: Ta, Carcinoma in situ: Tis) and dys- median follow-up time of 15.0 years. Out of all
plasia are characterized by its high recurrence rates after 33,761 UCB patients included in this study, 5 228 in-
transurethral resection of an initial tumor. Non-invasive dividuals died from UCB according to the cause of
papillary (Ta) tumors form the largest group and ac- death certificate.
count for half of all diagnosed urothelial carcinomas. Information on morphology, stage, grade, sex, age at
The majority of these tumors will recur, but the risk of diagnosis and date of diagnosis were retrieved from the
progression to invasive UCB is low (4–7 %) for low- Cancer Registry of Norway. Morphology, stage and grade
grade Ta tumors and approximately 12–23 % for high- were defined based on the most severe diagnosis within a
grade Ta tumors [11, 12]. Carcinoma in situ seems to be 5-month window including the first of the month when
more likely to progress than non-invasive papillary the first UCB diagnosis was received. We define five
tumors, especially if concurrent with papillary tumors morphology groups based on the available tumor categor-
[12, 13]. The high recurrence rates and the low but ies and grade information: Non-invasive papillary carcin-
imminent progression risk leads to a tight follow-up of oma low- and high-grade (Ta), non-invasive flat
the patients with frequent visits and resource demanding carcinoma (Tis), dysplasia (low-grade flat carcinoma) and
Andreassen et al. BMC Cancer (2016) 16:799 Page 3 of 11
invasive carcinoma (T1-T4). Grade information is based each of the four age-groups stratified for sex. Direct age-
on WHO 1973 [19] and grouped into low (LG, WHO standardized incidence rates were calculated applying
grade 1 and 2)- and high-grade (HG, WHO grade 3) (see the World Standard Population [20] according to sex as
Table 1). Stage is categorizsed as localized (non-invasive/ well as age group, morphology group and stage across
invasive cancer without any metastases), regional ad- all diagnostic periods. Temporal trends of the incidence
vanced (any infiltration into surrounding areas or regional rates were best represented by a linear model, where the
metastases) and distant advanced (distant metastases) tu- estimated regression coefficient β^I represents the average
mors. For the presentation of the results, age at diagnosis absolute annual incidence change. In order to
was divided into four age groups (≤49, 50–64, 65–79, summarize the observed trend over the last 34 years,
≥80). The year of diagnosis is grouped into 5-years inter- this parameter has been provided together with the
vals (diagnostic periods): 1981–1985, 1986–1990, …, standard error and p-values for the test of an incidence
2006–2010 and 2011–2014. change over time. We also implemented a joinpoint ana-
lysis [21] to uncover trends, which change over time. In
Statistics order to interpret trends in age-specific incidence rates
Incidence rates (per 100 000 person-years) were calcu- over time, we also apply an extension of the age-period-
lated based on the number of individuals getting their cohort model [22] to separate diagnosis period and birth
first UCB diagnosis and the number of individuals living cohort effects. An APC model incorporating restricted
in Norway for a certain sex, diagnostic time-period and cubic splines, implemented in Stata was used [23, 24].
age group. Age-specific incidence rates are presented for The APC model was applied for male patients with an
Andreassen et al. BMC Cancer (2016) 16:799 Page 4 of 11
age at diagnosis between 70 and 80, diagnosed between Table 2 Patient characteristics
1981 and 2010 and born between 1910 and 1930, which Men Women All
means that the model includes reliable information from % 75.6 24.4 100.0
the birth cohorts of interest. Age [25–75 % percentile] 72 [64–79] 73 [65–81] 72 [64–79]
5-year relative survival, based on the cohort ap-
Morphology
proach, was estimated using the age-standardardized
Non-inv pap trans carcinoma 43.4 43.0 43.4
Ederer II method applying national population life- low-grade
tables by sex, age group and diagnosis period [25]. The
Non-inv pap trans carcinoma 7.6 5.6 7.1
internal age-standardization used the age distribution high-grade
of the last diagnostic period 2011-14 as weights.
Displasia 3.9 4.1 3.9
Temporal trends of 5-year relative survival rates were
Carcinoma in situ 3.7 3.1 3.6
best represented by a linear model. Thus, the average
absolute change in annual 5-year relative survival esti- Inv trans carcinoma 41.3 44.3 42.0
mates was provided together with the standard error Stage
and p-values for the test of a significant trend. We also Localised 91.5 89.9 91.1
implemented a joinpoint analysis [21] to uncover those Regional advanced 5.6 5.9 5.7
trends, which change over time. The annual change in
Distant advanced 2.9 4.1 3.2
5-year survival proportions was estimated by the re-
Death
gression coefficient β^ RS : Because follow-up data for the
Bladder cancer 15.0 17.2 15.5
latest diagnostic period are lacking, 5-year survival esti-
mates for 2011-14 are based on a period approach. The Other cancer 22.1 21.4 22.0
corresponding column is marked with an (*) in order to Other than cancer 30.2 26.2 29.1
emphasize the differently derived estimates and these Unknown 2.7 2.6 2.8
estimates have not been included in the trend analysis. Alive 30.0 32.6 30.6
We fitted a proportional excess hazard model [26–28] Distribution of age, morphology group, stage and cause of death by sex and
where sex, diagnostic period, age group, morphology in total in the study population of patients diagnosed with urothelial
group and stage were included as categorical variables. carcinoma of the urinary bladder in Norway from 1981 to 2014
the incidence increased by 0.34 β^ I within a year or past 34 years. The corresponding trend was significant:
β^ I = 0.043 (p = 5.9 · 10-7).
2.7 from 1981 to 1989. The remaining 26 years of the
In men, age-specific incidence rates were increasing
study period, the incidence increased on average 0.02
during the past 34 years, especially for the oldest patients
per year or 0.5 from 1990 to 2014. The incidence of
UCB in men was between 18.3 and 21.4 per 100 000 (β^ = 3.5, p = 7.1 · 10-9) and those between 65 and 79 (β^ =
I I
person-years for all diagnostic periods during the study 0.9, p = 3.2 · 10-5). Similar age-dependent incidence trends
period. The incidence of UCB was lower in women could also be seen in women, although less pronounced
with incidence rates increasing from 4.7 to 6.2 over the probably due to the lower number of cases. This observed
Andreassen et al. BMC Cancer (2016) 16:799 Page 6 of 11
pattern was most likely mainly due to a birth cohort effect analysis reveals that the increase in incidence rates of
as illustrated in Fig. 1. The APC model confirmed the age- high-grade non-invasive papillary carcinoma is rather
effect (Fig. 1a) and suggested a larger birth cohort effect small until 2001 (men: p = 0.055) and 2003 (women: p
compared to the diagnosis period effect (Fig. 1b). The inci- = 0.105), but significant thereafter (men: p = 1.0 · 10-8,
dence rate ratio (IRR) was 1.22 (CI: 1.04–1.45) when com- women: men: p = 1.0 · 10-8).
paring the 1930 birth cohort to the one from 1910. This Both genders showed an increasing trend with respect
particular birth cohort effect stayed the same when redu- to the incidence rates for localized cancers. This trend
was more pronounced for women (p = 8.6 · 10-6) than
cing the model to an age-cohort model (results not
men (p = 0.001). Cases with advanced stage were rather
shown).
rare, such that the interpretation suffered from small
In men, there was a significant increase in high-grade
number of cases in both men and women. Still, there is
non-invasive papillary carcinoma (Ta HG: p = 1.5 · 10-10)
a decreasing tendency for distant advanced tumors in
over the study period. Age-standardized incidence rates
men (p = 0.380), while the corresponding tendency in
in men have been rather stable over the whole observa-
women is increasing (p = 0.172).
tion period for invasive carcinoma (p = 0.985) and low-
grade non-invasive papillary carcinoma (Ta LG p =
Relative Survival
0.335). The incidence of both high- and low-grade non-
Table 4 presents the sex-specific 5-year relative survival
invasive papillary carcinoma (Ta) was increasing in across 5-year diagnosis intervals from 1981 to 2014
women (HG p = 5.4 · 10-8, LG p = 1.0 · 10-4). The corre- stratified for age and morphology group as well as stage.
sponding increase of incidence rates for carcinoma in
situ has been less pronounced in women (p = 0.233), Furthermore, the average annual survival change β^ RS
possibly due to small numbers of cases. A joinpoint estimates the average trend of the 5-year relative survival
Fig. 1 Age-standardized incidence rates per 100 000 person-years (a) and incidence rate ratios for birth cohort and diagnostic period effects for
men diagnosed with urothelial carcinoma of the urinary bladder in Norway (b)
Andreassen et al. BMC Cancer (2016) 16:799
Table 4 Relative survival proportions
1981-85 1986-90 1991-95 1996-2000 2001-05 2006-10 2011-14a βRS (SE) p-value
Men 0.67 (0.64,0.70) 0.71 (0.68,0.74) 0.73 (0.70,0.76) 0.72 (0.70,0.75) 0.75 (0.72,0.77) 0.77 (0.75,0.79) 0.77 (0.75,0.79) 0.004 (0.001) 1.3E-06b
Women 0.63 (0.59,0.67) 0.68 (0.64,0.72) 0.65 (0.61,0.69) 0.70 (0.67,0.74) 0.70 (0.67,0.73) 0.72 (0.69,0.75) 0.74 (0.71,0.77) 0.003 (0.001) 4.5E-06b
Men Age (years)
0–49 0.90 (0.84,0.95) 0.85 (0.78,0.90) 0.93 (0.88,0.97) 0.92 (0.86,0.95) 0.89 (0.83,0.93) 0.91 (0.85,0.95) 0.94 (0.84,0.98) 0.001 (0.001) 0.623
50–64 0.78 (0.74,0.81) 0.81 (0.78,0.85) 0.83 (0.80,0.86) 0.84 (0.80,0.87) 0.84 (0.81,0.86) 0.83 (0.81,0.86) 0.89 (0.85,0.91) 0.003 (0.001) 0.006b
65–79 0.69 (0.65,0.72) 0.68 (0.65,0.72) 0.72 (0.70,0.75) 0.73 (0.70,0.76) 0.75 (0.72,0.78) 0.78 (0.76,0.81) 0.78 (0.73,0.81) 0.005 (0.001) 7.6E-07b
80+ 0.53 (0.45,0.63) 0.65 (0.57,0.73) 0.63 (0.56,0.71) 0.60 (0.53,0.66) 0.64 (0.58,0.70) 0.68 (0.62,0.73) 0.63 (0.54,0.72) 0.007 (0.003) 0.015b
Morphology
Non-inv pap carcinoma LG 0.85 (0.79,0.89) 0.92 (0.87,0.95) 0.91 (0.87,0.95) 0.93 (0.88,0.96) 0.91 (0.87,0.94) 0.94 (0.90,0.97) 0.93 (0.84,0.97) 0.003 (0.001) 0.001b
Non-inv pap carcinoma HG 0.94 (0.18,1.00) 0.76 (0.63,0.85) 0.84 (0.71,0.92) 0.80 (0.66,0.88) 0.82 (0.72,0.88) 0.87 (0.80,0.92) 0.88 (0.77,0.94) 0.004 (0.002) 0.050
Dysplasia 0.76 (0.56,0.87) 0.63 (0.47,0.76) 0.76 (0.61,0.86) 0.83 (0.68,0.92) 0.85 (0.67,0.93) 0.83 (0.66,0.92) 0.74 (0.54,0.86) 0.004 (0.003) 0.155
Carcinoma in situ 0.79 (0.45,0.93) 0.62 (0.48,0.74) 0.64 (0.51,0.75) 0.64 (0.53,0.73) 0.84 (0.69,0.92) 0.83 (0.71,0.90) 0.91 (0.70,0.97) 0.013 (0.004) 1.6E-04b
Inv carcinoma 0.47 (0.43,0.51) 0.49 (0.45,0.52) 0.51 (0.48,0.55) 0.50 (0.47,0.54) 0.54 (0.50,0.57) 0.55 (0.52,0.58) 0.58 (0.54,0.63) 0.003 (0.001) 2.3E-04b
Stage
Localised 0.73 (0.69,0.76) 0.76 (0.73,0.79) 0.77 (0.74,0.79) 0.77 (0.74,0.79) 0.80 (0.78,0.82) 0.82 (0.80,0.84) 0.81 (0.77,0.84) 0.004 (0.001) 7.0E-06b
Regional advanced 0.25 (0.17,0.34) 0.27 (0.20,0.36) 0.28 (0.19,0.38) 0.23 (0.15,0.31) 0.25 (0.18,0.32) 0.27 (0.21,0.33) 0.22 (0.04,0.49) <0.001 (0.002) 0.991
Distant advanced 0.05 (0.02,0.11) 0.08 (0.04,0.14) 0.05 (0.01,0.15) 0.04 (0.01,0.12) 0.09 (0.04,0.17) 0.07 (0.03,0.12) 0.05 (0.01,0.030) −0.001 (0.002) 0.509
Women Age (years)
0–49 0.90 (0.76,0.96) 0.82 (0.68,0.90) 0.87 (0.75,0.94) 0.95 (0.84,0.99) 0.82 (0.67,0.91) 0.79 (0.65,0.88) 0.78 (0.61,0.89) −0.003 (0.003) 0.409
50–64 0.78 (0.71,0.84) 0.85 (0.78,0.90) 0.79 (0.72,0.84) 0.84 (0.78,0.89) 0.82 (0.76,0.86) 0.89 (0.84,0.92) 0.86 (0.77,0.92) 0.004 (0.002) 0.032b
65–79 0.61 (0.56,0.66) 0.64 (0.59,0.69) 0.65 (0.60,0.69) 0.72 (0.67,0.76) 0.74 (0.69,0.79) 0.72 (0.67,0.76) 0.70 (0.63,0.77) 0.008 (0.001) 1.5E-05b
80+ 0.51 (0.40,0.62) 0.59 (0.48,0.70) 0.52 (0.42,0.61) 0.53 (0.44,0.62) 0.51 (0.44,0.59) 0.59 (0.51,0.66) 0.68 (0.56,0.79) 0.004 (0.003) 0.195
Morphology
Non-inv pap carcinoma LG 0.92 (0.82,0.96) 0.94 (0.83,0.98) 0.90 (0.82,0.94) 0.92 (0.85,0.96) 0.90 (0.84,0.94) 0.91 (0.85,0.95) 0.89 (0.78,0.95) −0.001 (0.001) 0.585
Non-inv pap carcinoma HG 0.74 (0.36,0.92) 0.90 (0.34,0.99) 0.71 (0.51,0.83) 0.88 (0.27,0.99) 0.79 (0.60,0.90) 0.81 (0.68,0.89) 0.88 ((0.69,0.95) <0.001 (0.005) 0.986
Dysplasia 0.52 (0.35,0.66) 0.65 (0.46,0.79) 0.84 (0.46,0.96) 0.78 (0.54,0.91) 0.96 (0.11,1.00) 0.78 (0.57,0.90) 0.93 (0.46,0.99) 0.011 (0.005) 0.035b
Carcinoma in situ 0.39 (0.15,0.62) 0.60 (0.41,0.75) 0.73 (0.52,0.86) 0.81 (0.57,0.93) 0.62 (0.50,0.72) 0.71 (0.51,0.84) 0.83 (0.29,0.97) 0.010 (0.006) 0.082
Inv carcinoma 0.43 (0.38,0.48) 0.43 (0.37,0.48) 0.42 (0.37,0.47) 0.46 (0.41,0.51) 0.45 (0.40,0.50) 0.51 (0.46,0.56) 0.50 (0.43,0.57) 0.003 (0.001) 0.010b
Stage
Localised 0.70 (0.66,0.74) 0.74 (0.69,0.78) 0.70 (0.66,0.73) 0.76 (0.72,0.79) 0.77 (0.74,0.80) 0.79 (0.76,0.82) 0.79 (0.74,0.83) 0.004 (0.001) 9.2E-06b
Regional advanced 0.14 (0.06,0.24) 0.19 (0.10,0.29) 0.18 (0.10,0.28) 0.30 (0.20,0.40) 0.18 (0.11,0.26) 0.25 (0.16,0.35) 0.30 (0.18,0.43) 0.004 (0.02) 0.055
Distant advanced 0.04 (0.01,0.15) 0.09 (0.01,0.27) 0.02 (0.01,0.10) 0.04 (0.01,0.10) 0.06 (0.01,0.16) 0.11 (0.05,0.22) 0.08 (0.01,0.41) −0.010 (0.006) 0.136
Page 7 of 11
and
5-year relative survival proportions (Ederer II) including confidence intervals by sex, morphology group stage stratified by 5-year diagnosis intervals from 1981 to 2014. We applied internal age-standardization
based on the latest diagnostic period 2011-14. Average annual relative survival proportion changes β^ RS are reported together with standard error (SE) and p-value for the test of a significant survival trend.
a
The relative survival values for the latest diagnostic period are based on a period approach
Significant p-values (based on the 5 % threshold) are marked withb
Andreassen et al. BMC Cancer (2016) 16:799 Page 8 of 11
proportions throughout the study period. It gives an in- had a diagnosis where the patient had metastases and/or
dicator for whether (and how much) survival changed any infiltration into surrounding areas. Patients with distant
over the past 30 years. On average, 5-year relative survival advanced tumors are 8.5 times more likely to die than pa-
proportions increased annually by β^ RS =0.004 in men (p = tients with localized tumors (excess mortality rate ratio
1.3 · 10-6) and β^ RS =0.003 in women (p = 4.5 · 10-6). In men, EMRR = 8.5, CI: 7.8–9.2). The corresponding EMRR for re-
the 5-year relative survival was 0.67 (CI: 0.64–0.70) in gional advanced tumors is 3.2 (CI: 3.0–3.4) when compared
1981-85 and 0.77 (CI: 0.75–0.79) in 2006-10. The corre- to localized tumors. The most severe diagnosis of having an
sponding 5-year relative survival in women were 0.63 (CI: invasive tumor lead to an EMRR of 6.1 (CI: 5.4–6.8) when
0.59–0.67) for 1981-85 and 0.72 (CI: 0.69–0.75) in 2006-10. comparing to the least severe diagnosis of a low-grade non-
The age-specific 5-year relative survival in men stayed invasive papillary carcinoma. Carcinoma in situ (EMRR 3.2,
mainly stable within the youngest age group (≤50 years), CI: 2.7–3.9), dysplasia (EMRR 2.4, CI: 1.9–2.9) and high-
while improvement in relative survival was the more pro- grade papillary carcinoma (EMRR 2.3, CI: 1.9–2.7) also in-
creased the EMRR significantly. The EMRR increased ex-
nounced the older the patient was (≥80 years: β^ RS =0.007,
ponentially with age with an EMRR of 4.0 (CI: 3.3–4.8) for
p = 0.015). In women, these trends were similar except that patients 80 years old (and older). The excess mortality rate
the increase in 5-year relative survival was most distinct in was 1.2 times higher in women compared to men (CI: 1.1–
the age group 65–79 years (β^ RS =0.008, p = 1.5 · 10-5). There 1.3). All these effects were strongly significant.
was a significant increase in 5-year relative survival for inva-
sive carcinomas in both men (β^ RS =0.003, p = 2.3 · 10-4) and
Discussion
women ( β^ RS =0.003, p = 0.010). Relative survival for local-
This paper presents trends in incidence and survival for
ized stages were significantly larger towards the end of the patients diagnosed with urothelial carcinoma of the urin-
study period in both men ( β^ RS =0.004, p = 7.0 · 10-6) and ary bladder in Norway between 1981 and 2014.
women ( β^ RS =0.004, p = 9.2 · 10-6). There is no significant Incidence of UCB in men and women has significantly
increase in survival for advanced stages, the tendency is increased throughout the study period. While this trend
towards decreasing survival for the distant advanced stage was rather linear for women, for men an initial increase
in both genders. Joinpoint analysis did not reveal any of incidence rates in the eighties was observed, followed
significant changes in the trend over time. by stable incidence rates. Interestingly, a similar pattern
We estimated the influence from the variables considered has been observed in lung cancer, which is also a
in our study (sex, age, diagnosis period, morphology group, smoking-related cancer type. A recent report [31]
stage) on the relative survival estimates and the results are showed that the lung cancer incidence rates in men lev-
illustrated in Fig. 2. The largest impact on relative survival elled off while incidence rates in females were still
Fig. 2 Estimated excess mortality rate ratios (EMRRs) and confidence intervals for sex, age group, diagnostic period, morphology and stage based
on a proportional excess hazard model
Andreassen et al. BMC Cancer (2016) 16:799 Page 9 of 11
increasing in Norway. A possible explanation is that the UCB and indicated the “necessity of debate of devel-
trends for lung cancer and UCB both reflect the vari- oping a valid screening procedure for UCB” at least
ation in smoking habits in the Norwegian population. for particular risk groups [16].
While the percentage of daily male smokers between 16 Modelling excess mortality with respect to the vari-
and 74 years has been almost linearly decreasing from ables included in our study confirmed advanced tu-
1973 (52 %) to 2014 (13 %) in Norway, the correspond- mors, invasive tumors, flat tumors and high-grade
ing percentage for female smokers kept stable from 1973 tumors as well as older age as risk factors. Sex and
through 1999 (31–34 %) and followed the smoking trend diagnosis period also play a significant role, but to a
in men thereafter [32]. In addition, the application of an lesser extent. Sex differences in survival have been
age-period-cohort model indicated that birth cohort ef- widely discussed. Differences with respect to the under-
fects, which are tightly connected to smoking patterns in lying anatomy, delays in diagnosis in females, as well as
the population, could at least partly, explain the ob- variations in hormone receptors and tumor biology
served trends. Furthermore, the overall increase in the might play a key role [36–38].
incidence of UCB can be explained by a significant in- Relative survival estimates rely on population life ta-
crease in the incidence of non-invasive tumours. In bles rather than using cause-specific death information.
comparison to our results, Abdollah et al [16] observed Pros and cons have been widely discussed with a general
a linear increasing trend in age-standardized incidence agreement on the use of relative survival to estimate net
of UCB from 21.0 to 25.5 per 100 000 person-years survival for population-based studies. The main concern
within the last three decades in US men. The same au- about using relative survival is the estimation of the
thors also reported an increased incidence for localized underlying expected survival in the population. The latter
stages, which is in line with our observations. In South needs to be a comparable group from the general popula-
Australia, incidence increased during 1980 to 2004 for tion, comparable also with respect to certain confounders
carcinoma in situ and invasive UCB combined [15] while like smoking. The use of a general population lifetable,
invasive UCB stayed stable in Norway. However, we also and not a lifetable adjusted for smoking, may have led to
observed an increase in high-grade non-invasive carcin- an underestimate of relative survival [39–41]. In a recent
oma (Tis, Ta) over time in men. Our data on sex differ- comparison of methods for estimating net survival, the
ences in incidence are in line with other contemporary Ederer II method [25] seemed to be the best choice [42].
publications [33–35]. The main limitation of this study is that we were not
We have shown a small overall improvement in 5- able to distinguish between muscle-invasive (T2-4) and
year relative survival proportions over the past three non-muscle invasive (T1) cancers because these tumors
decades. This improvement can particularly be seen in are condensed to the same morphology group in our
older patients and in those suffering from carcinoma cancer registry. However, we did have information about
in situ. There is no significant survival improvement the existence of metastases with tumors classified into
for advanced tumors in either sex. This could be inter- three stages: localized (non-invasive/invasive cancer
preted as a sign of a negligible effect of the increased without any metastasis), regional advanced (any infiltra-
use of cystectomy during the study period. Since this tion into surrounding areas or regional metastases) and
treatment was also increasingly used for elderly pa- distant advanced (distant metastases) tumors. The local-
tients, the same explanation could also apply to the ized group contains tumors without metastases but also
small but apparent survival improvement in elderly included those with unrecognized metastases. The rea-
patients. However, the largest improvement was seen son for that is a coding change in 1993 with respect to
for flat non-invasive tumors in women and non- the latter group, which does not allow us to separate no-
invasive tumors in men, which might reflect the intro- metastasis patients from those with unknown spread.
duction of immunotherapy (Bacillus Calmette-Guerin) Another drawback is that we had to use grading infor-
in the 1990s in Norway. In South Australia, there was mation based on the WHO 1973 system, such that our
a decrease in 5-year survival proportions from 64 to definition of low- and high grade is partly different from
58 % observed during 1980 to 2004 for in situ and in- the WHO/ISUP 2004 system since we define low-grade
vasive UCB combined [15]. Survival trends in tumors to include WHO grade 1 and 2 and high-grade
Switzerland for malignant UCB (non-invasive papillary tumors WHO grade 3.
and in situ carcinomas excluded) concluded with little
survival improvement based on data from 1991 to Conclusion
2010 [17]. A study investigating the variation of tem- This study gives a comprehensive overview over inci-
poral trends with respect to sociodemographic and so- dence and survival changes related to a diagnosis of
cioeconomic factors illustrated the underlying urothelial carcinoma of the urinary bladder in Norway
disparities associated with detection and treatment of from 1981 to 2014. To our knowledge, this is the only
Andreassen et al. BMC Cancer (2016) 16:799 Page 10 of 11
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CI: Confidence interval; EMRR: Excess mortality risk ratio; HG: High-grade;
cyclophosphamide for non-Hodgkin’s lymphoma. N Engl J Med. 1988;
LG: Low-grade; UCB: Urothelial carcinoma of the urinary bladder
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We thank Grete Kjølberg and Christine Mellem from the Cancer Registry of bladder cancer: a cohort study. J Natl Cancer Inst. 2012;104(18):1411–21.
Norway for their support with the morphological classification of the bladder doi:10.1093/jnci/djs328.
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Funding Accessed 9 Nov 2015.
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in the design of the study. All authors participated in writing of the economics of bladder cancer: costs and considerations of caring for this
manuscript and revised it critically. All authors have read and approved the disease. Eur Urol. 2014;66(2):253–62. doi:10.1016/j.eururo.2014.01.006.
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Competing interests
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The authors declare that they have no competing interests.
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