Improvement of quality of life and symptom burden after robot-assisted radical prostatectomy in patients with moderate to severe LUTS

The aim of this study was to assess clinically meaningful differences of preoperative lower urinary tract symptoms (LUTS) and quality of life (QoL) before and after robot-assisted radical prostatectomy (RARP). Therefore we identified 5506 RARP patients from 2007 to 2018 with completed International Prostate Symptom Score (IPSS) and -QoL questionnaires before and 12 months after RARP in our institution. Marked clinically important difference (MCID) was defined by using the strictest IPSS-difference of − 8 points. Multivariable logistic regression analyses (LRM) aimed to predict ∆IPSS ≤ − 8 and were restricted to RARP patients with preoperatively moderate (IPSS 8–19) vs. severe (IPSS 20–35) LUTS burden (n = 2305). Preoperative LUTS was categorized as moderate and severe in 37% (n = 2014) and 5.3% of the complete cohort (n = 291), respectively. Here, a postoperative ∆IPSS ≤ − 8, was reported in 38% vs. 90%. In LRM, younger age (OR 0.98, 95%CI 0.97–0.99; p = 0.007), lower BMI (OR 0.94, 95%CI 0.92–0.97; p < 0.001), higher preoperative LUTS burden (severe vs. moderate [REF.] OR 15.6, 95%CI 10.4–23.4; p < 0.001), greater prostate specimen weight (per 10 g, OR 1.12, 95%CI 1.07–1.16; p < 0.001) and the event of urinary continence recovery (OR 1.66 95%CI 1.25–2.21; p < 0.001) were independent predictors of a marked LUTS improvement after RARP. Less rigorous IPSS-difference of − 5 points yielded identical predictors. To sum up, in substantial proportions of patients with preoperative moderate or severe LUTS a marked improvement of LUTS and QoL can be expected at 12 months after RARP. LRM revealed greatest benefit in those patients with preoperatively greatest LUTS burden, prostate enlargement, lower BMI, younger age and the event of urinary continence recovery.

Prostate cancer (PCa) and benign prostatic hyperplasia (BPH) occur in men of advanced age and are frequently coexistent. Both may be associated with lower urinary tract symptoms (LUTS) and increased serum PSA levels.
To date, it remains unclear whether the association of PCa and BPH reflects a causal link, shared risk factors or pathophysiological mechanisms or detection bias 1 . Specifically, men suffering from LUTS often seek medical advice and receive PSA testing as part of the clinical evaluation [2][3][4][5] . In consequence, a substantial proportion of patients diagnosed with PCa and scheduled for radical prostatectomy (RP) suffer from preoperatively clinically important LUTS [3][4][5] . Such LUTS usually reduce patients' quality of life (QoL), driven by either storage-(e.g. urgency, nocturia) or voiding-symptoms (e.g. intermittency, weak voiding stream) 6,7 and can even have an impact on mortality risk 8 . Due to such impact on QoL, conventional oncological and functional outcomes, which are integral for PCa patient counselling, should be complemented with the postinterventional prospect of changed symptom burden and quality of life especially in the patients suffering from moderate or severe LUTS, which is often overlooked 9 . For outcomes after RARP, this neglect is reflected in the fact that most series focus on postoperative urinary continence recovery 10,11 , whereas corresponding data on LUTS and QoL is rather sparse 12 . Moreover, most published series, which focus on latter outcome, are limited by small sample sizes 10,11,13,14 , particularly of RARP patients with moderate or severe preoperative LUTS 2,10 . Accordingly, most series rely on exploratory analyses, but forego multivariable analyses (MVA) 10,15,16 . Similarly, most series focus on changes of mean IPSS or QoL scores but do so without reporting minimal or marked clinically important differences (MCIDs) of pre-vs. postoperative LUTS. Such MCIDs allow easier clinically meaningful interpretation. Finally, aforementioned RARP studies rarely differentiate between storage (e.g. frequency, urgency, nocturia) and voiding-symptoms (e.g. intermittency, weak voiding stream) 17 . Former might indicate urge incontinence or underlying medical conditions. In consequence, thorough preoperative IPSS evaluation may be essential to better estimate chances of postoperative continence recovery, too 2,11 .
Thus, we assessed clinically meaningful marked and moderate differences of pre-vs. postoperative LUTS and associated QoL 12 months after RARP and identified predictors of post-RARP improvement.

Material and methods
Within our database, we identified 11,711 PCa patients, who were treated with RARP in our hospital between 5/2006 and 12/2018. Inclusion criteria consisted of complete information on preoperative PSA and pathological characteristics. Functional parameters included urinary function and International Prostate Symptom Score (IPSS) and -QoL questionnaire-derived lower urinary tract symptoms (LUTS) burden preoperatively and at 12 months follow-up. All patients were preoperatively continent. Patients with radiation therapy of the pelvis or prostate (neoadjuvant/salvage/adjuvant), or local therapy of the prostate or bladder, or suspected metastases at preoperative staging were excluded. Finally, we selected 5506 RARP patients for further analysis. Preoperative medication such as: alpha-blocker therapy, 5-alpha-reductase inhibitor therapy, neoadjuvant antiandrogen therapy and/or luteinizing hormone-releasing hormone antagonist or agonist therapy (henceforth referred to as neoadjuvant ADT) did not represent exclusion criteria. No patients received adjuvant or salvage radiation therapy within that timeframe according to our exclusion criteria. The institutional review board at the St. Antonius-Hospital, Gronau, approved the retrospective study design and access to the patients' medical records. All methods were carried out in accordance with the Declaration of Helsinki. Written informed consent was obtained from individual participants in the study.
Outcomes. Urinary continence recovery was defined as a combination of 1) a score ≤ 2 for both the first and second question of the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (Q1 "How often do you leak urine?" and Q2 "How much urine do you usually leak (whether you wear protection or not)?") 18 , 2) International Continence Society male questionnaire score ≤ 1 for the questions 2, 3, 4 and finally up to one pad usage within 24 h. Preoperatively, no pad usage was permitted for being deemed continent.
For 12 months after RARP we used the strictest criterion of IPSS-difference of at least 8 points (∆IPSS 8) in relation to the preoperative IPSS score [19][20][21] , this was defined as a marked clinical important difference (MCID). Specifically, a ∆IPSS ≤ − 8 represents a marked improvement, whereas a ∆IPSS ≥ + 8 would represent a marked deterioration. It is important to note that a marked improvement ∆IPSS ≤ − 8 cannot be observed in those patients with lowest symptom burden (range 0-7 points), since a ∆IPSS ≤ − 8 exceeds any value within that point range. A less rigorous, moderate clinical important difference of ∆IPSS 5 was also utilized 15,19-21 . Statistical analyses. Proportions 22 , nerve-sparing (none vs. uni-vs. bilateral) and bladder neck reconstruction width (1-5 cm). The CAPRA-S is calculated with pre-surgical PSA, pathological Gleason score, surgical margin status, extracapsular extension, seminal vesicle invasion and lymph node invasion 22 . Similarly, as supplemental analyses, we also performed multivariable linear regression analyses for change of LUTS 12 months after RARP within the total cohort, i.e. those with any preoperative LUTS burden (IPSS range 0-35). Adjustment variables were the same as in LRM.

Discussion
Previous series with multivariable analyses on examining postoperative changes of LUTS were sparse, heterogeneous and limited by specific selection of variables or small sample size. Thus, we aimed to provide most comprehensive analyses of marked and moderate clinically important differences between pre-vs. post-RARP LUTS and associated QoL in a large cohort of PCa patients. Our findings aim to provide robust decision factors if local PCa treatment such as RARP should be considered as primary therapy 9 .
Our study revealed several important findings. First, there was a substantial proportion of 42% of PCa patients with moderate or severe preoperative LUTS (n = 2305). These patient numbers are more than 30-fold compared to previous series 2, 10 . Such sample size represents a prerequisite to identify predictors of LUTS improvement in multivariable analyses. Moreover, such extent of pre-existing LUTS burden and associated negative impact on QoL might greatly confound the perceived outcome after local treatment such as RARP, despite otherwise favourable functional and oncological outcomes. In consequence, it is of utmost importance to consider the treatment of the bothering LUTS as core part of the overall therapy 23 .
Second, RARP patients with moderate and severe preoperative LUTS showed substantial marked clinical improvement rates of 60 and 90%, respectively. It is of note that within the remaining 40% of former group with moderate LUTS, less than 2% experience a marked deterioration. Thus, we display great safety of RARP in this regard, at least in experienced centers. Conversely, we not only confirm postoperative improvement, but even demonstrate greater potential of LUTS improvement after RARP, even beyond previous reports 15 , since we applied the most rigorous MCID ∆IPSS ≤ − 8.
Third, there is a statistically significant association between LUTS burden and unfavourable pathological cancer characteristics as evidenced by increasing proportions of CAPRA-S high-risk from 14 to 19% (p < 0.001). These findings support the proposed link between BPH and increased risk of PCa and PCa-related mortality www.nature.com/scientificreports/ from epidemiological studies 1,24 . Since inverse stage migration trends demonstrate increasing proportions of senior PCa patients with unfavourable PCa characteristics, who receive local treatment such as RARP, those simultaneously suffering from moderate or severe LUTS will be even more prevalent 25,26 . Fourth, we clearly demonstrated that the RARP-mediated effect on postoperative LUTS is driven by voiding symptoms. This is in line with a previously proposed substratification 2,27 and series that compared pre-vs. postoperative voiding metrics 28 . In consequence, during surgical work-up the overall IPPS score as well as the voiding-subdomain should be evaluated. Specifically, a larger score in the voiding-subdomain indicates greater possible RARP-mediated improvement effect on LUTS. www.nature.com/scientificreports/ Fifth, the study at hand is one of the few to provide LRM to predict marked post-RARP improvement of LUTS 2,10,15,16,27 . We confirm preoperative LUTS burden as a strong predictor [14][15][16] . Moreover, larger prostate size and younger age were predictors as well, which are conceivable due to shared risk factors between BPH, associated LUTS and PCa 1,24 . Specifically, with regard to age, a longitudinal study impressively demonstrated LUTS progression in men over a period of 11 years 29 .
We also identified lower BMI as predictor. Several series demonstrated LUTS exacerbation in obese men 2 , often even unrelated to PCa [30][31][32][33] . In consequence, for those with residual post-RARP LUTS, obesity remains an important target for intervention, which can be already addressed while counselling the patient.
Finally, not surprisingly, urinary continence recovery is contributive for a marked improvement. It is of note that urinary continence recovery is neither a patient characteristic nor a preoperative condition unlike the aforementioned predictors, but a key functional outcome after RARP. Our findings confirm such association between this outcome and LUTS burden 2,27 . Interestingly, to our knowledge, we are the first to show these predictors in such multivariable fashion. For example, the Japanese RARP series by Haga et al. 14 confirmed our finding of preoperative LUTS burden as a main predictor. However, they identified nerve-sparing as predictor, which we are not able to confirm, potentially due to over 96% of patients who had at least unilateral nerve-sparing in our a b Figure 1. (a) "Marked clinically important differences 12 months after robot-assisted radical prostatectomy, defined as a change of at least 8 points in the International Prostate Symptom Score, in the overall cohort and stratified according to preoperative lower urinary tract symptoms burden, nothing or mild vs. moderate vs. severe". (b) "Moderate clinically important differences 12 months after robot-assisted radical prostatectomy, defined as a change of at least 5 points in the International Prostate Symptom Score, in the overall cohort and stratified according to preoperative lower urinary tract symptoms burden, nothing or mild vs. moderate vs. severe". Our study has limitations. First, our data originate from a highly specialized single tertiary referral center and are not necessarily generalizable. Direct comparison to open radical prostatectomy is not possible since our center performs only RARP. However, the presented findings are highly consistent with previous series. Second, LUTS represent a patient-reported outcome. Our data was not complemented by ultrasound post void residual urine (PVR) or maximum urinary flow rates after 12 months to objectively measure the effect of RARP on micturition 28 . However, direct post-RARP PVR are institutionally measured by suprapubic catheter, which is only removed if PVR is repeatedly below 100 ml. Finally, for purpose of post-RARP erectile function recovery, several patients medicate with phosphodiesterase-5 inhibitors (PDE-5I), which are known to alleviate LUTS in patients with concomitant BPH-LUTS 21 . Despite removal of the prostate a remaining effect on smooth muscle relaxation in the bladder and supporting vasculature is possible, thus potentially further improving LUTS post-RARP 34 . However, in our cohort higher LUTS severity was associated with lower potency rates: i.e. for mild vs. severe LUTS the corresponding preoperative potency rates were 52 vs. 37%. Such distribution strengthens our post-RARP findings, i.e. greatest LUTS improvement rates in exactly those with severe preoperative LUTS.

Conclusions
In one of the largest RARP cohorts with preoperative moderate or severe LUTS burden, we observed substantial proportions of patients with marked improvements of LUTS at 12 months after RARP, which translates to improvement of QoL. LRM revealed greatest benefit in those with preoperatively greatest LUTS burden, prostate enlargement, lower BMI, younger age and the event of urinary continence recovery. In presence of such findings, such postoperative functional and QoL prospects are integral for patient counseling regarding to the prostate cancer treatment.
Received: 28 April 2021; Accepted: 23 July 2021 Table 2. Multivariable logistic regression model for prediction of marked and moderate LUTS improvement after robot-assisted radical prostatectomy in patients with moderate or severe preoperative LUTS. CAPRA-S: the postsurgical Cancer of the Prostate Risk Assessment score; IPSS: International Prostate Symptom Score; LUTS: lower urinary tract symptoms; RARP: robot-assisted radical prostatectomy. a Adjusted for surgical experience, preoperative PSA, preoperative medication with alpha-blockers, 5-alpha-reductase inhibitors, neoadjuvant androgen deprivation, CAPRA-S score, nerve-sparing status and bladder neck reconstruction width.