The Europa Uomo Patient Reported Outcome Study 2.0—Prostate Cancer Patient-reported Outcomes to Support Treatment Decision-making

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Introduction
In 2019, Europa Uomo-the prostate cancer (PCa) patient coalition in Europe-initiated the Europa Uomo Patient Reported Outcome Study (EUPROMS), with the primary goal of collecting patient-reported outcomes (PROs) outside a clinical trial setting reflecting patients' quality of life (QoL) after PCa treatment [1]. From what they heard back from their members and supporters who underwent PCa treatment, the adverse effects of PCa treatment differed from the data of controlled clinical trials published in the literature [1]. Historically, the use of patientreported outcome measures (PROMs) has been limited to a research setting: the inquiry of pre-and posttreatment QoL was done by clinicians who recorded patients' answers. This has slowly shifted toward the development of validated questionnaires and patients self-reporting their QoL [2]. Over the years, measuring treatment-related QoL has become an increasingly requisite component of delivering high-quality care for PCa patients. Collecting information on physical functioning and mental well-being directly from patients is important because such outcomes may be under-reported by physicians [3,4]. PROMs in that sense may guide clinical practice to be more responsive to individual patients' needs and, in addition, can inform ways in which patients can self-manage their condition and well-being.
An overwhelming number of 2943 men participated in the EUPROMS study, and all together they provided a cross-sectional picture of the European PCa population and their reported QoL [1]. In October 2021, Europa Uomo launched the EUPROMS 2.0 survey aiming to increase the collection of patients' self-reported perspective on physical and mental well-being outside a clinical trial setting, to be able to investigate the burden of PCa treatment from a patient-to-patient perspective. In addition, men were invited to share their reasons for initial prostate-specific antigen (PSA) testing and experiences on shared decision-making (SDM) with health care professionals.

Patient screening criteria
The EUPROMS 2.0 survey was open to men diagnosed with PCa and currently undergoing PCa treatment or having received treatment for their PCa in the past.

Recruitment and data collection
Europa Uomo placed the EUPROMS 2.0 survey-available in 20 languages-on their website (www.europa-uomo.org). Europa Uomo used its network of, among others, national patient organizations and supportive urologists to promote the EUPROMS 2.0 survey as well as to stimulate PCa patients to complete it. Data collection was handled by Ydeal (ydeal.net) to meet with IT and legal requirements.
The characteristics of the validated EQ-5D-5L, EORTC-QLQ-C30, and EPIC-26 have been described previously [1]. The SDM-Q-9 is a selfreport instrument developed to measure the process of SDM in a consultation as perceived by the patient [12,13]. All nine items are scored on a six-point Likert scale, ranging from 0 (''completely disagree'') to 5 (''completely agree''). Adding up the scores of the nine items leads to an overall SDM-Q-9 summary score between 0 and 45, with 0 indicating the lowest and 45 the highest level of perceived SDM [12,13].

Statistical analysis
Descriptive statistics were used to assess the demographic and clinical characteristics of the men who completed the EUPROMS 2.0 survey, and to analyze the outcomes of the EQ-5D-5L, EORTC-QLQ-C30, EPIC-26, SDM-Q-9, and clinical scenarios. We performed a sensitivity analysis to assess whether differences existed between the group of men who already participated in the initial EUPROMS study and ''new participants''. R version 4.2.1 was used to perform all analyses [14].
PROs were described for the most frequently reported treatment modalities, that is, active surveillance (AS), radical prostatectomy (RP), radiotherapy (RT), AS + RP, RP + RT, RT + androgen deprivation therapy (ADT), RP-RT-ADT, and chemotherapy (either as a single treatment or after having received other treatments). For miscellaneous single or combinations of treatments, the numbers were too small to report PROs. Most respondents undergoing a single or two treatments reported no problems with mobility and self-care (Fig. 1). A somewhat larger proportion of men undergoing RT-ADT (14%), RP-RT-ADT (12%), or chemotherapy (24%) reported moderate/severe problems conducting their usual activities. With respect to pain/discomfort, 75-95% of respondents reported no or slight pain/discomfort. Men who were treated with RT-ADT (16%), RP-RT-ADT (18%), or chemotherapy reported a slightly higher level of pain/discomfort (25%). The rate of men reporting no or slight anxiety/depression ranges from 77% to 91%. The median EQ-VAS score for all 3571 men is 80 (IQR 70-90).

EORTC-QLQ-C30
Respondents reported no big impairments with respect to self-reported functioning (Table 3). Men who were treated with RT, either as a single treatment or in combination with other treatments (RP-RT, RT-ADT, or RP-RT-ADT), and chemotherapy had higher median fatigue and insomnia scores than those treated with the other treatment modalities.

EPIC-26
The impact of treatment is most prominently seen on the urinary incontinence (UI) and sexual function (SF) domains ( Fig. 2A-E). Men who underwent RP as a single treatment or in combination with another treatment reported the lowest UI scores. The median self-reported SF score is highest for men following AS.

Discussion
After the first EUPROMS survey, Europa Uomo was able to collect another 3571 responses of PCa patients who underwent treatment and to collect their self-reported perspective on the adverse effects of PCa treatment outside a clinical trial setting (EUPROMS 1.0 and 2.0 [new patients] >5400 responses). The outcomes of the EUPROMS 2.0 cross-sectional survey confirm the results of the EUPROMS 1.0 study and highlight that men treated actively experience lower health-related QoL than men who opt for AS, mainly regarding SF, fatigue, and insomnia. Lower UI levels were seen for men who underwent RP, either as a single treatment or in combination with other treatments. When asking about reasons to determine the PSA value, 42% of respondents indicated that it was part of a routine blood test. A quarter of men indicated that they wanted to undergo screening/early detection for PCa, and approximately 20% indicated that determining the PSA value had a clinical reason. A total of 81.7% of respondents indicated that the doctor shared what was felt when a DRE was performed. An MRI scan and a prostate biopsy were the most frequent other diagnostic tests that were performed. In light of the recent developments regarding the early detection of PCa and treatment of PCa in an earlier stage, we have looked into UI and SF levels according to Gleason score. When assessing UI and SF levels according to Gleason 6 or 7 PCa at diagnosis, no large differences were seen for UI scores as compared with the overall treatment groups. In the literature, in a study comparing prostate-specific functioning for men with Gleason 6 or 7 PCa at diagnosis undergoing AS, RP, or RT and having between 6 and 8 yr of followup after treatment, the mean EPIC UI scores were 90.0 for AS, 70.1 for RP, and 86.5 for RT [16], as compared with a median score of 100 for AS, 73.0 for RP, and 93.8 for RT in EUPROMS 2.0 (Supplementary Table 1). Healthy men without PCa reported a mean UI score of 90.4 [16], and the EPIC mean UI norm score for 112 controls without PCa was 92.9 ADT = androgen deprivation therapy; AS = active surveillance; IQR = interquartile range; PCa = prostate cancer; PSA = prostate-specific antigen; RP = radical prostatectomy; RT = radiotherapy. a Men who underwent chemotherapy as a single treatment or in combination with other, earlier treatments.
S X X X ( X X X X ) X X X -X X X [17]. With respect to SF, some small differences were seen between treatments for men with Gleason 6 [16], and the EPIC SF norm score for 112 controls without PCa was 55.8) [17]. Recently, Lane et al. [18] published PRO data of men who were randomized to, or chose one of, three treatments in the ProtecT study. In the ProtecT study, in both the randomized and the nonrandomized group, 97% of men had Gleason 6 or 7 PCa at diagnosis [19]. In the recent article, data were analyzed according to the treatment-received analyses [18].   ADT = androgen deprivation therapy; AS = active surveillance; Chemo = chemotherapy; CT = computed tomography; MRI = magnetic resonance imaging; PET = positron emission tomography; PSA = prostate-specific antigen; PSMA = prostate-specific membrane antigen; RP = radical prostatectomy; RT = radiotherapy. a Men who underwent chemotherapy as a single treatment or in combination with other, earlier treatments.
was acknowledged in the treatment-received analysis of the ProtecT PROs, where some impacts were greater in men aged 65-69 yr at diagnosis than in men aged 50-64 yr [18]. In the study by Barocas et al. [20], again a relation with age is seen on the reported UI and SF domain scores. Men aged 65-75 yr and following AS, RP, or RT had consistently lower scores than men aged 55-<65 yr. It should be noted, however, that results should be interpreted with caution.
International guidelines have been highlighting the importance of SDM for PCa treatment [21,22]. The SDM-Q-9 summary scores are at the top half of the score range for all treatments. However, when looking at some of the individual items reflecting elements of SDM, nuances are seen between treatments. For instance, 60.7% and 63.0% of men treated with RP-RT-ADT and chemotherapy, respectively, completely agreed that the doctor made it clear that a treatment decision needs to be taken, as opposed to 30.8% S X X X ( X X X X ) X X X -X X X for men on AS and 35.4% on AS-RP. This might be related to the tumor characteristics of men who have already undergone RP-RT-ADT or chemotherapy and hence the urgency of subsequent treatment, as opposed to men having the option to choose treatment for lower-risk disease. Sharing individual item data from SDM-Q-9 for the various treatments may help future patients in understanding the concept of SDM better and learning what elements contribute to such an overarching phenomenon. There will always be a share of patients who prefer that the doctor makes the final treatment decision. However, when men realize that SDM encompasses more than just making the final treatment decision, they can still feel engaged and actively involved in the SDM process, potentially influencing future feelings of decisional regret.
The strength of EUPROMS 2.0 is that Europa Uomo was again able to mobilize a large sample of international PCa patients to complete the EUPROMS 2.0 survey. About 30%    ADT = androgen deprivation therapy; AS = active surveillance; Chemo = chemotherapy; IQR = interquartile range; RP = radical prostatectomy; RT = radiotherapy. a Men who underwent chemotherapy as a single treatment or in combination with other, earlier treatments. b Functional scales/global health status: a higher score indicates better functioning/better quality of life. c Symptom scales: a higher score means more symptoms, worse functioning. d Single items: a higher score means more symptoms, worse functioning.
S X X X ( X X X X ) X X X -X X X of men had already participated in the first EUPROMS survey, and 70% of men were new respondents. Sensitivity analyses showed that responses from new respondents did not differ significantly from the men who had already participated in the first EUPROMS survey. Besides European, Canadian and American PCa patients were also represented. Furthermore, we were able to confirm the results of the first EUPROMS study and additionally grasp knowledge on reasons for undergoing a PSA test and levels of SDM experienced. A limitation is that no pretreatment PRO data were available, and therefore the impact of, for example, time after treatment on self-reported PRO data could not be assessed. However, as indicated earlier by Europa Uomo, it is its goal to inform future PCa patients about the impact of PCa treatment through self-reported PRO data of fellow patients collected outside a clinical trial setting [1]. Furthermore, a total of 65.7% of participants achieved higher education, which is not likely to reflect the educational levels of the general population. While we were able to collect more information about tumor stage and grade, information on which men were treated with uni-or bilateral nervesparing RP is missing. We know, however, that 18.5% of men who underwent RP was treated between 2010 and 2014 and >65% of men since 2015.

Conclusions
With the EUPROMS 2.0 survey, Europa Uomo has once more been able to collect a large sample of PROMS data outside a clinical trial setting on the adverse effects of PCa treatment. A total of 3571 international patients have contributed their experiences after PCa treatment confirming that treatment for PCa mainly affects UI (RP), functions, as well as fatigue and insomnia. Such information can be used to inform future fellow patients about the impact of PCa treatment and engage in informed decision-making and SDM. In doing so, Europa Uomo is bringing its mission forward to direct toward a better patient-doctor relationship, to offer patients ready access to responsible information and a better understanding of their disease and treatment.
Author contributions: Lionne D.F. Venderbos had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Obtaining funding: Deschamps.    (continued on next page) E U R O P E A N U R O L O G Y F O C U S X X X ( X X X X ) X X X -X X X ADT = androgen deprivation therapy; AS = active surveillance; Chemo = chemotherapy; IQR = interquartile range; RP = radical prostatectomy; RT = radiotherapy. a Men who underwent chemotherapy as a single treatment or in combination with other, earlier treatments. b Score range 0-45; a higher score indicates a higher level of perceived shared decision-making.