In this randomized controlled trial, we will evaluate if bipolar enucleation of the prostate (BEEP) is associated with better urinary voiding outcome than transurethral resection (TURP) in men with enlarged prostate referred to surgery. In addition we will investigate the association between symptom relief and the amount of removed tissue and if patients experience differ between the two methods. Finally, we will assess cost-effectiveness of BEEP compared to TURP. The main outcome for comparison of the two surgical methods is International Prostate Symptom Score (IPSS) assessed at 12-month follow-up. The primary outcome to assess patient experience is measured with the questionnaire Nordic Patients Experience Questionnaire (NORPEQ). Cost-effectiveness will be measured with incremental cost-effectiveness ratio (ICER).

Title:

Outcome and patient experiences after transurethral resection and bipolar enucleation of the prostate - a multi-center, randomized controlled trial.

Introduction:

In the present project we will evaluate if bipolar enucleation of the prostate (BEEP) is associated with better urinary voiding outcome than transurethral resection (TURP), and if the patients' experiences differ between these two methods. We will also investigate the association between symptom relief and the amount of tissue removed in the surgical procedure.

Lower urinary tract symptoms (LUTS) are prevalent in ageing men. LUTS encompasses several conditions such as for instance bladder dysfunction and pelvic pain. One major cause of LUTS is benign prostate hyperplasia (BPH) and secondary to this benign prostatic obstruction (BPO). About 50% of men in their 50s have BPH and in men aged above 70 years the prevalence is around 80%. The prostatic gland is located distally to the urinary bladder and surrounds the urethra. With increasing size, the prostate can cause bladder outflow obstruction and urinary voiding problems, most often weak urinary stream and increased residual urine. Residual urine, meaning incomplete emptying of the bladder, can lead to infections and urinary retention. Over time, it may cause damage to the urinary bladder muscle and the kidneys due to increased bladder pressure. LUTS caused by a hypertrophied prostate can be managed with lifestyle changes, medication or surgery.

Transurethral resection of the prostate (TURP) has for decades been the mainstay surgical treatment of urinary voiding problems in men with BPH. Over the years, several other methods have challenged TURP. One option is bipolar endoscopic enucleation of the prostate (BEEP). According to the guidelines from the European Association of Urology (EAU), TURP is still first choice surgical treatment for men with prostate sizes from 30mL to 80mL, while BEEP is listed as one of the alternative procedures. Both TURP and BEEP are transurethral procedures, but the techniques differ.

Performing TURP, the surgeon starts to remove central prostatic tissue from the bladder neck and in a distal direction. In contrast to TURP, BEEP is a method where the tissue is removed in a proximal direction, towards the bladder, and the dissection of prostatic tissue starts in the peripheral zone. The main aim of BHP surgery is to improve urinary voiding symptoms, and the recommended outcome measure for both TURP and BEEP is patient report by the International Prostate Symptom Score (IPSS).

Surgical treatment of LUTS in men are common procedures, but studies on direct comparison between TURP and BEEP are few. TURP is regarded cost-effective and has the advantage over BEEP that both surgeons' learning curve and operative time are shorter. A systematic review and meta-analysis from 2020 on current evidence regarding outcomes after TURP and BEEP, identified 14 studies including 5 randomized controlled trials (RCTs). The authors concluded that BEEP had several advantages. They found shorter length of stay, less complications and fewer reoperations after BEEP. Overall, BEEP showed better functional outcomes (lower patient-reported symptom score, improved urinary stream and reduced residual volume after micturition). Symptoms were patient-reported with IPSS in 6 of the studies. The differences in IPSS after treatment with BEEP or TURP were small, ranging from 0.1 to 5.1 (minimal important difference with IPSS has been reported to be 5).The RCTs had several weaknesses: single-center design, the procedures were performed by selected and high-volume surgeons, there were lack of data on health economics and sexual function. However, the main limitation was heterogeneity on prostate size. Of the three RCTs with follow-up data after 12 months, two of them reported data on men with prostate sizes > 70 mL. None of these RCTs found significant differences in IPPS after 12 months. Only one RCT included prostate sizes < 60 mL. This single-center study included prostate sizes down to 20 mL. The authors of this systematic review concluded that there is need for multi-center studies to strengthen current evidence. Another systematic review from 2019 on surgical treatment for BPH included 109 studies.The review stated that IPPS was lower (less symptoms) and the urinary stream was better after enucleations procedures compared to TURP. 8 studies on direct comparison with BEEP to TURP were included, only 4 (the same studies included in the systematic review from 2020 with one additional study) of them had follow-up data after 12 months. The fourth study with long term follow-up data reported better symptom relief with BEEP after 36 months. In addition, this study found no differences in patient-reported sexual function. Heterogeneity in study design was found to be a weakness of the included studies in the review from 2019. Additional weaknesses were missing information on how randomization was made and how complications were reported. 36 (33%) of the studies reported complications sufficiently. Since EAU guidelines have listed BEEP as an alternative to TURP for average sized glands (30mL to 80 mL) and RCTs on BEEP vs TURP exclusively on men with average sized glands are non-existing, this knowledge gap must be filled and is the main motivation for this study.

In line with existing studies, a larger proportion of hyperplastic tissue is removed with BEEP compared to TURP. As all surgical procedures have potential harms, and a more complete resection might increase the rate of adverse effects, for instance sexual adverse effects. However, studies that address the importance of a complete resection are few and knowledge on whether a complete resection has impact on quality of life and adverse effects is limited.

Another gap in existing knowledge is how the patients experience their journey through surgical treatment of BPH. Patient-reported experience measures (PREMs) are designed to capture patient experiences. There is no consensus on which PREM questionnaire that should be used for surgical BPH patients and only a few questionnaires are available for the purpose. Furthermore, there is currently no systematic registration of patient experiences for surgical BPH patients in Norway. One existing and validated PREM questionnaire is the Nordic Patients Experience Questionnaire (NORPEQ).

This project will increase knowledge of quality for surgical treatment for BPH in Norway, add knowledge of what determines outcomes after such procedures and measure patients' experiences. The latter has to the best of our knowledge previously not been reported in this group of patients. The results of the study will have the potential to change current clinical practice.

Needs description:

Surgery for BPH is one of the most common urological procedures. Unlike surgery for prostate cancer, the procedures are performed in every urological department. Surgery for BPH is also mandatory to perform during the practical education of urologists. BEEP has been introduced at several hospital in Norway, but systematic evaluation of the procedure and benchmarking against TURP is lacking. There are a limited number of studies that have made direct comparison between the two methods. Since both equipment and surgical methods are evolving over time, the existing studies have focus on larger glands and the existing RCTs were conducted several years ago, there is need for further and newer studies that evaluate outcomes and quality of current practice.

By comparing TURP and BEEP in an RCT, the present project will make a significant contribution to fill this need. Furthermore, it will contribute to clarify the question whether the success of surgery in BPH depends on the amount of removed tissue rather than the surgical procedure. This knowledge is of major importance for how surgery is performed, and thereby for outcomes in terms of both symptom relief and adverse effects. Finally, by applying PREM as an outcome, our study will provide new knowledge on how BHP patients rate their experiences through the surgical journey. By a systematic assessment of patients experience as planned in this study, we may identify areas where revision of routines for treatment and care is needed for quality improvement.

In conclusion, the results of the present study will contribute to improvement of surgical treatment and care for men with BHP. The widespread use of surgical procedures for this condition, few existing studies on the topic and the common occurrence of LUTS in men underline its importance.

Hypothesis, aims and objectives:

The overreaching aim of this study is to compare outcomes and patient experiences after TURP and BEEP.

Detailed objectives are to answer the following four research questions (RQ). RQ1: Is BEEP a more effective treatment of LUTS caused by BPH than TURP? RQ2: Are symptom-relief after BHP surgery associated with the amount of removed tissue, independent of surgical method? RQ3: Do patients experiences differ between TURP or BEEP? RQ4: To assess the cost-effectiveness of BEEP compared to TURP for the treatment of adult patients with LUTS caused by BPH.

We hypothesize that BEEP leads to better voiding outcome than TURP (RQ1) and that more removed tissue improves symptom relief (RQ2).

To answer RQ1, we will conduct a multi-center randomized controlled trial comparing BEEP to TURP. The study emerges from Innlandet Hospital Trust (IHT) in cooperation with Akershus University Hospital (Ahus). Eligible men will be recruited from the urological departments at both study sites. IHT has a large urological department and treats around 100 patients for BPH each year. Ahus has longer experience with BEEP and treats above 100 patients with either BEEP or TURP each year. TURP at IHT and Ahus is performed with bipolar technique. Recently, BEEP was introduced at IHT. With a multicenter design it will take shorter time to recruit a sufficient number of patients.

Men eligible for the study at both sites will be invited to participation when referred to surgery. They will then be given oral and written information and be included if they give their consent. The patients will be followed for 12 months after treatment. Administrative and clinical data (both at baseline and 12-month follow-up) will be obtained from the electronic medical record (EMR). Clinical data will then be registered in Viedoc by the PhD student or a study nurse. Viedoc is a web-based solution for data collection, and it is approved for clinical trials by the University of Oslo. Patient-reported data are administered and registered with Viedoc, including reminders to non-responders.

Inclusion criteria

• Men with prostate sizes between 30mL and 80mL on ultrasound.
• Referred to BPH.
• Detrusor pressure ≥ 20 cmH2O on urodynamic tests.
• Valid informed consent. Exclusion criteria
• Previous surgery for BPH.
• Men aged above 80 years old.
• Severe comorbidity (not suitable for surgery).
• Cognitive impairment.
• Prostate cancer (palliative surgery).
• Prior pelvic radiation therapy.
• Anticoagulation/antiplatelet therapy can't be stopped.

Randomization Eligible men will be randomized in a 1:1 ratio between intervention with TURP or BEEP. Once included in the study, randomization is a computer procedure with use of Viedoc. The statistician uploads a randomization list to Viedoc. The participants are blinded and will not be informed about the procedure they receive.

Outcomes and assessments The primary outcome for RQ1 and RQ2 is IPPS score. IPSS will be assessed at baseline and at 12-month follow-up. IPSS is recommended by the European Association of Urology to evaluate LUTS in men. The questionnaire is validated and translated to Norwegian. The questionnaire covers bladder emptying, urinary frequency, intermittency, urgency and straining, stream force and nocturia. The seven questions are answered on a six-point scale ranging from 0 (best) to 5 (worse) giving a total score from 0 to 35.

Secondary outcomes for RQ1 and RQ2 are flowmetry (a measure of the urinary stream in mL/s), residual urine (the amount of urine in mL left in the bladder after voiding) and pharmacological treatment for LUTS, all assessed at baseline and 12-month follow-up.

The primary outcome for RQ3 is patient experience measured with NORPEQ. It will be assessed at baseline, and 3- and 12 months after surgery. The NORPEQ is a validated PREM questionnaire with eight items . Each item is scored on a six-point Likert scale.

The primary outcome for RQ4 is incremental cost-effectiveness ratio (ICER), defined as the incremental cost per quality-adjusted life year (QALY) gained for BEEP compared to TURP over the study's 12-month period.

Secondary outcomes for RQ4 include overall QALYs gained and total costs - stratified by type - for BEEP and TURP over the study's 12-month period.

Other assessments:

• Days spent with catheter after surgery.
• Complications (Clavian-Dindo, blood transfusions, urethral sticture).
• Readmission within 30 days.
• Length of hospital stay (LOS).
• Estimated volume of removed tissue (weight of the resected specimen and measurement on CT scan at baseline and after 3 months).
• Operative time.
• If urinary retention was present at the time of surgery (defined as use of catheter - either intermittent or indwelling), catheter-free after 12 months.
• Urinary and sexual adverse effects assessed by items of the urinary incontinence and urinary irritation domains from the 26-item Expanded Prostate Cancer Index Composite (EPIC-26) and the 5-item questionnaire International Index of Erectile function (IIEF). Both questionnaires are widely used and tested. Since benign prostate surgery implies a risk of such adverse effects, we will also include questionnaires to address these issues. Hence the participants will be presented with the urinary incontinence and urinary irritation domains from the 26-item Expanded Prostate Cancer Index Composite (EPIC-26) and the five-item questionnaire International Index of Erectile function (IIEF). The scores of the urinary incontinence and urinary irritation domains from EPIC-26 will be assessed at baseline and 12-month follow-up. Sexual function at baseline and 12-month follow-up will be measured with IIEF.
• Health-related quality of life will be measured by EQ-5D-5L at baseline, and 3- and 12 months post-treatment. The questionnaire is well validated and used in a wide range of studies. Norwegian norm data are available.
• Healthcare resource utilization, including both first line care (primary care providers, allied health professionals, home-based services and medication) and second line care (emergency, hospital, and specialized outpatient services), to be evaluated through patient questionnaires at baseline, and 3- and 12 months post-treatment initiation.

Sample size/sample size estimate On the main outcome, IPSS score, we will compare the two randomised group with respect to change in score from baseline to 12 months follow-up. Based on findings in a recent systematic review, we assume that the mean score on IPSS at baseline is 20 with standard deviation (SD) of 4 - equal in both intervention groups [19], and that the SD is 4 also at 12-month follow-up in both groups. We further assume a 5-point difference (equals MID for IPSS) in change from baseline to 12-month in favour of the BEEP group. To show that this difference between TURP and BEEP groups in change in IPSS from baseline to 12-month follow-up is significant according to independent-samples t-test at the significance level of 5% with the power of 80% we need at least 22 patients in each group. Due to multi-centre (two hospitals) nature of the study, we assume a cluster effect of 5% at the hospital level. Adjusting the power calculation for the potential cluster effect yields sample size of 45+45=90 patients. Further, assuming a drop-out rate of approximately 10% and keeping in mind multiple outcomes to be assessed, we aim to include 120 men (60 in each group). Assessing the difference between the groups in change instead of difference at 12-month follow-up, we are able to provide a conservative sample size estimate (SD for change is larger (5.7) than SD at one time point (4)). Additionally, we preserve the possibility to adjust the calculations for potential baseline differences which might be present despite of randomisation due to multi-centre design.

Statistical analysis Even though independent-samples t-test is the basis for power calculation described above, there might be a cluster effect on hospital level present in the data, which was also considered when assessing the necessary sample size. Therefore, the difference between the groups in change from baseline to 12-month follow-up in main outcome, IPSS score (RQ1), will be assessed by a linear mixed model with random intercepts for hospitals. Linear mixed model properly accounts for cluster effect and thus reduces the chance for false positives. To assess association between the proportion of removed tissue and IPSS (RQ2), a linear regression analysis with estimated removed tissue as the main covariate will be performed. In the case of considerable cluster effect on hospital level, linear mixed model with random intercepts for hospitals will be applied instead. The model will be adjusted for potential confounders, thoroughly chosen based on literature and clinical knowledge. The primary outcome for RQ3, patient experience measured with NORPEQ, and other assessments listed under 3.1.5 will be presented descriptively.

Health economic analysis The calculation of costs involves multiplying the type and frequency of resource use by their respective unit costs (obtained from publicly available sources, such as diagnosis-related groups (DRGs)). Total costs are then derived by aggregating the costs by type. QALYs are computed by assigning utility weights, measured by EQ-5D-5L, to each time interval between measurements. These weights represent the health-related quality of life for the respective periods. An area-under-the-curve (AUC) method will be used to calculate patient-specific QALYs over the 12-month follow-up period. The incremental cost-effectiveness ratio (ICER) is determined by dividing the incremental costs by the incremental QALYs for BEEP compared to TURP.

To address missing data on resource use and EQ-5D-5L scores, Multivariate Imputation by Chained Equations (MICE) will be implemented. Multiple imputation will be combined with nonparametric bootstrapping to account for skewness, non-normality, and the correlation between costs and QALYs. Seemingly Unrelated Regression (SUR) models will be fitted to each bootstrapped dataset to obtain adjusted estimates of total costs and QALYs for each treatment arm. These SUR models will adjust the total costs and QALYs for baseline characteristics, such as age and gender, and for baseline imbalances in costs and health-related quality of life. Total and incremental adjusted costs and QALYs will be summarized by presenting means, standard errors, and 95% confidence intervals. Uncertainty about the ICER will be presented by constructing a cost-effectiveness acceptability frontier, which indicates the probability of the optimal intervention being cost-effective given a range of different willingness-to-pay thresholds.

Participants, organization and collaborations The project emerges from the Urological Department at Innlandet Hospital Trust (IHT) and the Research Centre for Age-related Functional Decline and Disease (AFS) in collaboration with the Urological Department at Akershus University Hospital (Ahus).

There are three planned papers:

1. Outcome after transurethral resection (TURP) and bipolar enucleation of the prostate (BEEP) - a multi-center, randomized controlled trial.
2. The association between resected prostate tissue volume and voiding outcome.
3. Patient-experiences after benign prostate surgery

Ethical considerations All participants will provide an informed and written consent. Data will deidentified and stored on a secure server and Viedoc. Only the PhD candidate and the project leader will have access to the data on the secure server. The necessary applications to the data protection officers and the Regional Ethics Committee (REC) are sent. The project will be performed according to the rules of the Helsinki-declaration, and registered in the ClinicalTrials.gov database. Participation will not imply any health risks or deviation from good clinical practice.

Inclusion Criteria:

Men with prostate sizes between 30mL and 80mL on ultrasound, referred to BPH surgery, detrusor pressure ≥ 20 cmH2O on urodynamic tests, valid informed consent.

Exclusion Criteria:

Previous surgery for BPH, men aged above 80 years old, severe comorbidity (not suitable for surgery), cognitive impairment, prostate cancer (palliative surgery), prior pelvic radiation therapy, anticoagulation/antiplatelet therapy can't be stopped.