Observational Study Medicine ® Follow-up care of 12 months of patients with bladder cancer in Spain A multicenter prospective cohort study Downloaded from http://journals.lww.com/md-journal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy Xavier Bonfill, MD, PhDa,b,c,d, María José Martinez-Zapata, MD, PhDa,b,e,* , Leslie Barrionuevo-Rosas, MD, PhD, MPHb, Robin WM Vernooij, PhD, MPHb, María José Sánchez, MD, PhDa,f, María Morales-Suárez-Varela, MD, PhDa,g, wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 07/17/2023 Javier De la Cruz, MD, PhDa,h, José Ignacio Emparanza, MD, PhDa,i, Montserrat Ferrer, MD, PhDa,j, José Ignacio Pijoan, MD, PhDca,k, Joan Palou, MD, PhDl, Albert Frances, MD, PhDm, Eva Madrid, MD, PhDn, Claudia Coscia, PhDco, Javier Zamora, PhDo,p, on behalf of the EMPARO-CU study group Abstract The therapeutic approach of bladder cancer strongly determines its prognosis. We describe the treatments and outcomes for a Spanish cohort of patients with bladder cancer for the first 12 months after diagnosis and identify the factors that influenced the decision to undergo the treatment received. We conducted a multicenter, prospective, cohort study including primary bladder cancer patients during the first 12 months after diagnosis. The clinical outcomes were performance status (ECOG), adverse events and any cause of mortality. We stratified the analysis by factors that might influence the treatments received. We conducted univariate and multivariable logistic regression models to assess which patient and tumor characteristics were associated with receiving adjuvant treatment in the subgroup of noninvasive bladder cancer patients. In total, 314 patients were included (85% men; 53.8% >70 years) in 7 tertiary Spanish hospitals; 82.2% had a noninvasive urothelial bladder cancer (NMIBC). Patients received mostly surgery plus adjuvant therapy (67.7%). BCG (32.8% patients) was the most frequently administered adjuvant therapy, followed by intravesical chemotherapy (17.8% patients) and radiotherapy (10.8%). The variability of administered treatments among hospitals was low. Patients with NMIBC were more likely to receive adjuvant therapy if they had a higher educational level, some comorbidities and a high-grade tumor. The number of fully active patients (ECOG 0) significantly decreased during the first year of follow-up from 58% to 36 % (OR: 2.41, 95%CI 1.82–3.20); at 12-month follow-up 10.8% patients had died from any cause. In conclusion, most of the patients had a NMIBC. Surgery alone or plus adjuvant therapy were the commonest curative options of bladder cancer. BCG therapy was the adjuvant therapy most frequently administered. Higher educational level, presence of comorbidities and a high-grade tumor were associated with adjuvant therapy. Patient performance status was worsening over time. Almost 1 of 10 patients died during the first year of follow-up. Abbreviations: BCG = bacilli of Calmette-Guerin, BMI = body mass index, CI = confidence intervals, ECOG = eastern cooperative oncology group, NMIBC = non-invasive urothelial bladder cancer, OR = odds ratios, QoL = quality of life, TURB = transurethral resection of the bladder, WHO = World Health Organization. Keywords: bladder neoplasms, cohort study, male urogenital diseases, multicenter study, multivariable analysis Instituto Carlos III: Grants PS09/01204 and PS09/01619 (Fondo de Investigación San Sebastian, Spain, j Health Services Research Group, IMIM (Hospital del Mar Sanitaria. Spain). Medical Research Institute), Barcelona, Spain, k Clinical Epidemiology Unit, Hospital, The authors have no funding and conflicts of interest to disclose. Universitario Cruces. Biocruces, Barakaldo, Spain, l Fundació Puigvert, Barcelona, Spain, m Urology Service. Hospital Ntra. Sra. Del Mar, Barcelona, Spain, n Cochrane The datasets generated during and/or analyzed during the current study are Centre Universidad de Valparaíso, Chile. Interdisciplinary Centre for Health Studies available from the corresponding author on reasonable request. CIESAL. Department of Public Health - School of Medicine - Universidad de This study was approved by the Ethics Committee of Hospital de la Santa Creu i Sant Valparaíso - Chile, o Unidad de Bioestadística Clínica, Hospital Universitario Ramón Pau (Barcelona), Fundación Puigvert (Barcelona), Hospital 12 de Octubre (Madrid), y Cajal, IRYCIS, Madrid, Spain, p Barts and the London School of Medicine and Hospital Ramón y Cajal (Madrid), Hospital Universitario Donostia (San Sebastián), Hospital Dentistry, Queen Mary University London, London, UK. Nuestra Señora del Mar (Barcelona), Hospital Virgen de las Nieves (Granada), Consorcio * Correspondence: María José Martínez Zapata, CIBER de Epidemiología y Salud Hospital General Universitario de Valencia and Basque Country Ethics Committee Pública (CIBERESP), Barcelona, Spain (e-mail: mmartinezz@santpau.cat). Previously to inclusion in this study, all patients were informed about the study, Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc. they accepted to participate and signed the consent form. This is an open-access article distributed under the terms of the Creative Commons Supplemental Digital Content is available for this article. Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to a CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain, b download, share, remix, transform, and buildup the work provided it is properly Iberoamerican Cochrane Centre, Institute of Biomedical Research Sant Pau (IIB cited. The work cannot be used commercially without permission from the journal. Sant Pau), Barcelona, Spain, c Public Health and Clinical Epidemiology Service How to cite this article: Bonfill X, Martinez-Zapata MJ, Barrionuevo-Rosas L, Vernooij Hospital de la Santa Creu I, Barcelona, Spain, d Universitat Autònoma de Barcelona, RWM, Sánchez MJ, Morales-Suárez-Varela M, De la Cruz J, Ignacio Emparanza J, Barcelona, Spain, e Cochrane Ecuador. Centro de Investigación en Salud Pública Ferrer M, Pijoan JI, Palou J, Frances A, Madrid E, Coscia C, Zamora J, on behalf of the y Epidemiología Clínica (CISPEC). Facultad de Ciencias de la Salud Eugenio EMPARO-CU study group. Follow-up care of 12 months of patients with bladder cancer Espejo, Universidad Tecnológica Equinoccial, Quito, Ecuador, f Escuela Andaluza in Spain: A multicenter prospective cohort study. Medicine 2022;101:42(e31175). de Salud Pública, Instituto de Investigación Biosanitaria de Granada, Barcelona, Spain, g Unit of Public Health and Environmental Care, Department of Preventive Received: 23 April 2020 / Received in final form: 14 September 2022 / Accepted: Medicine, University of Valencia, Valencia, Spain, h Hospital 12 de Octubre, Madrid, 15 September 2022 Spain, i Clinical Epidemiology Unit, Hospital Universitario Donostia, BioDonostia, http://dx.doi.org/10.1097/MD.0000000000031175 1 Bonfill et al. • Medicine (2022) 101:42Medicine 1. Introduction with high school or 10-14 years of schooling-, post-second- Bladder cancer is the fourth most commonly diagnosed cancer ary-subjects with university degree or post-graduate studies cor- in the European Union in men, and the 12th in women, with responding to 15 years or more of schooling-), Charlson index an incidence of 55.4 and 12.1/100,000 person per year, respec- (0, 1, 2, ≥3), number of tumors (1, ≥2) and largest tumor size tively.[1] It is the fifth cancer with higher mortality with an inci- (<30 mm, ≥30 mm). We obtained mean and standard deviation dence of 31/100,000 people per year for both sexes.[1] In Spain for continuous variables (age and BMI) and relative and abso- it is globally, the fifth most commonly diagnosed cancer with an lute frequencies for categorical variables. incidence of 37.8/100,000 people per year and mortality rate of In addition, we imputed missing values for variables with missing data using the Multiple Imputation by Chained Downloaded from http://journals.lww.com/md-journal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy 11/100,000 people per year.[1] In general, symptoms start with hematuria (around 90% Equations method, where each variable has its own imputation of the cases), the tumor is confined to the bladder, and the model. most common histological type is urothelial cell carcinoma.[2] We performed a subgroup analysis selecting only the wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 07/17/2023 Prognosis of bladder cancer depends not only on patient and non-muscle-invasive urothelial carcinomas cases (Ta, Tis, stage tumor characteristics, but also on the capability of the health- T1). Univariate and multivariate logistic regression models care system to identify the disease and treat the patients in a were constructed to assess associations between clinical and timely manner and to perform an adequate follow-up as well. demographic variables (independent variables) and any adju- The follow-up of patients with bladder cancer remains compli- vant treatment (intravesical Bacilli of Calmette-Guérin -BCG-, cated due to the high frequency of recurrence and progression chemotherapy, and radiotherapy administered up to 1 year after treatment.[3–5] Although there are guidelines about diag- after diagnosis) received after surgery (dependent variables). nosis and treatment procedures, little is known regarding how Specifically, independent variables considered as potentially bladder cancer patients are treated in a prospective follow-up associated with adjuvant treatment were age, sex, BMI, educa- with a representative large cohort in multiple centers. tion level, performance status, Charlson index, primary tumor, We therefore conducted a prospective cohort study of Spanish Tis associated with Ta or T1, tumor histology grade, size and bladder cancer patients. Baseline characteristics, diagnostic and number of tumors. therapeutic intervals in this cohort were previously published.[2] Repeated measures of performance status (ECOG/WHO) Quality of life (QoL) of this cohort was also reported.[6] In this within participants (at baseline, 6 months and 12 months) were article, we presented patient-important outcomes and treat- analyzed using generalized estimating equation models where ments received during the first 12-months follow-up after diag- each patient has 1 value of performance status for each period. nosis. Our first objective was to describe the clinical outcomes An autoregressive correlation structure was chosen. We tested and treatments received by bladder cancer patients during the the presence of a linear trend of deterioration of performance first 12-month-follow-up after diagnosis. Secondly, we aim to status overtime, by introducing time to assessment (at baseline, identify factors associated with the prescription of adjuvant 6 months and 12 months) as independent variable in the model, treatment in patients with non-muscle-invasive bladder cancer. and any deterioration of performance status (Yes/No) as depen- dent variable. Odds ratios (OR) with 95% confidence intervals (CI) were used as association estimates. Level of significance was set to 2. Methods α = 0.05. The statistical software used was SPSS, v24.0 (SPSS We performed a multicenter, prospective cohort study in patients INC., Chicago, IL) and Stata, v14.1 (College Station, TX: with a newly diagnosed bladder cancer in Spain from October StataCorp LP). 2010 to September 2011. Methods were previously published.[2] The research ethics committees from the 7 tertiary participating hospitals approved the protocol. Consecutive bladder cancer 3. Results patients were identified from the urology and oncology depart- Three-hundred and fourteen patients from 347 recruited patients ments. The eligibility criteria were: being diagnosed of bladder with a first diagnosis of bladder cancer fulfilled the inclusion cri- cancer during the study period; being diagnosed and treated at teria. During 12 months follow-up after diagnosis 34 (10.8%) the participating hospitals; and agree to participate and signing patients died and 5 (1.6%) were losses of follow-up (Fig. 1). The the informed consent form. reasons of death were bladder cancer progression (15 patients), The information sources were medical records and struc- other non-neoplasm diseases (6 patients), and unknown causes tured interviews with patients (baseline, at 6 and 12 months (13 patients). of follow-up). The collected data were: socio-demograph- The majority of bladder cancer patients were men (85.0%), ics, body mass index (BMI), Charlson co-morbidity index, older than 70 years of age (53.8%, median age 71.7, range: Eastern Cooperative Oncology Group/WHO performance sta- 36–100), overweight or obese (67.6%, median BMI 26.6, range: tus (ECOG/WHO), bladder biopsy pathology reports, Tumor 15.6–49.8), had low level of education (52.9%) and had some lymph Nodes Metastases stage, received treatments, patient-re- comorbidities (64.0%) (Table 1). ported adverse events, disease status and mortality. The most frequently recorded co-morbidities were other cancers (21.7%), diabetes (21.0%), congestive heart failure (17.8%), chronic pulmonary disease (15.9%), renal disease 2.1. Statistical analysis (11.1%), myocardial infarction (8.9%), peripheral vascular We performed a descriptive analysis stratified by received treat- disease (5.4%), cerebrovascular disease (5.1%), liver disease ment (only surgery or surgery with any adjuvant therapy). We (4.1%) and others (4.8%). analyzed the following variables: age, sex, BMI, educational Two-hundred sixteen (68.8%) patients underwent surgery level, ECOG/WHO status, Charlson index, primary tumor, with some adjuvant therapy (32.8% intravesical BCG, 17.8% tumor in situ (Tis) associated, tumor histological grade, number intravesical chemotherapy, 10.8% radiotherapy or systemic che- of tumors, and largest tumor size. motherapy, 7.4% non-specified) and, 91 (29.0%) patients were Using European organization of research and treatment of treated with only surgery (Transurethral resection of the bladder cancer and urological club for oncological treatment risk tables -TURB- and/or radical cystectomy) (Table 1). In general, TURB for recurrence and progression,[7–9] the following variables were alone or surgery plus intravesical BCG were the usual treat- categorized: age (<60, 60–70, ≥71years), BMI (≤24.9, 25–29.9, ments in all hospitals, except in hospital E, which treated their ≥30), educational level (illiterate-primary, secondary-subjects patients most commonly with TURB or surgery plus intravesical 2 Bonfill et al. • Medicine (2022) 101:42www.md-journal.com Assessed for eligibility N= 347 Excluded (n=32) Enrolment -Did not meet inclusion criteria Downloaded from http://journals.lww.com/md-journal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 07/17/2023 Included N=314 Follow-Up and Analyses Losses: -13 Deaths -3 Discontinued follow-up 6-month follow-up N=298 Losses: -21 Deaths -2 Discontinued follow-up 12-month follow-up N=275 Figure 1. Flow diagram of the bladder cancer cohort follow-up. chemotherapy (Supplementary material, TS1, http://links.lww. 5% died from progression of bladder cancer and 10.8% had com/MD/H647). died from any cause (Table 4). Three hundred and two patients (96.2%) had a urothe- One hundred-eight (34.4%) patients suffered treatment-re- lial cell carcinoma. In 258 (82.2%) patients the bladder can- lated adverse events, mostly related to surgery and systemic che- cer was non-muscle-invasive; 33.1% of tumors were multiple motherapy (Supplementary material, TS2, http://links.lww.com/ and 29.6% large size (≥30 mm). A low number of patients had MD/H648). positive lymph nodes (5.0%) and distance metastases (3.2%) (Table 2). 4. Discussion Among patients with a non-muscle-invasive bladder cancer, the factors significantly associated to receive any adjuvant ther- Overall, 314 patients, mainly men older than 70 years, were apy were educational level, Charlson index and tumor histology recruited over 1-year in our prospective cohort from 7 tertiary grade. Patients with higher studies (secondary or post-secondary Spanish hospitals. All patients received surgery, either alone (1 studies) were more likely to receive adjuvant therapy than those third) or with adjuvant therapy (more than two thirds). One who had a lower educational level (OR: 2.93, 95%CI 1.09– third of patients received BCG that was the most frequent adju- 7.89; OR: 9.88, 95%CI 2.18–44.78, respectively) (Table 3). vant therapy administered, followed by intravesical chemother- Patients with Charlson index 1 or 2 received adjuvant therapy apy and radiotherapy or systemic chemotherapy. more frequently than those who did not have any comorbidity We found 82% of patients had non-muscle-invasive urothe- (OR 3.28, 95%CI 1.05–10.27; OR: 4.81, 95%CI 1.37–16.88, lial bladder cancer (NMIBC); they were more likely to receive respectively). Furthermore, patients with high-grade carcinoma adjuvant therapy if they had a high-grade carcinoma, higher were more likely to receive adjuvant therapy than those who level of studies and 1 or 2 co-morbidities. Previous studies had a lower grade carcinoma (OR: 4.85, 95%CI 1.65–14.26). showed an association between a high grade NMIBC and the Considering all included patients, performance status (ECOG) risk of progression or recurrence.[5] We did not find studies with was worsening over time (Fig. 2). Comparing with basal per- information about study co-morbidities and educational level as formance status, the number of fully active patients (ECOG 0) predictors for receiving adjuvant therapy. However, other can- decreased significantly during the first year of follow-up from cers it has been shown association of high level of studies with 58% to 36 % (OR: 2.41, 95%CI 1.82–3.20). the likelihood of receiving adjuvant therapy.[10] Concerning the disease condition at 12-month-follow-up, In addition, our study reveals that there was not a signifi- 33.3% of patients had persistence or progression of the disease, cant variability among centers in the indications of the different 3 Bonfill et al. • Medicine (2022) 101:42Medicine Table 1 Patient characteristics by treatment received. Only surgery Surgery and adjuvant therapy All TURB & radical Intravesical BCG Radiotherapy or Surgery plus non-specified Unknown patients TURB cystectomy chemotherapy intravesical systemic chemotherapy adjuvant therapy Treatment N = 314 N = 82 N=9 N = 56 N = 103 N = 34 N = 23 N=7 Downloaded from http://journals.lww.com/md-journal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy n (%) n n n n n n n Age at presentation  <60 yrs 61 (19.4) 20 2 14 16 3 3 3  60-70 yrs 84 (26.8) 18 2 19 26 10 7 2 wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 07/17/2023  ≥71 yrs 169 (53.8) 44 5 23 61 21 13 2  Missing 0 (0.0) 0 0 0 0 0 0 0 Sex (0.0)  Men 267 (85.0) 67 8 43 93 30 20 6  Women 47 (15.0) 15 1 13 10 4 3 1 Body mass index  ≤24.9 87 (27.7) 22 2 15 27 7 9 5  25 to 29.9 149 (47.5) 41 3 26 50 19 9 1  ≥30 63 (20.1) 17 1 14 19 7 4 1  Unknown 15 (4.7) 2 3 1 7 1 1 0 Educational level  Illiterate- 166 (52.9) 53 3 22 57 16 11 4 primary  Secondary 103 (32.8) 23 3 19 34 15 8 1  Post- 40 (12.7) 5 3 14 11 3 3 1 secondary  Unknown 5 (1.6) 1 0 1 1 0 1 1 Charlson index score  0 113 (36.0) 35 3 20 35 7 10 3  1 61 (19.4) 14 3 15 19 7 2 1  2 69 (22.0) 15 1 9 24 11 8 1  ≥3 71 (22.6) 18 2 12 25 9 3 2 Surgery plus non-specified adjuvant therapy: the patient received an adjuvant therapy but it was not possible to identify whether it was intravesical chemotherapy or BCG intravesical or radiotherapy or systemic chemotherapy. Unknown Treatment: it was not possible to know what kind of treatment the patient underwent after surgery. BCG = Bacilli of Calmette-Guerin, TURB = Transurethral resection of the bladder. therapeutic alternatives, except for 1 hospital that preferably We have not identified any published prospective multicenter administered intravesical chemotherapy as adjuvant therapy. study focused on incident cases of bladder cancer and their In this hospital more than 88% of patients had a NMIBC treatment during the first year after diagnosis. Previously pub- and intravesical chemotherapy is an option of this stage of lished observational studies focused on a specific cancer stage cancer.[11,12] and were retrospective in design.[9,12–14] Other studies, based on Our results showed that bladder cancer has important health database registries,[14–16] have focused on prognosis factors for consequences during the 12 months after the diagnosis, partly recurrence or progression[14] or on preventive measures like the due to adverse events related to treatments (more than a third of influence of diet and lifestyle on recurrence and the relationship patients suffered adverse events) and persistence or progression between progression of NMIBC and genetic profiles.[17] of the disease (1 of every 4 patients) and, 1 of every 10 patients died of any cause of mortality. Furthermore, the number of fully active patients decreased significantly during the first year of 5. Conclusions follow-up after diagnosis. We published QoL of the subgroup of patients with a Based on our results, the first year after diagnosis of bladder NIMBC that underwent TUR with or without intravesical cancer has important health consequences in terms of treat- therapy.[6] QoL was measured by the Health Survey Short ments used, disability of the patients and mortality. Surgery with Form-36 version 2 and the Bladder Cancer Index. The results adjuvant therapy was the main curative options received after showed that physical and mental health remained quite the diagnosis of non-muscle invasive bladder cancer. BCG ther- stable during 12-month follow-up although with a subtle apy was the most frequently administered adjuvant treatment. decline, urinary and bowel function improved, but sexual Higher educational level, presence of 1 or 2 comorbidities and a function worsened. Differences between QoL and perfor- high-grade tumor were associated with more frequent adjuvant mance status of our study could be attributed to the fact therapy in NMIBC. that QoL was analyzed only in a subgroup of patient and did not include tumor stages II, III, and IV and patients that underwent cystectomy. Acknowledgements Our study might have been exposed to some limitations Dr Mª José Martinez Zapata is funded by a Miguel Servet due to potential information bias. However, to minimize this II research contract from the Instituto de Salud Carlos III bias the information was prospectively obtained from hospital (CP1120/00023). The researchers listed are considered as records and from patients through the use of structured inter- authors of the EMPARO study group. views. Other limitation was the relatively short follow-up time EMPARO study Group: of the study, which did not allow for estimates of long-term Coordinating investigator: Xavier Bonfill Cosp (Iberoamerican impact of this entity. Cochrane Centre. Public Health and Clinical Epidemiology 4 Bonfill et al. • Medicine (2022) 101:42www.md-journal.com Table 2 Tumor characteristics by treatment received. Only surgery Surgery and adjuvant therapy Surgery & TURB & radical Intravesical BCG Radiotherapy or non-specified Unknown All patients TURB cystectomy chemotherapy intravesical systemic chemotherapy adjuvant therapy treatment N = 314 N = 82 N=9 N = 56 N = 103 N = 34 N = 23 N=7 n (%) n n N n n n n Downloaded from http://journals.lww.com/md-journal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy Tumor histology  Adenocarcinoma 9 (2.9) 5 0 0 2 0 1 1 wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 07/17/2023  Urothelial cell 302 (96.2) 77 9 56 100 33 22 5 carcinoma  Squamous cell 1 (0.3) 0 0 0 0 0 0 1 carcinoma  Others 0 (0.0) 0 0 0 0 0 0 0  Unknown 2 (0.6) 0 0 0 1 1 0 0 Number of tumors  1 tumor 170 (54.1) 47 2 46 39 20 14 2  ≥2 tumors 104 (33.1) 22 4 5 54 12 6 1  Missing 40 (12.8) 13 3 5 10 2 3 4 Largest Tumor Size (mm)  <30 mm 148 (47.2) 44 4 24 52 13 9 2  ≥30 mm 93 (29.6) 20 2 19 25 15 10 2  Missing 73 (23.2) 18 3 13 26 6 4 3 Primary tumor (T)  Ta 107 (34.1) 45 0 31 27 0 4 0  Tis 10 (3.2) 0 2 1 6 0 1 0  T1 141 (44.9) 37 1 24 69 4 6 0  T2a 27 (8.6) 0 5 0 1 14 5 2  T2b 18 (5.7) 0 1 0 0 9 5 3  T3a 2 (0.6) 0 0 0 0 0 1 1  T3b 3 (1.0) 0 0 0 0 2 1 0  T4a 6 (1.9) 0 0 0 0 5 0 1  T4b 0 (0.0) 0 0 0 0 0 0 0 Tis associated  Yes 24 (7.6) 1 2 1 14 3 2 1  No 273 (87.0) 76 7 53 81 30 20 6  Missing 17 (5.4) 5 0 2 8 1 1 0 Lymph nodes (N)  N0 298 (95.0) 82 9 56 103 23 20 5  N1 7 (2.2) 0 0 0 0 6 1 0  N2 7 (2.2) 0 0 0 0 3 2 2  N3 2 (0.6) 0 0 0 0 2 0 0 Distant metastasis (M)  M0 304 (96.8) 82 9 56 103 27 21 6  M1 10 (3.2) 0 0 0 0 7 2 1 TNM stage  0a 107 (34.1) 45 0 31 27 0 4 0  0is 10 (3.2) 0 2 1 6 0 1 0  I 140 (44.6) 37 1 24 69 4 5 0  II 37 (11.8) 0 6 0 1 18 8 4  III 2 (0.6) 0 0 0 0 0 2 0  IV 18 (5.7) 0 0 0 0 12 3 3 Surgery plus non-specified adjuvant therapy: the patient received an adjuvant therapy but it was not possible to identify whether it was intravesical chemotherapy or BCG intravesical or radiotherapy or systemic chemotherapy. Unknown Treatment: it was not possible to know what kind of treatment the patient underwent after surgery. BCG = Bacilli of Calmette-Guerin, TNM = tumor lymph nodes metastases, TURB: transurethral resection of the bladder. Service. Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Spain); Gael Combarros Herman, Judit Tirado Muñoz Barcelona, Spain) (IMIM, Barcelona, Spain) Project manager: Mª José Martínez Zapata (Iberoamerican Statistical analysis: Robin W.M. Vernooij and Leslie Barrionuevo- Cochrane Centre. IIBSant Pau, Barcelona, Spain) Rosas (Iberoamerican Cochrane Centre. IIBSant Pau, Barcelona, Clinical research assistants: Alborada Martínez (Universidad Spain); Javier Zamora and Claudia Coscia (Unidad de de Valencia); Enrique Morales Olivera (Escuela Andaluza Bioestadística Clínica. Hospital Universitario Ramón y Cajal. de Salud Pública, Granada, Spain); Esther Canovas, Laura IRYCIS, Madrid, Spain) Muñoz, Gemma Mas, René Acosta, Ekaterina Popova Co-investigators: Barcelona, Spain (Iberoamerican Cochrane Centre. IIBSant Pau, Barcelona, Albert Frances (Hospital del Mar); Carola Orrego Villagran, Spain); Irma Ospina (Hospital 12 de Octubre, Madrid, Spain); Rosa Suñol (Instituto Universitario Avedis Donabedian); Mª José Velázquez (Hospital Donostia, Donostia, Spain); Dimelza Osorio, Gemma Sancho Pardo, Ignasi Bolívar, José Tamara Ruiz Merlo (Hospital Ramón y Cajal, Madrid, Pablo Maroto, Mª Jesús Quintana, Martin Lorente, Cristina 5 Bonfill et al. • Medicine (2022) 101:42Medicine Table 3 Probability of receiving any adjuvant treatment in patients with non-muscle-invasive urothelial carcinoma: univariate and multivariate logistic regression models. Risk of having any adjuvant treatment Only surgery Univariate model n (%) Surgery plus any adjuvant therapy n (%) OR (95% CI) Multivariate model aOR (95% CI) All patients* 80(32.3) 168(67.7) Downloaded from http://journals.lww.com/md-journal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy Age at presentation  <60 yrs 18(22.5) 31(18.5) 1.00 reference 1.00 reference wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 07/17/2023  60 to 70 yrs 18(22.5) 51(30.4) 1.65 (0.75-3.63) 2.15 (0.63-7.31)  ≥71 yrs 44(55.0) 86(51.2) 1.13 (0.57-2.25) 1.31 (0.39-4.35) Sex  Men 65(81.3) 145(86.3) 1.00 reference 1.00 reference  Women 15(18.8) 23(13.7) 0.69 (0.34-1.40) 0.90 (0.29-2.80) Body mass index (BMI) at presentation  ≥30 16(20.8) 33(20.6) 1.00 reference 1.00 reference  25 to 29.9 39(50.6) 83(51.9) 1.03 (0.51-2.09) 1.19 (0.43-3.29)  ≤24.9 22(28.6) 44(27.5) 0.97 (0.44-2.13) 0.46 (0.14-1.58) Educational level  Illiterate-primary 51(64.6) 80(48.5) 1.00 reference 1.00 reference  Secondary 22(27.8) 57(34.5) 1.65 (0.90-3.02) 2.93 (1.09-7.89)  Post-secondary 6(7.6) 28(17.0) 2.97 (1.15-7.69) 9.88 (2.18-44.78) Performance status (ECOG/WHO) at presentation  Fully active 48(60.0) 102(60.7) 1.00 reference 1.00 reference  Restricted or worse 32(40.0) 66(39.3) 0.97 (0.56-1.67) 1.00 (0.41-2.45) Charlson index score at presentation  0 36(45.0) 58(34.5) 1.00 reference 1.00 reference  1 14(17.5) 36(21.4) 1.60 (0.76-3.36) 4.81 (1.37-16.88)  2 11(13.8) 33(19.6) 1.86 (0.84-4.14) 3.28 (1.05-10.27)  ≥3 19(23.7) 41(24.4) 1.34 (0.68-2.66) 1.76 (0.59-5.26) Primary tumor (T)  Ta 43(55.1) 61(38.1) 1.00 reference 1.00 reference  T1 35(44.9) 99(61.9) 1.99 (1.15-3.45) 1.76 (0.71-4.39) Tis associated  No 73(96.1) 142(89.3) 1.00 reference 1.00 reference  Yes 3(3.9) 17(10.7) 2.91 (0.83-10.26) 0.96 (0.08-11.20) Tumor histology grade  Low grade papillary urothelial carcinoma 72(92.3) 100(62.5) 1.00 reference 1.00 reference  High grade papillary urothelial carcinoma 6(7.7) 60(37.5) 7.20 (2.95-17.57) 4.85 (1.65-14.26) Number of tumors  1 tumor 45(66.2) 91(59.9) 1.00 reference 1.00 reference  ≥ 2 tumors 23(33.8) 61(40.1) 1.31 (0.72-2.38) 0.96 (0.39-2.34) Largest tumor size (mm)  <30 mm 43(68.3) 80(62.5) 1.00 reference 1.00 reference  ≥30 mm 20(31.7) 48(37.5) 1.29 (0.68-2.45) 1.45 (0.62-3.38) *Ten patients were excluded due they had missing information about adjuvant treatment. OR: odd ratio; it shows for example the probability of receiving any adjuvant treatment ifr patients have secondary or post-secondary studies as compared to illiterate-patients or those with primary studies. aOR: adjusted odd ratio; it shows the probability of receiving any adjuvant treatment adjusted for other variables in the specified model. 95% CI: 95% Confidence Interval. In bold type when confidence interval is significant. ECOG = eastern cooperative oncology group, WHO = World health organization. (Hospital de la Santa Creu i Sant Pau); Ferran Algaba, Palou Ana Isabel Díaz Moratinos, Angel Montero Luis, Asunción Redorta, Salvador Esquena (Fundació Puigvert); Jordi Bachs Hervás, Carmen Vallejo Ocaña, Costantino Varona, Javier (Fundació Privada Hospital de la Santa Creu i Sant Pau); Burgos, Javier Zamora, Jose Alfredo Polo Rubio, Luis López- Mª José Martínez Zapata (Iberoamerican Cochrane Centre. Fando Lavalle, Miguel Angel Jimenez Cidre, Muriel García IIBSant Pau); Montserrat Ferrer Fores, Stefanie Schmidt, Alfonso, Nieves Plana Farras, Rosa Morera Lopez, Sonsoles Olatz Garin, Virginia Becerra Bachito, Yolanda Pardo Sancho Garcia, Victor Abraira, Victoria Gomez Dos Santos (IMIM - Hospital del Mar Medical Research Institute-) (Hospital Ramón y Cajal); Agustín Gómez de la Cámara, Javier Bilbao, Spain de la Cruz, Juan Passas Martínez, Humberto García Muñoz, Amaia Martínez Galarza, José Ignacio Pijoán Zubizarreta, Mª Ángeles Cabeza Rodríguez (Hospital 12 de Octubre) San (Hospital Universitario Cruces/BioCruces-Bizkaia Health Sebastián, Spain Research Institute) Tenerife, Spain Irune Ruiz Díaz, José Ignacio Emparanza, Juan Pablo Sanz Jaka David Manuel Castro Diaz, Juan Manuel Ramos Goñi, Julio (Hospital Universitario Donostia) Valencia, Spain Lopez Bastida (HTA Unit of the Canary Islands Health Service) Agustín LLopis González, María Morales (Universidad de Granada, Spain Valencia); Carlos Camps, Cristina Caballero Díaz, Emilio Armando Suárez Pacheco, Cesar García López, José Manuel Marqués Vidal, Francisco Sánchez Ballester, Joaquín Ulises Cozar Olmo (Hospital Universitario Virgen de las Nieves); Juan Escudero, Jorge Pastor Peidro, José López Torrecilla, Carmen Martínez, Daysy Chang Chan, Mª José Sánchez Pérez Mª Macarena Ramos Campos, Miguel Martorell Cebollada (Escuela Andaluza de Salud Pública) Madrid, Spain (Consorcio Hospital General Universitario de Valencia). 6 Bonfill et al. • Medicine (2022) 101:42www.md-journal.com 100% 0% 0% 4% 0% 0% 3% 3% 0% 2% 0% 3% 2% 11% 3% 12% 6% 2% 2% 6% 1% 2% 7% 2% 2% ECOG 5 2% 4% 90% 5% Dead 5% 7% 1% 6% 1% 3% 2% 5% 5% 80% ECOG 4 Downloaded from http://journals.lww.com/md-journal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy 70% wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 07/17/2023 60% 34% 33% 35% ECOG 3 50% 40% 42% 45% 40% 43% 45% ECOG 2 44% 30% ECOG 1 20% 10% ECOG 0 58% 43% 36% 57% 46% 37% 57% 42% 36% 0% Baseline 6m 12m Baseline 6m 12m Baseline 6m 12m All Only surgery Surgery plus adjuvant therapy Figure 2. Performance status (ECOG/WHO) over the study follow-up by treatment received. ECOG = eastern cooperative oncology group, WHO = World health organization. Table 4 Disease status and patient survival by initial treatment at 12 months of follow-up. Only surgery Surgery and adjuvant therapy Surgery & Radiotherapy non-specified All TURB & radical Intravesical BCG or systemic adjuvant Unknown patients TURB cystectomy chemotherapy intravesical chemotherapy therapy treatment N = 314 N = 82 N=9 N = 56 N = 103 N = 34 N = 23 N=7 n (%) n (%) n (%) n(%) n(%) n(%) N (%) n(%) Disease status at 12 months  No evidence of remaining disease 226(72.0) 65 (79.34) 8 (88.9) 49 (87.5) 84 (81.6) 10 (29.4) 9 (39.1) 1 (1.4)  Local disease 31(9.9) 11 (13.4) 0 6 (10.7) 10 (9.7) 3 (8.8) 1 (4.4) 0  Regional disease 5(1.6) 0 0 0 3 (2.9) 1 (3.0) 1 (4.4) 0  Metastasis 37 (11.8) 3 (3.6) 1 (11.1) 1 (1.8) 5 (4.8) 16 (47.0) 7 (30.4) 4 (5.7)  Unknown 15 (4.7) 3 (3.6) 0 0 1 (1.0) 4 (11.8) 5 (21.7) 2 (2.9) Survival at 12 months  Live 275 (87.6) 76 (92.7) 8 (88.9) 54 (96.4) 98 (95.1) 25 (73.5) 12 (52.2) 2 (2.9)  Dead 34 (10.8) 4 (4.9) 1 (11.1) 2 (3.6) 5 (4.8) 9 (26.5) 9 (39.1) 4 (5.7)  Missing 5(1.6) 2 (2.4) 0 0 0 0 2 (8.7) 1 (1.4) Only percentages for cases above 9 are shown. Surgery plus non-specified adjuvant therapy: the patient received an adjuvant therapy but it was not possible to identify whether it was intravesical chemotherapy or BCG intravesical or radiotherapy or systemic chemotherapy. Unknown Treatment: it was not possible to know what kind of treatment the patient underwent after surgery. BCG = Bacilli of Calmette-Guerin, TURB = transurethral resection of the bladder. Author contributions Morales-Suárez-Varela, Javier De la Cruz, José Ignacio Emparanza, Montserrat Ferrer. Conceptualization: Xavier Bonfill, María José Martinez-Zapata. Formal analysis: María José Martinez-Zapata, Leslie Barrionuevo- Data curation: María José Martinez-Zapata, Leslie Barrionuevo- Rosas, Robin WM Vernooi, Claudia Coscia, Javier Zamora. Rosas, Robin WM Vernooi, María José Sánchez, María Funding acquisition: Xavier Bonfill, Javier Zamora. 7 Bonfill et al. • Medicine (2022) 101:42Medicine Investigation: María José Martinez-Zapata, María José Sánchez, [6] Schmidt S, Francés A, Lorente Garin JA, et al. Quality of life in patients María Morales-Suárez-Varela, Javier De la Cruz, José Ignacio with non-muscle-invasive bladder cancer: one-year results of a multi- Emparanza, Montserrat Ferrer, Joan Palou, Albert Frances. centre prospective cohort study. Urol Oncol. 2015;33:19.e7–19.e15. Methodology: Xavier Bonfill, María José Martinez-Zapata, Leslie [7] Cambier S, Sylvester RJ, Collette L, et al. EORTC nomograms and risk groups for predicting recurrence, progression, and disease-spe- Barrionuevo-Rosas, Robin WM Vernooi, José Ignacio Pijoan, cific and overall survival in non-muscle-invasive stage Ta-T1 urothelial Joan Palou, Eva Madrid, Claudia Coscia, Javier Zamora. bladder cancer patients treated with 1-3 years of maintenance Bacillus Project administration: María José Martinez-Zapata. Calmette-Guérin. Eur Urol. 2016;69:60–9. Resources: Xavier Bonfill, Javier Zamora. [8] Fernandez-Gomez J, Madero R, Solsona E, et al. Predicting nonmuscle Supervision: Xavier Bonfill, María José Martinez-Zapata. invasive bladder cancer recurrence and progression in patients treated Downloaded from http://journals.lww.com/md-journal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy Validation: María José Martinez-Zapata, Leslie Barrionuevo- with bacillus Calmette-Guerin: the CUETO scoring model. J Urol. Rosas, Robin WM Vernooi, José Ignacio Emparanza, 2009;182:2195–203. 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