Sureda et al. Health and Quality of Life Outcomes (2019) 17:11 https://doi.org/10.1186/s12955-019-1082-4 RESEARCH Open Access Health-related quality of life in men with prostate cancer undergoing active surveillance versus radical prostatectomy, external-beam radiotherapy, prostate brachytherapy and reference population: a cross-sectional study A. Sureda1,2, L. Fumadó1* , M. Ferrer2,3,4, O. Garín3,4,5, X. Bonet6, M. Castells6, M. C. Mir1, J. M. Abascal1, F. Vigués6, L. Cecchini1 and J. F. Suárez6 Abstract Background: The purpose of this study is to describe Health-Related Quality of Life (HRQoL) of localized prostate cancer patients in an Active Surveillance (AS) program, and to compare them with those undergoing radical prostatectomy (RP), external-beam radiotherapy (XRT) and brachytherapy (BT). Methods: Multi-institutional pooled cross-sectional analysis on patients in an AS protocol: < 75 years old; pathologically confirmed LPC (maximum of three positive cylinders); Gleason score < 3 + 4; clinical stage T1a-T2b; and PSA < 15 ng/ml. Exclusion criteria for this study were: less than 6 months in AS, termination of AS protocol, or incomplete data. Patients in AS were matched with those treated with RP, XRT or BT from the ‘Spanish Multicentric Study of Clinically Localized Prostate Cancer’ cohort according to risk group, time from treatment selection to HRQoL survey, and age. Prostate-specific (EPIC) and generic (SF-36) HRQoL instruments were completed. Analysis was stratified by HRQoL survey moment (>or < 2.5 years from treatment selection), and age (>or < 70 years old). Results: Median of time from treatment selection to HRQoL survey in the total 396 patients (99 per treatment group) was 2.4 years (range 0.5–8.3). Patients in AS presented higher (better) urinary incontinence scores than RP ones in both stratus of time from treatment selection to HRQoL survey (92.6 vs 67.0 and 81.4 vs 64.4, p < 0.01). Patients in AS for < 2.5 years presented greater sexual scores than any active treatment (p < 0.01), but only statistically higher than RP for those in AS for longer than 2.5 years. The magnitude of the differences between AS and RP groups in both EPIC domains ranged from moderate (0.7 SD) to large (1.0 SD). Regardless of treatment applied, patients presented similar and slightly increased SF-36 scores than US general population reference norms. Nonetheless, patients in AS for < 2.5 years reported worse outcomes than other treatment groups on physical health domains, especially in bodily pain (0.5–0.6 SD), and vitality (0.6–0.8 SD). (Continued on next page) * Correspondence: lfumado@hospitaldelmar.cat 1 Urology Department, Hospital del Mar-IMIM, Autonomous University of Barcelona, Passeig Marítim 25-29, 08003 Barcelona, Spain Full list of author information is available at the end of the article © The Author(s). 2019 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. Sureda et al. Health and Quality of Life Outcomes (2019) 17:11 Page 2 of 9 (Continued from previous page) Conclusions: Considering patients’ well-being, AS can be a good therapeutic option due to the low impact caused on urinary continence and sexual function. However, longitudinal studies are required to take into account HRQoL evolution over time. Keywords: Active surveillance, Brachytherapy, External-beam radiotherapy, Health-related quality of life, Radical prostatectomy Background without any other treatment. In order to compare them Prostate cancer (PC) is overdiagnosed and overtreated due with those undergoing RP, XRT and BT, data from the to the increased utilization of prostate-specific antigen ‘Spanish Multicentric Study of Clinically Localized Pros- (PSA) [1]. The PIVOT trial demonstrated no decrease in tate Cancer’ [23, 24] was used. Physical and mental prostate cancer mortality with the use of surgical treatment, health components were also compared to general popu- compared to observation, for localized PC, except for the lation [25, 26]. Our hypothesis are that: 1) HRQoL of lo- high-risk population [2]. Available curative treatments for calized PC patients in an AS program is better than in localized PC [radical prostatectomy(RP), external-beam those treated by available curative treatments, since they radiotherapy(XRT) and brachytherapy(BT)] may decrease presented less side effects; and 2) Patients in AS have the patient’s health-related quality of life (HRQoL) [3, 4]. poorer mental health, in comparison to those undergoing Active Surveillance(AS) has been postulated as a safe alter- available curative treatments or general population, due to native for patients with favourable-risk PC in order to re- the uncertainty regarding their disease’s progression. duce treatment side effects, with no impact on short-term survival. Several published series have demonstrated its val- Methods idity reducing overtreatment [5–8]. Cross-sectional study of patients undergoing AS in two Although living with cancer may cause psychological hospitals, matched with patients treated with RP, XRT or disorders, several studies proved that the impact of AS on BT from the ‘Spanish Multicentric Study of Clinically patient’s mental health is low or null [9–11]. Previous Localized Prostate Cancer’ [23, 24] cohort, according to studies [12–18] have evaluated the impact of AS using risk group, elapsed time from treatment selection to generic HRQoL measures, with results consistently dem- HRQoL survey (+/− 1 year), and age (+/− 5 years old). onstrating minimal declines in comparison to active treat- ments. The English ProtecT study, the first randomized Subjects clinical trial comparing treatments for localized prostate Patients who entered in the AS protocol at the host institu- cancer in the PSA era, showed that patients allocated to tions (Hospital Universitari de Bellvitge - l’Hospitalet de the arm of AS presented similar sexual dysfunction and Llobregat, Spain - and Hospital del Mar - Barcelona, Spain) sexual bother than those allocated to radiotherapy at the with primary diagnosis of PC between January 2008 and 3rd year of follow-up [4]. These results are consistent with June 2015, were included (n = 180). The institutional review findings from a previous population-based Australian pro- board at each institution approved the AS protocols inde- spective cohort study [19], and with a longitudinal study pendently, and written consent from the participants was from USA [20]. However, another USA study showed sig- obtained. AS protocol criteria were: < 75 years old; patho- nificantly less sexual dysfunction among AS patients than logically confirmed PC (maximum of three positive cylin- those treated with radiotherapy at the 3rd year of ders); Gleason score < 3 + 4; clinical stage T1a-T2b; and follow-up [21]. It is important to highlight that, since these PSA < 15 ng/ml. Exclusion criteria for this study were: less studies evaluated the treatments’ efficacy and effective- than 6 months in AS, termination of AS protocol, incom- ness, the AS arm included also patients who underwent plete data, or refusal to participate. Risk stratification was RP or XRT at some point during follow-up: 14% at the performed according to d’Amico criteria [27]. 2nd year in the Australian study [19]; 19% at the 2nd year Demographic and clinical baseline characteristics were [20] and 24% at the 3rd year [21] in the USA studies; and collected at the pre-assessment visit (age, PSA level, clinical around 20, 40 and 55% at 2nd, 5th and 10th year, respect- stage, Gleason grade). From a total of 180 patients regis- ively, in the ProtecT trial [22]. This ‘intention to treat’ ana- tered in the AS program: 23 were excluded because they lytical strategy prevents a clear picture of patients who did not meet protocol criteria, 22 because they had remained on AS without radical treatment. switched to active treatment due to clinical progression, The main purpose of this study was to describe and 25 due to missing data (Fig. 1). Finally, during 2016, HRQoL of patients with localized PC in an AS program, the HRQoL survey was administered centrally by telephone Sureda et al. Health and Quality of Life Outcomes (2019) 17:11 Page 3 of 9 interview (see below “HRQoL instruments”) to 110 4 and 5). Those 500 patients were matched with the 110 patients at a median of 2.4 years after entering AS in AS by randomized selection according to risk group, (range 0.5–8.3). elapsed time from treatment selection to HRQoL survey (+/− 1 year), and age (+/− 5 years old). Supplementary data related to non-matched patients is ‘Spanish Multicentric Study of Clinically Localized Prostate also described (See Additional file 1: Table S1). Cancer’ cohort Data for comparative active treatment groups were ex- tracted from the “Spanish Multicentric Study of Clinic- HRQoL instruments ally Localized Prostate Cancer”, which included patients A single trained nurse performed the telephone interviews treated with RP, XRT and BT, while not in AS since it and data collection, avoiding potential internal differences was not a usual option in Spain when the study was de- due to interviewer bias. Total telephone interview time signed in 2000. Details of this cohort have been de- took between 45 and 60 min. scribed previously [23, 24]. Briefly, a total of 704 patients The disease-specific instrument used to evaluate the diagnosed of low/intermediate risk PC were recruited impact of treatment side effects on HRQoL was the Ex- between 2003 and 2005. Patients were prospectively en- panded Prostate Cancer Index Composite (EPIC) [28]. It rolled in the protocol and followed subsequently. Treat- contains 50 items from five domains (urinary incontin- ment was elected at patient-physician choice: 193 ence, urinary irritative-obstructive, bowel, sexual and underwent RP, 194 XRT and 317 BT (Fig. 1). HRQoL hormonal). All EPIC items have a reminder period of data were collected by telephone interview before treat- four weeks, and are answered on a 5-point Likert scale. ment and at one, three, six and twelve months Scores are transformed linearly to scales from 0 to 100. post-treatment the first year, and annually thereafter. The 36-Item Short Form Health Survey (SF-36) ver- Of the 704 patients, 26 had died at the third year after sion 2 [25, 29] contains 36 items covering 8 domains treatment - only 4 deaths related to PC. From the 678 (physical functioning, role-physical, bodily pain, general alive, 500 completed the HRQoL assessment at three health, vitality, social functioning, role-emotional and years after treatment (74% HRQoL completion rate), and mental health). Two additional component summaries only 87 (12.8%) missed the consecutive interviews (years were generated (physical and mental). All domains and Fig. 1 Study flowchart of enrolment and exclusion criteria that was used to select the cases suitable for the analysis Sureda et al. Health and Quality of Life Outcomes (2019) 17:11 Page 4 of 9 summary scores were obtained following the authors’ Statistical analysis recommendations [29] by standardization to a mean of Each of the 110 patients undergoing AS was matched to 50 and a standard deviation (SD) of 10 for the US gen- one patient from each attempted curative treatment eral population. These standardized scores were devel- group by randomized selection according to pre-defined oped to facilitate interpretability [30, 31] by allowing the attributes (risk group, elapsed time from treatment se- direct comparison with the mean of the US general lection to HRQoL survey, and age), giving priority to pa- population, and an easy translation of score differences tients with less potential pairs. The matching process in terms of effect sizes given its SD = 10. allowed to pair 99 patients treated by AS with patients In both HRQoL instruments, EPIC and SF-36, higher under each treatment group from the ‘Spanish Multi- scores imply better quality of life. The magnitude or centric Study of Clinically Localized Prostate Cancer’ co- clinical importance of score differences can be inter- hort (total n = 396). The statistical power was 80%, with preted using the standard categorization of effect size a type I error of 5% to detect differences of twelve points [32], whereby 0.2, 0.5 and 0.8 of the SD represent small, (effect size of 0.5 SD) on the sexual score of EPIC ques- moderate and large differences, respectively. tionnaire between groups with 50 patients. Table 1 Demographic and clinical baseline characteristics according to treatment group Active Surveillance (n = 99) Radical prostatectomy (n = 99) External-beam radiotherapy (n = 99) Brachytherapy (n = 99) p-value Risk group* Low risk 74 (74.7%) 74 (74.7%) 74 (74.7%) 74 (74.7%) 1.000 Intermediate risk 25 (25.3%) 25 (25.3%) 25 (25.3%) 25 (25.3%) Age at HRQoL survey, 70.6 (5.4) 68.2 (5.4) 73.2 (5.3) 71.9 (5.0) 0.065 mean (SD), years Elapsed time from treatment selection to HRQoL survey, years Mean (SD) 2.6 (1.5) 3.1 (1.9) 2.8 (1.9) 2.9 (1.7) 0.434 Median [IQR] 2.4 [1.4–3.6] 3.1 [1.0–4.1] 2.0 [1.0–4.1] 3.0 [1.0–4.1] Minimum - 0.53–7.32 0.45–8.32 0.46–8.32 0.48–7.06 Maximum PSA, mean (SD), ng/ml 6.8 (2.9) 7.3 (2.8) 7.7 (3.0) 7.6 (2.6) 0.087 PSA ≤ 10 84 (84.8%) 88 (89.8%) 84 (84.8%) 85 (85.9%) 0.709 PSA > 10 15 (15.2%) 10 (10.2%) 15 (15.2%) 14 (14.1%) Gleason score 2–5 0 12 (12.1%) 30 (30.3%) 28 (28.2%) < 0.001a,b,c 6 90 (90.9%) 72 (72.7%) 53 (53.5%) 64 (64.6%) 7 (3 + 4) 9 (9.1%) 15 (15.2%) 16 (16.2%) 7 (7.1%) Clinical stage T1a-T1c 78 (78.8%) 71 (71.7%) 68 (68.7%) 80 (80.3%) 0.157 T2a-T2b 21 (21.2%) 28 (28.3%) 31 (31.3%) 19 (19.2%) Comorbidities Osteoarthritis or 31 (43.1%) 44 (48.9%) 40 (50.6%) 0.623 Rheumatism High blood 26 (36.1%) 33 (36.7%) 33 (41.8%) 0.723 pressure Depression or 13 (18.1%) 12 (13.3%) 17 (21.5%) 0.370 Mental disorders Chronic respiratory 7 (9.7%) 17 (18.9%) 16 (20.3%) 0.168 diseases Ischemic heart 6 (8.3%) 16 (17.8%) 11 (13.9%) 0.220 disease Diabetes mellitus 8 (11.1%) 13 (14.4%) 10 (12.7%) 0.818 Stroke 2 (2.8%) 3 (3.3%) 4 (5.1%) 0.737 *According to d’Amico prostate cancer risk classification a: active surveillance vs radical prostatectomy; b: active surveillance vs external-beam radiotherapy; c: active surveillance vs brachytherapy Sureda et al. Health and Quality of Life Outcomes (2019) 17:11 Page 5 of 9 To describe baseline characteristics, mean (SD) was cal- mean and 95% confidence interval of HRQoL scores by culated for quantitative variables or frequencies, and per- treatment group, and also the mean of men aged 65–74 centages for categorical variables. Comparisons among four years old in the general population reference norm of treatment groups were tested using Chi squared test or the SF-36. one-way analysis of variance (ANOVA), depending on the variable’s nature. Post hoc comparisons to test differences between AS and any other treatment were performed by Results the Tukey Studentized Range (HSD) test for continuous Relevant baseline characteristics of the 396 patients (99 variables or by Chi squared test for categorical variables. per treatment group) are described in Table 1. No differ- Taking into account that HRQoL may differ according ences were found among groups on the variables used in to the elapsed time from treatment selection to survey the matching process, except for age: patients in the AS and age, we performed the analyses stratifying by them. group were older than RP ones (70.6 vs 68.2 year) and In order to obtain two groups of similar size, the cut-off younger than XRT ones (70.6 vs 73.2 year). The median that approximated the median was selected for each of (range) of time elapsed from treatment selection to the these two variables. Figures were constructed to show HRQoL survey was: 2.4 (0.53–7.32) in the AS group, 3.1 A B Fig. 2 Health-related quality of life (HRQoL) in patients with localized prostate cancer, measured with EPIC. a Stratified by elapsed time from treatment selection to HRQoL survey. b Stratified by age at HRQoL survey Sureda et al. Health and Quality of Life Outcomes (2019) 17:11 Page 6 of 9 (0.45–8.32) in the RP group, 2.0 (0.46–8.32) in the XRT EPIC results stratified by age at HRQoL survey, shows a group and 3.0 (0.48–7.06) in the BT group. similar pattern of differences. EPIC results are described in Fig. 2. AS patients re- Most of SF-36 physical health dimensions (Fig. 3a) pre- ported higher urinary incontinence scores (higher scores sented statistically significant higher scores for RP groups mean better continence) related to RP in both stratus of than among patients in AS for < 2.5 years, while no differ- time from treatment selection to HRQoL survey (92.6 vs ences were found among those with more than 2.5 years 67.0 and 81.4 vs 64.4, p < 0.01). Patients in AS for 2.5 from treatment selection. Figure 3b, with results stratified years or less presented increased EPIC sexual domain by age, only shows a difference between AS and RP for scores than the rest of the treatment groups (p < 0.01), physical functioning among patients < 70 years old. but only statistically higher than RP for those in AS for No differences were found in SF-36 mental health di- longer than 2.5 years (Fig. 2a). Moreover, differences in mensions among treatment groups (Fig. 4a nd b), except hormonal scores between AS and the other treatment for lower (worse) scores in vitality among patients in AS groups were only statistically significant among those for < 2.5 years or < 70 years of age (p = 0.001). with time longer than 2.5 years since treatment selection. Figures 3 and 4 show that patients of all treatment No differences were found among the other domains groups reported similar or even better SF-36 scores than (urinary irritative-obstructive and bowel). Figure 2b, with the general population reference norm (men aged 65–74). A B Fig. 3 Physical health dimensions and Physical Component Summary of the SF-36 in patients with localized prostate cancer. Mean (SD) by treatment group. In red, US general population reference norm (men aged 65–74). a Stratified by elapsed time from treatment selection to HRQoL survey. b Stratified by age at HRQoL survey Sureda et al. Health and Quality of Life Outcomes (2019) 17:11 Page 7 of 9 A B Fig. 4 Mental health dimensions and Mental Component Summary of the SF-36 in patients with localized prostate cancer. Mean (SD) by treatment group. In red, US general population reference norm (men aged 65–74). a Stratified by elapsed time from treatment selection to HRQoL survey. b Stratified by age at HRQoL survey Discussion treat’ analytical approach applied in these studies, and their Patients in the AS group presented better sexual out- worse results be caused by those patients who underwent comes than any active treatment at short term, differ- radical prostatectomy or radiotherapy at some point during ence which persisted only with the RP group beyond 2.5 follow-up (14% [19], 19% [20], and 20% [22] at the 2nd years after treatment selection. The magnitude of the year). A longitudinal study of predictors of sexual dysfunc- differences between AS and RP groups was large in both tion in men on AS only identified age, diabetes and PSA as stratums of elapsed time to HRQoL survey (1.0 and 0.74 the factors independently associated [33]. SD). This is explained by the well-known erectile dys- In our study, patients in AS group reported higher urin- function that RP may cause in some cases [3, 4]. Our ary incontinence scores (better continence) compared to good sexual results for patients in the AS program are RP, with large differences regardless of time elapsed from similar to those reported in the USA observational study treatment selection (0.99 and 0.74 SD). It may be ex- showing their statistically significant better sexual func- plained by the loss of continence associated to surgery, al- tion than RP and XRT groups at 3rd year of follow-up though it usually improves over time [3, 4]. These results [21]. Sexual dysfunction for patients in AS reported by are in line with the lack of sexual and urinary continence ProtecT trial [4], the Australian cohort [19], and a USA side effects showed in a study that compared patients in study [20] could be partly explained by the ‘intention to AS with men without cancer after a prostate biopsy [34]. Sureda et al. Health and Quality of Life Outcomes (2019) 17:11 Page 8 of 9 Regardless of the treatment applied, our results proved have progressed: slightly smaller declines in erectile function that physical and mental components of health are very with robotic radical prostatectomy than with open tech- similar to those reported by US general population, indicat- nique [35, 36], and slightly better bowel results for IMRT ing a good health status in patients with favourable-risk PC. than for older 3D conformal radiation therapy [37, 38]. Fur- These results are consistent with those obtained in the Pro- thermore comorbidity, which could be a major factor in tecT [4] and in a systematic review [9], which concluded choice of therapy, was not collected for patients in AS. Fi- that there was no major perturbation of HRQoL and psy- nally, the SF-36 reference norms used were from the US chological well-being in men undergoing AS in comparison general population. However, as the Spanish and US refer- to radical treatments. Nonetheless, patients in AS reported ence norms of SF-36 were very similar [25, 31] both of them worse outcomes than other treatment groups at short term are suitable and US reference norms facilitate international on physical and mental health domains: especially in bodily comparisons. pain (0.46–0.63 SD) and vitality (0.55–0.77 SD). The mag- nitude of these differences was moderate. Pain-related ef- Conclusions fects of repeated prostate biopsies in the AS group could In conclusion, considering treatment side effects and pa- explain, partly, bodily pain differences. They can be also ex- tients’ well being, AS can be a good therapeutic option plained by differences at baseline between AS and RP due to the low impact caused on HRQoL. Moreover, pa- groups: younger and healthier patients may tend to choose tients undergoing AS do not seem to suffer major nega- more active treatments like RP, with better subsequent re- tive psychological effects in comparison to active covery. In fact, differences between treatments in the phys- treatments or general population. Our results provide a ical health domains do not appear after stratifying by age. first approximation of AS patient-reported outcomes in Our main strengths are the HRQoL evaluation, which HRQoL. However, longitudinal studies may be required included two of the most widely used generic and to take into account HRQoL evolution over the years, in disease-specific instruments at this moment, and the order to make clear recommendations showing the per- matching of patients in the AS program with the “Span- centage of patients who remain in AS without radical ish Multicentric Study of Clinically Localized Prostate treatment and their HRQoL at different follow-up times. Cancer” cohort. Moreover, the cross-sectional design of the study clearly shows us the real HRQoL status of the patients remaining in the AS group, without contamin- Additional file ation of those who switched to active treatments. Additional file 1: Table S1. Comparison between matched and non- Our matching process reduced baseline differences, matched patients. (DOCX 19 kb) providing comparable groups. Statistically significant dif- ferences were found on mean age at diagnosis: The AS Abbreviations group’s mean age was intermediate between RP and AS: Active surveillance; HRQoL: Health-Related Quality of Life; LPC: Localized XRT (see Table 1). Besides, patients in the AS group prostate cancer; RP: Radical prostatectomy; XRT: External-beam radiotherapy; were more likely to be diagnosed in T2 stage in com- BT: Brachytherapy; EPIC: Expanded Prostate Cancer Index Composite; SF- 36: 36-Item Short Form Health Survey (SF-36); PC: Prostate cancer; parison to other treatments, which may surprise since PSA: Prostate specific antigen; SF-36: The 36-Item Short Form Health Survey; AS is a strategy to delay or avoid curative treatment in SD: Standard deviation; ES: Effect size; NRMI: Nuclear magnetic resonance localized PC [5–8], but we should bear in mind that AS imaging patients are more likely to be defined by NRMI (nuclear Acknowledgements magnetic resonance imaging), with consequent staging We would like to acknowledge Aurea Martin for her help in the English as T2. All groups were equivalent in terms of PSA and proofreading and editing process. Gleason score. The main limitation is that this is a cross-sectional Funding This work was supported by grants from Instituto de Salud Carlos III FEDER study, not enabled to assess patients’ evolution or to (PI11/01191 and PI13/00412); DURSI-GENCAT (2014-SGR-748 and 2017 SGR avoid selection bias. Patients in AS for longer than 6 452); AATRM 086/24/2000 and 436/05/2008. months assessed in this study were those who tolerate it well physically and mentally, and those who did not have Availability of data and materials progressive disease or symptoms resulting in termination The dataset used and analysed during the current study are available from the corresponding author on reasonable request. of AS protocol. The study could also overestimate differ- ences between AS and active treatments, especially be- Authors’ contributions cause treatments in the interventional arms (RP, XRT Principal investigators: LF, MF, JFS. Study design: LF, MF, OG, JFS. Field and BT) were performed during the 2003–2005 period, so investigators: LF, XB, MC, MCM, JMA, FV, LC, JFS. Data analysis and management: AS, LF, MF, OG. Manuscript preparation: AS, LF, MF. Manuscript techniques and procedures have evolved. Nowadays, func- editing: AS, LF, MF and all. All authors reviewed, contributed and approved tional outcomes in these attempted curative treatments the final manuscript. Sureda et al. Health and Quality of Life Outcomes (2019) 17:11 Page 9 of 9 Ethics approval and consent to participate 17. Vasarainen H, Lokman U, Ruutu M, Taari K, Rannikko A. Prostate cancer All recruitment and research protocol were approved by the ethics active surveillance and health-related quality of life: results of the Finnish committee, CEIC- Parc de Salut Mar, Barcelona, Spain. Eligible patients signed arm of the prospective trial. BJU Int. 2012;109:1614–9. an informed consent form. 18. Watts S, Leydon G, Eyles C, et al. 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