Observational Study Medicine ® OPEN Follow-up care over 12 months of patients with prostate cancer in Spain A multicenter prospective cohort study ∗ Xavier Bonfill, MD, PhDa,b,c,d, María José Martinez-Zapata, MD, PhDa,b,e, , Robin WM Vernooij, PhDb, María José Sánchez, MD, PhDa,f, María Morales-Suárez-Varela, MD, PhDa,g, José Ignacio Emparanza, MD, PhDa,h, Montse Ferrer, MD, PhDa,i, José Ignacio Pijoan, MD, PhDa,j, Joan Palou, MD, PhDk, Eva Madrid, MD, PhDl, Víctor Abraira, PhDm, Javier Zamora, PhDa,m,n, on behalf of the EMPARO-CU study group Abstract The therapeutic approach is crucial to prostate cancer prognosis. We describe treatments and outcomes for a Spanish cohort of patients with prostate cancer during the first 12 months after diagnosis and identify the factors that influenced the treatment they received. This multicenter prospective cohort study included patients with prostate cancer followed up for 12 months after diagnosis. Treatment was stratified by factors such as hospital, age group (<70 and ≥70 years), and D’Amico cancer risk classification. The outcomes were Eastern Cooperative Oncology Group (ECOG) performance status, adverse events (AEs), and mortality. The patient characteristics associated with the different treatment modalities were analyzed using multivariate logistic regression. We included 470 men from 7 Spanish tertiary hospitals (mean (standard deviation) age 67.8 (7.6) years), 373 (79.4%) of which received treatment (alone or in combination) as follows: surgery (n = 163; 34.7%); radiotherapy (RT) (n = 149; 31.7%); and hormone therapy (HT) (n = 142; 30.2%). The remaining patients (n = 97) were allocated to no treatment, that is, watchful waiting (14.0%) or active surveillance (5.7%). HT was the most frequently administered treatment during follow-up and RT plus HT was the most common therapeutic combination. Surgery was more frequent in patients aged <70, with lower histologic tumor grades, Gleason scores <7, and lower prostate-specific antigen levels; while RT was more frequent in patients aged ≥70 with histologic tumor grade 4, and higher ECOG scores. HT was more frequent in patients aged ≥70, with histologic tumor grades 3 to 4, Gleason score ≥8, ECOG ≥1, and higher prostate-specific antigen levels. The number of fully active patients (ECOG score 0) decreased significantly Editor: Giuseppe Lucarelli. This study was funded by an Instituto de Salud Carlos III (ISCIII) Grant PS09/01204 (Fondo de Investigación Sanitaria [FIS], Spain). Dr María José Martinez Zapata is funded by a Miguel Servet II research contract from the ISCIII (CP1120/00023). ISCIII had any role in the design or execution of the study; in the data collection, management, or interpretation; or in the writing, reviewing, or approval of the manuscript. This study was individually 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 Donostia (San Sebastián), Hospital Nuestra Señora del Mar (Barcelona), Hospital Virgen de las Nieves (Granada), and Consorcio Hospital General Universitario de Valencia and also by the Basque Country Ethics Committee. Prior to inclusion in this study, all patients were informed about the study, agreed to participate, and signed a consent form. Consent for publication is not applicable to this study. The authors have no conflicts of interest to disclose. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. a CIBER de Epidemiología y Salud Pu blica (CIBERESP), Barcelona, Spain, b Iberoamerican Cochrane Centre, Institute of Biomedical Research Sant Pau (IIB Sant Pau), Barcelona, Spain, Public Health and Clinical Epidemiology Service, Hospital de la Santa Creu i Sant Pau, Spain, d Universitat Autònoma de Barcelona, Barcelona, c Spain, e Cochrane Ecuador, Centro de Investigación en Salud Pu blica y Epidemiología Clínica (CISPEC), Facultad de Ciencias de la Salud Eugenio Espejo, Universidad Tecnológica Equinoccial, Quito, Ecuador, f Escuela Andaluza de Salud Pu blica, Instituto de Investigación Biosanitaria de Granada, Barcelona, Spain, g Unit of Public Health and Environmental Care, Department of Preventive Medicine, University of Valencia, Valencia, Spain, h Clinical Epidemiology Unit, Hospital Universitario Donostia, BioDonostia, San Sebastian, Spain, i Health Services Research Group, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain, j Clinical Epidemiology Unit, Hospital, Universitario Cruces, Biocruces, Barakaldo, Spain, k Fundació Puigvert, Barcelona, Spain, l Cochrane Centre Universidad de Valparaíso, Chile, Interdisciplinary Centre for Health Studies CIESAL, Department of Public Health - School of Medicine - Universidad de Valparaíso, Chile, m Unidad de Bioestadística Clínica, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain, n Barts and the London School of Medicine and Dentistry, Queen Mary University London, London, UK. ∗ Correspondence: María José Martinez-Zapata, Iberoamerican Cochrane Centre-Public Health and Clinical Epidemiology Service, Hospital de la Santa Creu i Sant Pau, Pavillion 18, Sant Antoni M Claret, 165, Barcelona 08025, Spain (e-mail: mmartinezz@santpau.cat). Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite this article: Bonfill X, Martinez-Zapata MJ, Vernooij RW, Sánchez MJ, Morales-Suárez-Varela M, Emparanza JI, Ferrer M, Pijoan JI, Palou J, Madrid E, Abraira V, Zamora J. Follow-up care over 12 months of patients with prostate cancer in Spain: a multicenter prospective cohort study. Medicine 2021;100:47(e27801). Received: 24 April 2020 / Received in final form: 3 June 2021 / Accepted: 28 October 2021 http://dx.doi.org/10.1097/MD.0000000000027801 1 Bonfill et al. Medicine (2021) 100:47 Medicine during follow-up, from 75.3% at diagnosis to 65.1% at 12 months (P < .001); 230 (48.9%) patients had at least 1 AE, and 12 (2.6%) patients died. Surgery or RT were the main curative options. A fifth of the patients received no treatment. Palliative HT was more frequently administered to older patients with higher tumor grades and higher Gleason scores. Close to half of the patients experienced an AE related to their treatment. Abbreviations: AE = adverse event, ECOG = Eastern Cooperative Oncology Group, HT = hormone therapy, PSA = prostate- specific antigen, RT = radiotherapy, WHO = World Health Organization. Keywords: hormone therapy, multicenter study, multivariate analysis, prostate cancer, prostatic neoplasms, radiotherapy, surgery 1. Introduction We collected the following data: age; body mass index; World Health Organization (WHO) histologic tumor grade (1–4)[7]; Prostate cancer is the most common cancer in men in both prostate-specific antigen (PSA) value at diagnosis; total Gleason Western Europe (over lung cancer, in second place) and in Spain, score[8]; clinical cancer stage (I–IV); tumor stage (T(Tumor size) with an estimated incidence of 171.4 and 147.9 patients per N (lymph Nodes ) M (Metastasis) Classification of Malignant 100,000 men per year, respectively.[1] However, mortality for Tumors Staging System)[9]; intervention, that is surgery, RT, prostate cancer is relatively low in comparison with other hormone therapy (HT), or watchful waiting/active surveillance malignancies. Prognosis depends not only on patient character- (defined as no treatment other than diagnostic tests such as rectal istics, but also on the ability of healthcare systems to timely detect examination, prostatic ultrasound, biopsy, or PSA measure- and treat patients with prostate cancer. ment); Eastern Cooperative Oncology Group (ECOG) perfor- Once diagnosed, patients are generally treated according to mance status score; adverse events (AEs) based in the Common their performance status, clinical cancer stage, tumor character- Terminology Criteria for Adverse Events,[10] and mortality istics, and—ideally—individual values and preferences. In during follow-up. addition to making recommendations to guide clinical manage- Using TNM tumor stages, PSA values, and Gleason scores, we ment of prostate cancer patients,[2,3] it is important to conduct classified patients into the following D’Amico risk[11] groups: low studies that focus on how patients are treated in the real world risk (PSA 10 ng/mL, Gleason 6, and T1c-T2a); intermediate risk and the association between their characteristics and the specific (PSA 10–20 ng/mL, Gleason 7, and T2b); and high risk (PSA >20 treatment modalities. Some initiatives have been recently ng/mL, Gleason ≥8, and T2c-T3a). We stratified the analysis by published in this regard, such as an international prospective age (<70 years and ≥70 years), initial treatment, D’Amico risk, cohort study that reported the characteristics of cancer patients hospital, and ECOG score. and toxicity related to radiotherapy (RT).[4] Another interna- We established the cut-off age at 70 years based on a national tional initiative has been developed in Asia in a cohort of patients male life expectancy of 80 years,[12] and the fact that clinical with advanced prostate cancer.[5] treatment guideline recommendations depend on whether the We also published the baseline clinical characteristics, patient’s life expectancy is more or less than 10 years at the time diagnoses, and factors affecting patient care intervals for a of diagnosis.[13] prospective cohort study of the incidence of prostate cancer in For the descriptive analyses, we used relative frequencies for Spain.[6] The current article reports the results of the first 12- categorical variables, and either mean and standard deviation or month follow-up after diagnosis of this cohort of patients; we median and interquartile range for continuous variables, describe the treatments and outcomes, and identify the factors depending on the skewness of the data distribution. that influenced the therapy received during this follow-up period. The proportion of missing values for each variable is reported. To study baseline patient characteristics associated with specific 2. Methods treatment modalities, we used 3 independent multivariate logistic We conducted a multicenter observational cohort study on regression models. Each model had a binary outcome measure patients with prostate cancer attending 7 tertiary hospitals in representing whether a patient received as first-line treatment the Spain: Hospital Universitario 12 de Octubre (Hospital A); modalities: surgery (model 1), RT (model 2), or hormonal Hospital Universitario Ramón y Cajal (Hospital B) in Madrid; therapy (model 3). We performed a backward elimination Hospital Universitario Donostia (Hospital C) in Donostia-San strategy to fit the most final parsimonious model containing the Sebastián; Hospital General Universitario de Valencia (Hospital clinical and demographic factors significantly associated to the D) in Valencia; Hospital Universitario Virgen de las Nieves odds of receiving each one of the treatment alternatives. At each (Hospital E) in Granada; Fundació Puigvert-Hospital de la Santa iteration, we excluded a variable from the model when its P value Creu i Sant Pau (Hospital G) (co-ordinating center); and Hospital was greater than .05, excluding first the variable with higher P del Mar (Hospital F) in Barcelona. The protocol was approved by value. The potential predictors included in the maximal model all centers’ Research Ethics Committees. were selected based on clinical plausibility, and included age, Patients with prostate cancer were consecutively enrolled from body mass index, WHO histological tumor grade, TNM tumor October 2010 to September 2011. Inclusion criteria were patients stage, total Gleason score, and PSA value at diagnosis. We report with histologically proven and newly diagnosed prostate cancer the odds ratio and the corresponding 95% confidence interval. at any stage of the disease, who were being treated at any of the 7 We used the non-parametric Friedman test for repeated measures participating hospitals, and who had provided their informed to estimate ECOG within-patient change across follow-up consent. assessments (i.e., baseline, 6 months, and 12 months). This 2 Bonfill et al. Medicine (2021) 100:47 www.md-journal.com analysis was performed on the overall cohort and stratified by the Gleason scale, 26.8% scored 7, and 15.7% scored ≥8 received treatment modality (i.e., surgery, RT, and HT). (Table 1). Data were analyzed using SPSS statistical software version 20.0 After diagnosis, 97 patients (20.6%) were allocated to (SPSS Inc., Chicago, IL) and Stata v12 software (StataCorp. 2011 watchful waiting and 373 (79.4%) were treated as follows: Stata Statistical Software: Release 12. StataCorp LP, College surgery (n = 163; 34.7%); RT (n = 149; 31.7%); and HT (n = 142; Station, TX). 30.2%) (Table 1). Most patients treated with surgery were <70 years (83.4%) and had T1b-T2b tumor stage (66.3%). Among the patients treated with RT, 45% were ≥70 years, 67.1% had 3. Results T1b-T2b tumor stage, and 12.8% had a Gleason score ≥8. In total, we recruited 470 patients: 451 (96.0%) of them Patients treated with HT were generally ≥70 years (57.7%), had completed the 12-month follow-up, 12 (2.6%) died, and 7 higher Gleason scores (≥8; 30.3%); around half each had T1b- dropped out of the study (Fig. 1). The cause of death for 4 patients T2b and T2c-T4 tumor stages (50.7% and 46.5%, respectively) was prostate cancer progression; 2 died from other cause (Table 1). unrelated to cancer; and the cause was unknown for 1 patient. Just under one fifth of patients (n = 87; 18.5%) received a Mean (standard deviation) age was 67.8 (7.6) years, and 277 combination of treatments, most frequently RT plus HT (n = 72; (58.9%) patients were under 70 years old (Table 1). 15.3%) (Table 2). During the follow-up period, 165 patients The most frequent WHO histological grades were 2 (n = 195; (35.1%) underwent surgery, 164 (34.9%) received RT, and 193 41.5%) and 3/4 (n = 169; 36.0%). Most patients (62.5%) had (41.1%) received HT. By the end of this period, 27 patients T1b-T2b tumors. Over half of the patients (55.1%) scored 6 on (5.7%) allocated to watchful waiting at baseline were reallocated Assessed for eligibility (n=502) Enrolment Excluded (n=32) -Did not meet inclusion criteria Included (n=470) Follow-Up and Analyses Losses (n=11) - 4 dropouts - 7 deaths (4 cancer progression, 2 unrelated to cancer, 1 unknown cause) 6-month follow-up (n=459) Losses (n=8) - 3 dropouts - 5 deaths (cancer progression) 12-month follow-up (n=451) Figure 1. Patient flow chart. 3 Bonfill et al. Medicine (2021) 100:47 Medicine Table 1 Descriptive characteristics of patients by baseline treatment. All patients Surgery Radiotherapy Hormone therapy Watchful waiting N = 470 N = 163 N = 149 N = 142 N = 97 n (%) n (%) n (%) n (%) n (%) Age <70 yrs 277 (58.9) 136 (83.4) 81 (54.4) 55 (38.7) 51 (52.6) ≥70 yrs 182 (38.7) 25 (15.3) 67 (45.0) 82 (57.7) 42 (43.3) Missing data 11 (2.3) 2 (1.2) 1 (0.7) 5 (3.5) 4 (4.1) BMI <25 95 (20.2) 32 (19.8) 25 (16.7) 27 (19.0) 27 (27.8) ≥25–<30 232 (49.4) 89 (54.6) 69 (46.3) 65 (47.8) 43 (44.3) ≥30 125 (26.6) 36 (22.1) 49 (32.9) 46 (32.4) 23 (23.7) Missing data 18 (3.8) 6 (3.7) 6 (4.0) 4 (2.8) 4 (4.1) D’Amico risk Low 169 (36.0) 66 (40.5) 61 (40.9) 26 (18.3) 33 (34.0) Intermediate 114 (24.3) 53 (32.5) 32 (21.5) 27 (19.0) 23 (23.7) High 186 (39.6) 44 (27.0) 55 (36.9) 88 (62.0) 41 (42.3) Missing data 1 (0.1) 0 1 (0.7) 1 (0.7) 0 Histologic grade 1 23 (4.9) 7 (4.3) 7 (4.7) 4 (2.8) 7 (7.2) 2 195 (41.5) 87 (53.4) 61 (40.9) 46 (32.4) 31 (32.0) 3/4 169 (36.0) 45 (27.6) 49 (32.9) 75 (52.8) 41 (42.3) Missing data 81 (17.7) 24 (14.7) 32 (21.5) 17 (11.9) 18 (18.6) Tumor stage Tx 1 (0.2) 0 0 1 (0.7) 0 T1a-c 193 (41.1) 70 (42.9) 64 (43.0) 38 (26.8) 41 (42.3) T2a-c 188 (40.0) 73 (44.8) 54 (36.2) 55 (38.7) 41 (42.3) T3a-b 74 (15.7) 16 (9.8) 28 (18.8) 41 (28.9) 12 (12.4) T4 8 (1.7) 0 0 5 (3.5) 2 (2.1) Missing data 6 (1.3) 4 (2.5) 3 (2.0) 2 (1.4) 1 (1.0) Gleason grade 1 (6) 261 (55.1) 103 (63.2) 88 (59.1) 54 (38.0) 50 (51.5) 2 (7 = 3+4) 98 (20.9) 42 (25,8) 30 (20.1) 24 (16.9) 21 (21.6) 3 (7 = 4+3) 28 (6.1) 9 (5.6) 9 (6.0) 15 (10.6) 4 (4.1) 4 (8) 42 (8.9) 3 (1.8) 14 (9.4) 24 (16.9) 12 (12.4) 5 (9, 10) 32 (6.8) 3 (1.8) 5 (3.4) 19 (13.4) 10 (10.3) Missing data 9 (1.9) 3 (1.8) 3 (2.0) 6 (4.2) 0 PSA Median (IQR) 7.6 (7.8) 6.5 (4.4) 7.8 (7.8) 13.0 (14.4) 6.7 (5.2) Eighty-seven patients received a combination of treatments. BMI = body mass index, IQR = interquartile range, PSA = prostate-specific antigen. to active surveillance, and 66 (14.1%) continued in watchful with 69.3% scoring 0 at 6 months, and 65.1% scoring 0 at 12 waiting (Table 2). months. While 75.3% of the patients had an ECOG score of 0 at Among the patients <70 years undergoing surgery, 41.2%, baseline (Fig. 2), this percentage was observed to fall over time, 30.9%, and 27.9% had low, intermediate, and high D’Amico Table 2 Treatment distribution at baseline per patient and during 12-month follow-up (N = 470 patients). Treatment Baseline Follow-upa n (%) n (%) Surgery 151 (32.1) 3 (0.6) Radiotherapy 71 (15.1) 15 (3.2) Hormone therapy 66 (14.1) 49 (10.4) Chemotherapy 0 3 (0.6) Other 2 (0.4) 6 (1.3) Surgery + radiotherapy 7 (1.5) 0 Surgery + hormone therapy 5 (1.1) 0 Radiotherapy + hormone therapy 71 (15.1) 2 (0.4) Watchful waiting 97 (20.6) 66 (14.1) Active surveillance 0 27 (5.7) Only baseline treatment – 299 (63.7) a Patients with new treatments during follow-up. 4 Bonfill et al. Medicine (2021) 100:47 www.md-journal.com Note: Friedman test with all three measurement time-points (baseline, 6 months, 12 months). The differences were significant for all patients (p<0.001) and surgery patients (p=0.03), but not significant for patients receiving radiotherapy (p=0.585) or hormone therapy (p=0.099). Figure 2. Eastern Cooperative Oncology Group (ECOG) scores by study time-points and treatments. risk, respectively (P = .027); and among those receiving HT, (50.7%); RT for hospitals A (22.9%) and B (38.5%); and HT for 18.2%, 20.2%, and 61.8% had low, intermediate, and high risk, hospitals D (42.3%) and E (50.0%). HT was the most prescribed respectively (P < .001). In this age group there was no difference treatment in the 12-month follow-up, although its use ranged in the odds of patients receiving RT (P = .098) or being assigned from 5.5% in hospital B to 50% in hospital E. to watchful waiting (0.748) (Table 3). Among the patients ≥70 The multivariate logistic regression analysis (Table 4) revealed years undergoing surgery, 32.0%, 44.0%, and 24.0% had low, that patients <70 years, with low tumor histologic grades, intermediate, and high D’Amico risk, respectively (P = .044); Gleason scores <7, and low PSA levels were more likely to among those receiving RT, 36.4%, 28.8%, and 34.8% had low, undergo surgery as first-line treatment for prostate cancer. intermediate, and high risk, respectively (P = .030); and among Patients with a histologic tumor grade 4 and higher ECOG scores those receiving HT, 17.3%, 18.5%, and 64.2% had low, were more likely to be treated with RT. Lastly, patients ≥70 years, intermediate, and high risk, respectively (P < .001). In this age with tumor grades 3 or 4, Gleason scores ≥8, ECOG scores ≥1, group, there was no difference in the odds of patients being and higher PSA levels were most likely to be treated with HT. assigned to watchful waiting (0.756) (Table 3). A total of 230 AEs were reported, with 48.9% of patients At baseline, the first-line treatments for patients with prostate experiencing at least one (Table 5). By intervention, the most cancer were surgery for hospitals C (51.4%), F (63.6%), and G frequent AEs were urinary incontinence (50.3%) and impotence Table 3 D’Amico risk stratified by age and treatment at baseline. <70 yrs ≥70 yrs N = 277 N = 182 D’Amico risk Low Intermediate High P Low Intermediate High P N = 115 N = 68 N = 94 N = 49 N = 46 N = 86 n (%) n (%) n (%) n (%) n (%) n (%) Surgery 56 (41.2) 42 (30.9) 38 (27.9) .027 8 (32.0) 11 (44.0) 6 (24.0) .044 Radiotherapy 36 (44.4) 13 (16.1) 32 (39.5) .098 24 (36.4) 19 (28.8) 23 (34.8) .030 Hormone therapy 10 (18.2) 11 (20.2) 34 (61.8) <.001 14 (17.3) 15 (18.5) 52 (64.2) <.001 Watchful waiting 23 (46.0) 12 (24.0) 15 (30.0) .748 10 (23.3) 11 (25.6) 22 (51.2) .756 Patients could receive more than 1 treatment. Percentages are calculated for rows. Data for 11 cases were missing for D’Amico risk. 5 Bonfill et al. Medicine (2021) 100:47 Medicine Table 4 Multivariate logistic regression: baseline patient characteristics associated with treatment modalities. Surgery Radiotherapy Hormone therapy OR (CI 95%) P OR (CI 95%) P OR (CI 95%) P Age (yrs) <70 1 (Reference) 1 (Reference) ≥70 0.22 (0.13–0.38) <.001 2.17 (1.27–3.72) .005 Histologic grade 2 1 (Reference) 1 (Reference) 3 1.08 (0.49–2.35) .851 0.84 (0.53–1.32) .450 4 0.21 (0.09–0.51) .001 1.90 (1.03–3.50) .040 Gleason score 6 1 (Reference) 1 (Reference) 7 1.08 (0.49–2.35) .842 1.02 (0.57–1.83) .938 ≥8 0.08 (0.01–0.43) .003 4.24 (1.86–9.73) .001 Log (PSA) 0.53 (0.36–0.77) .001 3.17 (2.07–4.84) <.001 ECOG score 0 1 (Reference) 1 (Reference) 1 1.41 (0.85–2.32) .178 1.94 (1.06–3.56) .033 ≥2 3.05 (0.99–9.37) .052 10.98 (1.91–63.1) .007 CI = confidence interval, ECOG = Eastern Cooperative Oncology Group, OR = odds ratio, PSA = prostate-specific antigen. (45.4%) for surgery; impotence (12.8%) and cystitis (12.8%) for 6-month follow-up study. Our watchful waiting percentage RT; and hot flushes (26.1%), impotence (15.5), and reduced decreased to 14% at 12-month follow-up, as the remaining 5.7% libido (14.8%) for HT. During the 12-month follow-up, 12 were moved to active surveillance. In contrast, Hoffman et al[13] (2.6%) patients died. described that more patients were in active surveillance at 18-month follow-up, while fewer than 2% remained in watchful waiting. 4. Discussion In our study a high proportion of patients with T1b-T2b tumor This prospective cohort study describes healthcare practices at 7 stage underwent surgery and received either RT or HT. A lower- Spanish hospitals for newly diagnosed prostate cancer patients, than-expected proportion of patients with T2c-T4 tumor stage focusing on primary therapy and patient-relevant clinical received RT or HT. outcomes observed within the first 12 months since diagnosis. In agreement with guideline recommendations,[3] surgery was The majority of the 470 included patients were under 70 years old more frequent in younger patients (<70 years) with low or and 81% had localized prostate cancer. Primarily, surgery or RT intermediate cancer risk (D’Amico classification), whereas HT were the initial treatment modalities for 1 in 3 patients, as per was more frequent in high-risk cases and older patients (≥70 guideline recommendations.[3] HT was also administered in one years). However, RT administration was only influenced third of patients as palliative treatment. During the 12-month significantly by the risk classification in older patients and those follow-up, HT was the most frequent treatment and RT plus HT with higher histological grade. was the most frequent treatment combination. According to a recently published clinical trial, there is no One fifth of patients was assigned to watchful waiting after single best treatment option for localized prostate cancer, as diagnosis, a similar rate to that reported by Hoffman et al[13] in a overall survival is similar for patients undergoing radical Table 5 Adverse events by treatment through the 12-month follow-up period. Surgery Radiotherapy Hormone therapy N = 163 N = 149 N = 142 n (%) n (%) n (%) Urinary incontinence 82 (50.3) Impotence 19 (12.8) Hot flushes 37 (26.1) Impotence 74 (45.4) Cystitis 19 (12.8) Impotence 22 (15.5) Urethral stricture 5 (3.1) Intestinal alteration 10 (6.7) Reduced libido 21 (14.8) Fecal incontinence 2 (1.2) Urinary incontinence 8 (5.4) Diarrhea 6 (4.2) Other 10 (6.1) Proctitis 8 (5.4) Rash 5 (3.5) Enteritis 5 (3.4) Gynecomastia 4 (2.8) Others 21 (14.1) Diarrhea 3 (2.1) Acne 2 (1.4) Breast tenderness 2 (1.4) Pruritus 2 (1.4) Osteoporosis 1 (0.7) Other 12 (8.5) ≥1 adverse effect 113 (69.3) 61 (40.9) 56 (39.4) 6 Bonfill et al. Medicine (2021) 100:47 www.md-journal.com prostatectomy, RT, or active surveillance.[14] However, we found experienced an AE related to the treatment. Performance status that certain factors influenced decision-making regarding differ- decreased steadily in the first year after diagnosis. The treatments ent therapeutic options: patients who underwent surgery were administered by the participating hospitals varied widely. younger and had better prognostic factors (lower histologic tumor grades, Gleason scores, and PSA levels); patients treated Acknowledgments with RT had higher histological tumor grades and poorer ECOG scores; and lastly, patients who received palliative HT were older Ailish Maher and Andrea Cervera Alepuz revised the English in a and had poorer prognostic factors (more advanced tumors, version of this manuscript. Maria José Martinez Zapata is funded higher Gleason scores, higher PSA levels, and higher ECOG by a Miguel Servet research contract (CPII20/00023). scores). EMPARO Study Group: Coordinating investigator: Xavier Other cohort studies have been published recently, but their Bonfill Cosp (Iberoamerican Cochrane Centre, Public Health and results are not completely comparable to our study. These studies Clinical Epidemiology Service, Hospital de la Santa Creu i Sant included prevalent and incident patients,[4,5] and our study only Pau, IIB Sant Pau, Barcelona, Spain). focused on incident prostate cancer patients. One international Project manager: María José Martínez Zapata (Iberoamerican multicenter cohort study focused on patients receiving RT.[4] Cochrane Centre, IIBSant Pau, Barcelona, Spain). Twenty-seven percent of included patients underwent a prosta- Clinical research assistants: Alborada Martínez (Universidad tectomy before RT, whereas in our study the proportion was only de Valencia); Enrique Morales Olivera (Escuela Andaluza de 1.5%. The proportion of patients receiving RT and HT also Salud Publica, Granada, Spain); Esther Canovas, Laura Muñoz, differed between studies—69% and 15%, respectively. Another Gemma Mas, René Acosta, Ekaterina Popova (Iberoamerican international multicenter cohort study included advanced Cochrane Centre, IIB Sant Pau, Barcelona, Spain); Irma Ospina prostate cancer, whereas our study mainly included localized (Hospital 12 de Octubre, Madrid, Spain); María José Velázquez prostate cancer.[5] (Hospital Donostia, Donostia, Spain); Tamara Ruiz Merlo While the Spanish National Health System is a public system (Hospital Ramón y Cajal, Madrid, Spain); Gael Combarros providing universal coverage and free-of-charge treatments to Herman, Judit Tirado Muñoz (IMIM-Hospital del Mar Medical patients, we found important differences in therapeutic choices Research Institute, Barcelona, Spain). between the 7 participating hospitals, with some preferring Statistical analysis: Robin W.M. Vernooij (Iberoamerican surgery, whereas others preferred RT or HT. This variability was Cochrane Centre, IIB Sant Pau, Barcelona, Spain); Javier Zamora and probably related to patient characteristics and differing hospital Claudia Coscia Requena (Hospital Ramón y Cajal, Madrid, Spain). criteria regarding treatments. Co-investigators: Barcelona, Spain At baseline, 3 quarters of patients had a good performance Albert Frances (Hospital del Mar); Carola Orrego Villagran, status that worsened over the follow-up period. Only a small Rosa Suñol (Instituto Universitario Avedis Donabedian); proportion of patients (2.6%) died during the first year, mainly Dimelza Osorio, Gemma Sancho Pardo, Ignasi Bolívar, José due to cancer-related reasons. The most common AEs match Pablo Maroto, María Jes us Quintana, Cristina Martin (Hospital those reported in previous studies,[14,15] such as urinary de la Santa Creu i Sant Pau); Ferran Algaba, Palou Redorta, incontinence and impotence for surgery, impotence[4] and cystitis Salvador Esquena (Fundació Puigvert); Jordi Bachs (Fundació for RT, and hot flushes for HT. Privada Hospital de la Santa Creu i Sant Pau); María José Regarding limitations, our study may be affected by potential Martínez Zapata (Iberoamerican Cochrane Centre, IIB Sant information bias, given that our data were prospectively obtained Pau); Montserrat Ferrer Fores, Stefanie Schmidt, Olatz Garin, from hospital records and participants. However, we consider Virginia Becerra Bachito, Yolanda Pardo (IMIM-Hospital del this limitation of little actual relevance. Mar Medical Research Institute). A main strength of our study is that our patient sample is Bilbao, Spain probably representative of the annual incident cases of patients Amaia Martínez Galarza, José Ignacio Pijoán Zubizarreta diagnosed with prostate cancer in Spain, since they were recruited (Hospital Universitario Cruces/BioCruces Health Research in 7 hospitals located in 5 different regions. In addition, the Institute). prospective nature of the study guarantees greater data Granada, Spain consistency and accuracy, and so overcomes the typical Armando Suárez Pacheco, Cesar García López, José Manuel shortcoming of retrospective data collection affecting similar Cozar Olmo (Hospital Universitario Virgen de las Nieves); studies carried out elsewhere. The relatively small number of Carmen Martínez, Daysy Chang Chan, María José Sánchez Pérez patients lost to follow-up (4.2%) reinforces the validity of our (Escuela Andaluza de Salud P ublica). results. A longer follow-up will undoubtedly be useful in further Madrid, Spain assessing the impact of diagnosis and therapy on prostate cancer Ana Isabel Díaz Moratinos, Angel Montero Luis, Asunción patients. Hervás, Carmen Vallejo Ocaña, Costantino Varona, Javier Burgos, Javier Zamora, Jose Alfredo Polo Rubio, Luis López- Fando Lavalle, Miguel Angel Jimenez Cidre, Muriel García, 5. Conclusion Alfonso, Nieves Plana Farras, Rosa Morera Lopez, Sonsoles Surgery and RT were the most common curative options used on Sancho Garcia, Victor Abraira, Victoria Gomez Dos Santos initial diagnosis of prostate cancer. Watchful waiting was applied (Hospital Ramón y Cajal); Agustín Gómez de la Cámara, Javier to 1 in 5 patients after diagnosis. Palliative HT was the most de la Cruz, Juan Passas Martínez, Humberto García Muñoz, prescribed follow-up treatment. Surgery was more frequently María Ángeles Cabeza Rodríguez (Hospital 12 de Octubre). indicated in younger patients with better prognostic factors. HT San Sebastián, Spain was more frequent in older patients, with more advanced tumor Irune Ruiz Díaz, José Ignacio Emparanza, Juan Pablo Sanz stages and higher Gleason scores. Around half of the patients Jaka (Hospital Universitario Donostia). 7 Bonfill et al. Medicine (2021) 100:47 Medicine Valencia, Spain [2] European Association Urology (EAU) guidelines. Edn. Presented at the EAU Annual Congress Copenhagen 2018. ISBN 978-94-92671-01-1. Agustín Llopis González, María Morales (Universidad de [3] Sanda MG, Cadeddu JA, Kirkby E, et al. Clinically localized prostate Valencia); Carlos Camps, Cristina Caballero Díaz, Emilio cancer: AUA/ASTRO/SUO guideline. Part I: risk stratification, shared Marqués Vidal, Francisco Sánchez Ballester, Joaquín Ulises Juan decision making, and care options. J Urol 2018;199:683–90. Escudero, Jorge Pastor Peidro, José López Torrecilla, María [4] Seibold P, Webb A, Aguado-Barrera ME, et al. REQUITE: a prospective Macarena Ramos Campos, Miguel Martorell Cebollada (Con- multicentre cohort study of patients undergoing radiotherapy for breast, lung or prostate cancer. Radiother Oncol 2019;138:59–67. sorcio Hospital General Universitario de Valencia). [5] Uemura H, Ye D, Kanesvaran R, et al. United in Fight against prOstate cancer (UFO) registry: first results from a large, multi-centre, prospective, longitudinal cohort study of advanced prostate cancer in Asia. BJU Int Author contributions 2020;125:541–52. Conceptualization: Xavier Bonfill. [6] Bonfill X, Martinez-Zapata MJ, Vernooij RW, et al. Clinical intervals and diagnostic characteristics in a cohort of prostate cancer patients in Data curation: Maria Jose Martinez-Zapata. Spain: a multicentre observational study. BMC Urol 2015;15:60. Formal analysis: Robin WM Vernooij, Víctor Abraira, Javier [7] Eble JN, Sauter G, Epstein JI, et al (Eds.). World Health Organization Zamora. Classification of Tumours. Pathology and Genetics of Tumours of the Funding acquisition: Xavier Bonfill, Javier Zamora. Urinary System and Male Genital Organs. Lyon: IARC Press; 2004. [8] Epstein JI, Allsbrook WCJr, Amin MB, Egevad LL. ISUP Grading Investigation: Xavier Bonfill, Maria Jose Martinez-Zapata, CommitteeThe 2005 International Society of Urological Pathology María José Sánchez, María Morales-Suárez-Varela, José (ISUP) consensus conference on Gleason grading of prostatic carcinoma. Ignacio Emparanza, Montse Ferrer, José Ignacio Pijoan, Joan Am J Surg Pathol 2005;29:1228–42. Palou. [9] American Joint Committee on Cancer: AJCC Cancer Staging Manual. Methodology: Xavier Bonfill, Maria Jose Martinez-Zapata, Eva 6th ed.New York, NY: Springer; 2002. 335–340. [10] Therapy evaluation program, common terminology criteria for adverse Madrid, Víctor Abraira, Javier Zamora. events, Version 4.0, DCTD, NCI, NIH, DHHS. June 3, 2010. Supervision: Xavier Bonfill, Maria Jose Martinez-Zapata. [11] D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome Validation: Maria Jose Martinez-Zapata, Robin WM Vernooij. after radical prostatectomy, external beam radiation therapy, or Writing – original draft: Xavier Bonfill, Maria Jose Martinez- interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280:969–74. Zapata, Robin WM Vernooij, María Morales-Suárez-Varela, [12] Instituto Nacional de Estadística (INE), Spain 2018. Mujeres y hombres Eva Madrid, Javier Zamora. en España /Salud /4.1 Esperanza de vida. Available at: http://www.ine.es/ Writing – review & editing: Xavier Bonfill, Maria Jose Martinez- ss/Satellite?c=INESeccion_C&p=1254735110672&pagename=Produc Zapata, Robin WM Vernooij, María José Sánchez, María tosYServicios%2FPYSLayout&cid=1259926380048&L=1. Accessed Morales-Suárez-Varela, José Ignacio Emparanza, Montse June 23, 2019. [13] Hoffman KE, Niu J, Shen Y, et al. Physician variation in management of Ferrer, José Ignacio Pijoan, Joan Palou, Eva Madrid, Víctor low-risk prostate cancer: a population-based cohort study. JAMA Intern Abraira, Javier Zamora. Med 2014;174:1450–9. [14] Hamdy FC, Donovan JL, Lane JA, et al. 10-Year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N References Engl J Med 2016;375:1415–24. [1] European Cancer Information System (ECIS). © European Union, 2018. [15] Wilt TJ, Jones KM, Barry MJ, et al. Follow-up of prostatectomy versus Available at: https://ecis.jrc.ec.europa.eu. Accessed June 23, 2019. observation for early prostate cancer. N Engl J Med 2017;377:132–42. 8