Clinical interval and diagnostic characteristics in a cohort of bladder cancer patients in Spain: a multicenter observational study
Bonfill et al. BMC Res Notes
Clinical interval and diagnostic characteristics in a cohort of bladder cancer patients in Spain: a multicenter observational study
Xavier Bonfill 0 1 2 9 10 11
María José Martinez‑Zapata 0 1 2 10 11
Robin W. M. Vernooij 0 1 2 10
María José Sánchez 1 2 11 16
María Morales SuárezV‑arela 1 2 11 15
Javier De la Cruz 1 2 11 14
José Ignacio Emparanza 1 2 11 13
Montserrat Ferrer 1 2 11 18
José Ignacio Pijoan 1 2 11 17
Joan Palou 1 2 7 12
Stefanie Schmidt 1 2 18
Eva Madrid 1 2 5 6 8
Víctor Abraira 1 2 11
Javier Zamora 1 2 3 4 11
0 Iberoamerican Cochrane Centre, Institute of Biomedical Research Sant Pau (IIB Sant Pau) , Barcelona , Spain
1 Madrid, Spain Ana Isabel Díaz Moratinos, Angel Montero Luis, Asunción Hervás, Carmen Vallejo Ocaña, Costantino Varona, Javier Burgos, Javier Zamora, Jose Alfredo Polo Rubio, Luis López‐Fando Lavalle, Miguel Angel Jimenez Cidre, Muriel García Alfonso, Nieves Plana Farras, Rosa Morera Lopez, Sonsoles Sancho Garcia, Victor Abraira, Victoria Gomez Dos Santos (Hospital Ramón y Cajal); Agustín Gómez de la Cámara, Javier de la Cruz, Juan Passas Martínez, Hum‐ berto García Muñoz, Ma Ángeles Cabeza Rodríguez, Hospital 12 de Octubre
2 Authors' contributions Study concepts: XB. Study design: XB, MJM. Data acquisition: XB, MJM, RV, MJS, MMS, JDC, JIE, MF, JIP, JP, SS, EM, VA, JZ. Quality control of data and algorithms: MJM, RV. Data analysis and interpretation: XB, MJM, RV, JZ. Statistical analysis: RV, VA, JZ. Manuscript preparation: XB, MJM, RV, EM. Manuscript editing: XB, MJM, RV, MJS, MMS, JDC, JIE, MF, JIP, JP, SS, EM, VA, JZ. Manuscript review: XB, MJM, RV, MJS, MMS, JDC, JIE, MF, JIP, JP, SS, EM, VA, JZ. All authors read and approved the final manuscript
3 Unidad de Bioestadística Clínica, Hospital Universitario Ramón y Cajal, IRYCIS , Madrid , Spain
4 Barts and the London School of Medicine and Dentistry, Queen Mary University London , London , UK
5 Biomedical Research Centre‐Universidad de Valparaiso‐ Chile , Valparaiso , Chile
6 Department of Public Health‐School of Medicine, Universidad de Valparaiso‐ Chile , Valparaiso , Chile
7 Universitat Autònoma de Barcelona , Barcelona , Spain
8 Iberoamerican Cochrane Centre , Barcelona , Spain
9 Public Health and Clinical Epidemiology Service, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona , Bar‐ celona , Spain
10 Iber‐ oamerican Cochrane Centre, Institute of Biomedical Research Sant Pau (IIB Sant Pau) , Barcelona , Spain
11 CIBER de Epidemiología y Salud Pública (CIBERESP) , Barcelona , Spain
12 Fundació Puigvert , Barcelona , Spain
13 Clinical Epidemiol‐ ogy Unit, Hospital Universitario Donostia, BioDonostia , San Sebastian , Spain
14 Hospital 12 de Octubre , Madrid , Spain
15 Unit of Public Health and Envi‐ ronmental Care, Department of Preventive Medicine, University of Valencia , Valencia , Spain
16 Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria de Granada , Barcelona , Spain
17 Clinical Epidemiology Unit, Hospital , Universitario Cruces. Biocruces, Barakaldo , Spain
18 Health Services Research Group, IMIM (Hospital del Mar Medical Research Institute) , Barcelona , Spain
Objective: We performed a cohort study in seven hospitals in Spain to determine the clinical characteristics of incident patients with bladder cancer, the diagnostic process, and the conditions that might affect health care interval times. Results: 314 patients with bladder cancer were included, 70.3 (Standard Deviation [SD] 11.2) years old and 85.0% male. Clinical stage was T1 in 45.9% of patients. The median interval time between first consultation and diagnosis was of 104.0 days (Inter quartile range [IQR]:112.0; range from 0 to 986), being shorter for those patients who attended a hospital for their first consultation. The median interval time between diagnosis and first treatment was of 0.0 days (IQR: 0.0; range from 0 to 366), being longer when the patient had a pathologic tumor stage ≥ T2a.
Urinary bladder neoplasm; Neoplasm staging; Time factors; Diagnostic techniques and procedures; Observational study
Bladder cancer is the ninth most common diagnosed
cancer worldwide, contributing with 429,793 new cases
]. In Spain it is the fifth most common diagnosed
cancer with 13,789 new cases yearly [
]. In 2012, the
estimated number of deaths due to bladder cancer was
of 165,068 worldwide and 5007 in Spain, making it the
twelfth leading cause worldwide and the sixth in Spain
Bladder cancer is one of the malignant tumors where a
large proportion of health resources are being allocated
due to its increasing survival rates and lifelong routine
monitoring which involves associated treatment costs,
and high recurrence rates [
Some international initiatives have been undertaken
to obtain trustworthy information regarding the
healthcare process for bladder cancer patients [
]. In Spain,
several studies reported information from hospital
minimum data sets and hospital-based cancer registries [
]. These sources of information, however, are quite
limited in describing the diagnostic processes,
therapeutic approaches, and prognostic factors in bladder cancer.
One study conducted in Spain, estimated the annual
incidence of bladder cancer and described the clinical
profile of patients with bladder cancer, but did not assess the
diagnostic and therapeutic processes and potential
factors influencing time intervals [
]. For these reasons, the
objective of the present study was to examine the
clinical care process and health outcomes in incident cases
of bladder cancer. In a future article, we will report the
results related to the clinical follow-up.
We performed a multicenter, cohort study of bladder and
prostate cancer, in Spain [
]. The research ethics
committee from each of the seven tertiary participating
hospitals (Additional file 1) approved the protocol. Patient
recruitment was done from October 2010 to September
2011. Consecutive patients were selected from the
urology and oncology departments and the inclusion criteria
were: (1) being diagnosed of bladder cancer during the
study period; (2) being diagnosed and treated at one of
the participating hospitals; and (3) agree to participate
and sign the informed consent form.
Clinical information was gathered by reviewing the
medical records and structured interviews to patients
(Additional file 2). The outcomes of interest were:
sociodemographic data, body mass index (BMI), Charlson
index, ECOG WHO score, setting of the first consultation,
tests performed to diagnose bladder cancer, pathological
results of bladder biopsy, patient tumor clinical stages,
and time length of diagnostic and therapeutic intervals
(Fig. 1). The time length from first symptoms to first
consultation was defined as the period between the date of
appearance of the first symptom related to bladder cancer
and the date of attendance to the first medical visit (coded
as less than 1 month, between 1 and 12 months, after
12 months), which then led to a bladder cancer diagnosis.
For asymptomatic patients, the first consultation date was
determined by the date when the bladder biopsy was
performed. We took the positive biopsy report as the
confirmatory diagnosis of the disease, whose date was used to
calculate the diagnostic interval. The therapeutic interval
was defined as the period between the dates of the
pathological diagnosis and the initiation of the first treatment.
For categorical variables we calculated relative
frequencies; and for continuous variables, the mean and standard
deviation (SD) or median and interquartile range (IQR) if
We assessed the association between time variables and
potential predictors by using multilevel logistic
regression models (patients at first level and hospitals at second
level). As potential predictors we considered the
following variables: age, BMI, gender, educational level, ECOG
WHO score, setting of the first consultation, primary
tumor clinical stage, and time since appearance of first
symptoms. Continuous time variables were transformed
into dichotomous variables. Based on previous
studies we established an interval of 100 days as the optimal
diagnostic interval, and 30 days for the optimal treatment
]. Firstly, an empty model was adjusted
considering only the random effect of hospital’s location
based on the variability of the two outcomes investigated.
Univariate models where then adjusted for each potential
predictor. The final model was fitted through a backward
selection procedure based on the Wald tests results. Both
the empty model and the final multilevel models were
estimated by maximum likelihood using the adaptive
Time between first symptom and consultation
Time between diagnosis and first treatment
First symptom of bladder cancer
First consultation to a healthcare professional
Diagnostic confirmation of cancer
First treatment of bladder cancer
Time between first consultation and diagnosis
Time between first consultation and first treatment
Fig. 1 Time intervals considered in our study
Gaussian quadrature approximation (with seven
quadrature points) [
The effect measure was the odds ratio (OR) with 95%
confidence interval, and was considered statistically
significant if p < 0.05. We calculated the intra-cluster
correlation coefficient (ICC) and the median odds ratio (MOR)
to estimate the random inter-hospital variability. A lower
ICC indicates a lower probability of patients sharing
similar hospital experiences. The MOR is the increased risk
of moving a patient to a hospital with longer diagnostic
and therapeutic intervals [
]. The statistical software
used was SPSS, v20.0 (SPSS INC., Chicago, IL, United
States of America) and Stata, v12.1 (College Station, TX:
Of the 347 patients recruited, 314 patients participated in
the study and 33 were excluded for not meeting the
inclusion criteria. Mean age was 70.3 years (SD: 11.2), 267
(85.0%) were male, 194 (61.9%) had at least completed
primary studies, and 216 (68.8%) were retired (Table 1).
The mean BMI was 27.2 (SD: 4.8) and 180 (57.3%)
patients were full active according to the ECOG WHO
performance status. The Charlson co-morbidity index
was between one and three for 284 patients (90.5%).
First consultation for bladder-related symptoms was
performed in primary care settings for 151 participants
(48.1%), and in hospital settings for the remaining 138
patients (43.9%). In 9.8% of the patients, the disease was
diagnosed during a routine visit; in these cases, patients
did not report symptoms, or only a certain degree of
discomfort caused by the bladder cancer. From the total
group, 85.0% were symptomatic; being hematuria the
most frequent symptom (73.9%). The time from the first
symptoms to first consultation was between 1 month and
1 year for 60.5% of the participants. The most common
pathologic malignant diagnosis was urothelial cell
carcinoma (90.1%). Other pathologic diagnoses were
adenocarcinoma (8.6%), and squamous cell carcinoma (0.6%).
The most frequent primary tumor clinical stage was T1
A bladder ultrasound was reported in 79.0% of the
patients and a cystoscopy in 52.2% (Additional file 3).
The median diagnostic time interval was 104.0 days (IQR:
112.0) (Table 1). A statistically significant variability was
found among hospitals for this interval (MOR: 1.47, 95%
CI: 1.14–3.06) (Table 2). Patients who went to primary
care setting presented an OR of 1.64 (95% CI 1.03–2.63,
p = 0.038) of having a diagnostic interval longer than
100 days compared to patients who were first attended
at the hospital. Furthermore, patients who experienced
first symptoms longer than 1 month presented an OR of
2.38 (95% CI 1.25–4.51, p = 0.008) of having a diagnostic
interval longer than 100 days compared to patients who
experienced their symptoms in less than 1 month. There
were no significant differences in terms of gender, age,
BMI, educational level, ECOG WHO score, or primary
tumor stages (Table 2; Additional file 4). The multivariate
analysis did not show statistically significant variability
among hospitals for this time interval.
The median therapeutic interval was 0.0 days (IQR: 0.0)
(Table 1). There was a statistically significant
variability among hospitals for this interval (MOR: 2.81, 95% CI
1.56–11.06, p < 0.001). Patients with a BMI ≥ 25 showed
a significant lower odd of having a therapeutic
interval longer than 30 days (OR = 0.39; 95% CI 0.16–0.94,
p = 0.037). Patients in a tumor stage from T2a–T4b
presented an OR of 4.39 (95% CI 1.72–11.21, p = 0.002) of
having a therapeutic interval longer than 30 days
compared to patients with inferior clinical stages. No
significant differences were found within the other outcomes.
The multivariate analysis showed statistically significant
variability among hospitals in the therapeutic
interval and the only factor that significantly influenced this
interval was the tumor stage (Table 2).
Our multicenter study in Spain included 314 patients
mostly diagnosed with bladder urothelial cell carcinoma.
The population characteristics were similar to those
described in previously published studies [
majority of bladder cancers started with symptoms, being
hematuria the most frequent. The percentage (42.3%) of
localized tumors was similar to another study conducted
in Spain , but considerably higher than other previous
Most patients in our study population had an early
stage of bladder cancer and the diagnosis interval was
relatively long, with a median of 104.0 days. Patients who
experienced first symptoms for no longer than 1 month
before the first consultation and those who went to a
hospital for their first consultation had a significantly
narrower diagnostic interval; this was expected as the
hospital has the possibility of performing TUR
(TransUrethral Resection) and biopsy (diagnosis of certainty
and treatment), and in primary care only basic imaging
tests. There was not significant variability among
hospitals in relation to this time interval. The delay in
diagnostic interval is concordant with other studies [
consequently some European initiatives have emerged
to narrow this interval [
]. These initiatives suggest
that expediting the initial ultrasonography/cystoscopy
in all patients could improve the time of diagnosis and
treatment for bladder cancer. The European Association
of Urology guideline recommends ultrasound as one of
the initial staging techniques for patients with hematuria,
N = 314, n
(%)/x ± SD
N = 314, n
(%)/x ± SD
and cystoscopy only for patients experiencing symptoms
suggestive of bladder cancer .
Previous Spanish studies assessed the diagnostic and
therapeutic time intervals in cancer patients, however
they were mainly performed in a single hospital and they
all included other types of cancer [
], except for
one conducted more than 20 years ago . One
Spanish multicenter study reported a mean treatment interval
longer than ours (73.2 days) due to a different
definition of this variable [
]. They measured the time from
the first performed diagnostic tests and not from the
date of histological confirmation of bladder cancer until
In addition, our results reveal that among centers there
is a significant variability in terms of treatment intervals.
Diverse population characteristics, health care
organizations (e.g. health care pathways connecting primary
and specialized care) and clinical policies across the
different Spanish regions may explain, at least in part, this
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Some patients’ and tumor features were also associated
with the length of time between diagnosis and treatment;
e.g. among patients with a higher primary tumor clinical
stage. This finding may be explained because this group
of patients is generally treated with cystectomy and
chemotherapy and require a more complex process than
a TUR approach.
This study may be prone to some limitations. Information
bias is a potential issue as the study is based exclusively
on information obtained from hospital clinical records.
As a result, some outpatient factors, such as those related
to consultations in primary care settings, may not have
been properly forethought.
Additional file 1. List of Ethic Committees that approved the study.
Additional file 2. Patients’ structured interview.
Additional file 3. Diagnostic tests for bladder cancer patients.
Additional file 4. Characteristics of bladder cancer patients by hospitals.
BMI: body mass index; ECOG: Eastern Cooperative Oncology Group; ICC: intra‑
cluster correlation coefficient; IQR: interquartile range; MOR: median odds
ratio; OR: odds ratio; SD: standard deviation; USA: United States of America;
USD: United States dollar; WHO: World Health Organization.
We would like to thank Andrea Cervera Alepuz and Montserrat León for the
English review and editing of the manuscript. Dr. Mª José Martinez Zapata
is funded by a Miguel Servet research contract from the Instituto de Salud
Carlos III (CP15/00116). The researchers listed are considered as authors of the
EMPARO study group.
EMPARO study Group:
Coordinating investigator: Xavier Bonfill Cosp (Iberoamerican Cochrane Cen‑
tre. Public Health and Clinical Epidemiology Service. Hospital de la Santa Creu i
Sant Pau, IIB Sant Pau, Barcelona, Spain).
Project manager: Mª José Martínez Zapata (Iberoamerican Cochrane Centre.
IIBSant Pau, Barcelona, Spain).
Clinical research assistants: Alborada Martínez (Universidad de Valencia);
Enrique Morales Olivera (Escuela Andaluza de Salud Pública, Granada, Spain);
Esther Canovas, Laura Muñoz, Gemma Mas, René Acosta, Ekaterina Popova
(Iberoamerican Cochrane Centre. IIBSant Pau, Barcelona, Spain); Irma Ospina
(Hospital 12 de Octubre, Madrid, Spain); Mª José Velázquez (Hospital Donostia,
Donostia, Spain); Tamara Ruiz Merlo (Hospital Ramón y Cajal, Madrid, Spain);
Gael Combarros Herman, Judit Tirado Muñoz (IMIM, Barcelona, Spain).
Statistical analysis: Robin W.M. Vernooij (Iberoamerican Cochrane Centre.
IIBSant Pau, Barcelona, Spain); Victor Abraira and Javier Zamora (Unidad de
Bioestadística Clínica. Hospital Universitario Ramón y Cajal. IRYCIS, Madrid,
Albert Frances (Hospital del Mar); Carola Orrego Villagran, Rosa Suñol (Instituto
Universitario Avedis Donabedian); Dimelza Osorio, Gemma Sancho Pardo,
Ignasi Bolívar, José Pablo Maroto, Mª Jesús Quintana, Martin Lorente Cristina
(Hospital de la Santa Creu i Sant Pau); Ferran Algaba, Palou Redorta, Salvador
Esquena (Fundació Puigvert); Jordi Bachs (Fundació Privada Hospital de la
Santa Creu i Sant Pau); Mª José Martínez Zapata (Iberoamerican Cochrane
Centre. IIBSant Pau); Montserrat Ferrer Fores, Stefanie Schmidt, Olatz Garin,
Virginia Becerra Bachito, Yolanda Pardo (IMIM ‑ Hospital del Mar Medical
Amaia Martínez Galarza, José Ignacio Pijoán Zubizarreta, (Hospital Universitario
Cruces/BioCruces Health Research Institute).
David Manuel Castro Diaz, Juan Manuel Ramos Goñi, Julio Lopez Bastida (HTA
Unit of the Canary Islands Health Service).
Armando Suárez Pacheco, Cesar García López, José Manuel Cozar Olmo (Hos‑
pital Universitario Virgen de las Nieves); Carmen Martínez, Daysy Chang Chan,
Mª José Sánchez Pérez (Escuela Andaluza de Salud Pública).
San Sebastián, Spain
Irune Ruiz Díaz, José Ignacio Emparanza, Juan Pablo Sanz Jaka (Hospital
The authors declare that they have no competing interests.
Availability of data and materials
The datasets during and/or analyzed during the current study are available
from the corresponding author on reasonable request.
Consent to publish
Ethics approval and consent to participate
This study was approved by the Ethics Committees of Hospital de la Santa
Creu i Sant Pau (Barcelona), Fundación Puigvert (Barcelona), Hospital 12 de
Octubre (Madrid), Hospital Ramón y Cajal (Madrid), Hospital Universitario Don‑
ostia (San Sebastián), Hospital Nuestra Señora del Mar (Barcelona), Hospital
Virgen de las Nieves (Granada), Consorcio Hospital General Universitario de
Valencia and Basque Country Ethics Committee.
Previous inclusion in this study, all patients were informed about the study,
they accepted to participate and signed the consent form.
Instituto Carlos III: Grants PS09/01204 and PS09/01619 (Fondo de Investi‑
gación Sanitaria. Spain).
Springer Nature remains neutral with regard to jurisdictional claims in pub‑
lished maps and institutional affiliations.
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