UROLOGICAL ONCOLOGY Lower Urinary Tract Symptoms and Efficacy of Anticholinergic Drugs in Patients Remaining Disease- Free After Radical Retropubic Prostatectomy. Seung Woo Yang,1 Yong Gil Na,1 Ki Hak Song,1 Ju Hyun Shin,1 Young Seop Chang,2 Jong Mok Park,1 Chung Lyul Lee,1 Jae Sung Lim1* Purpose: This study was conducted to evaluate lower urinary tract symptoms (LUTS) change in patients with localized prostate cancer after radical retropubic prostatectomy (RRP) and examine the efficacy of anticholinergic drugs to treat patients suffering from storage symptoms. Materials and Methods: Among 50 patients who underwent RRP for prostate cancer, 40 who did not undergo ad- ditional treatment that might affect their urination pattern were included in the analysis. The International Prostate Symptom Score (IPSS), quality of life (QoL) score, and uroflowmetry were analyzed prior to RRP and 12 months after RRP. Twelve months after RRP, patients desiring improvement of storage symptoms were administered an- ticholinergic drugs for 6 months; the effects of such treatments were analyzed 3 and 6 months later. Results: Preoperatively and at 12 months after surgery, the mean IPSS for patients were 10.9 ± 6.7 and 9.2 ± 5.7, respectively. The mean IPSS for patients desiring improvement of storage symptoms before and after administra- tion of medication were 9.7 ± 5.9 and 9.0 ± 4.4, respectively. In particular, the mean storage symptom composites improved significantly after administration of medication. There were no statistically significant differences in frequency between baseline and 3-month, but frequency was improved significantly after 6 months. Urgency and nocturia were improved significantly after 3 months. Conclusion: In patients undergoing RRP, urinary symptoms change over time, with worsening storage symptoms. Our results suggest that, in patients who had discomfort with storage symptoms after RRP, anticholinergic drugs significantly improved symptoms and QoL. Keywords: lower urinary tract symptoms/etiology; prospective studies; prostatectomy/methods; postoperative complications; prostatic neoplasms/surgery; quality of life; urination disorders/drug therapy. INTRODUCTION Prostate cancer is the second most common cause of cancer-related deaths and the most common malig- nancy diagnosed in the United States.(1) There are many treatment options for early stage prostate cancer includ- ing watchful waiting, radical prostatectomy, radiothera- py, and hormonal therapy depending upon each patient’s performance status, demands, and the doctor – patient relationship. Despite many years of treating prostate cancer, there is no gold standard in terms of efficacy. However, radical prostatectomy is most frequently used to treat localized prostate cancer because this technique can lead to complete removal of cancer cells.(2) Indeed radical prostatectomy can lead to secondary effects, such as sphincter dysfunction, that require clinical man- agement. Radical prostatectomy removes the prostate and divides the trigone and posterior urethra, thereby inducing denervation and ischemic change.(3) It is well known that storage and voiding symptoms are common in men with prostate cancer who undergo radical pros- tatectomy, significantly affecting their quality of life (QoL).(4) Because many of these patients have bladder outlet obstruction (BOO) and detrusor overactivity be- fore treatment, it is important to understand the impact of radical prostatectomy on lower urinary tract symp- toms (LUTS) and urinary incontinence.(5) According to the European Association of Urology guidelines, a trial of antimuscarinic drugs is the appropriate medical approach for post-radical prostatectomy patients with mixed urinary incontinence symptoms and/or urgency. (6) Because of increasing awareness of health and QoL for patients with LUTS, the patient-reported health-re- lated QoL has become an important barometer when evaluating the effect of treatment for people who suffer 1 Department of Urology, Chungnam National University School of Medicine, Daejeon, Korea. 2 Department of Urology, Konyang University College of Medicine, Daejeon, Korea. *Correspondence: Department of Urology, Chungnam National University Hospital, 282 Monwha-ro, Jung-gu, Daejeon 35015, Korea. Tel: +82 42 2807779. Fax: +82 42 2570966. E-mail: uro17@cnu.ac.kr. Received November 2015 & Accepted March 2016 Vol 13 No 03 May-June 2016 2684 from urinary symptoms.(7) Here, we present the results of a longitudinal study to clarify the effect of radical retropubic prostatectomy (RRP) on LUTS, except pure stress urinary incontinence. The aim of this study was to evaluate changes in LUTS and the efficacy of anticho- linergic drugs in patients remaining disease-free after RRP. MATERIALS AND METHODS Medical records were collected prospectively for all patients who underwent RRP in our hospital between January 2009 and January 2012 (mean age 66.5 years, mean prostate specific antigen [PSA] 12.3 ng/mL). This study was approved by the Chungnam National University Hospital institutional review board (IRB No. CNUH 1007-86), and all participants signed in- formed consent forms. All patients were suspected of having prostate cancer based on positive results from digital rectal examinations, serum PSA, and transrec- tal ultrasonography (TRUS). All patients underwent TRUS-guided prostate biopsy, and prostate cancer was confirmed by pathology after RRP. All patients were < 75 years old and had serum PSA < 50 ng/mL. We included patients who agreed not to seek or use any other form of treatment for bladder dysfunction during the study. Exclusion criteria included prior treatment with radiation therapy, concomitant use of medica- tions with antiandrogenic activity, prior history of can- cer, biochemical recurrence, or severe renal or hepatic impairment. We also excluded patients with active or recurrent urinary tract infections, uncontrolled diabe- tes, or pure stress urinary incontinence. Fifty patients were initially enrolled in the study; however, 10 had undergone adjuvant or salvage radio- and/or hormonal therapy during or up to 12 months after RRP, and were therefore excluded from the study since such additional therapies may impact LUTS. A total of 40 patients were enrolled in the study. LUTS was assessed based on the International Prostate Symptom Score (IPSS) and the IPSS QoL score, which are both validated.(8) The IPSS is a self-administered seven-item questionnaire survey- ing incomplete emptying, intermittency, weak stream, and straining (voiding symptom composites), and fre- quency, urgency, and nocturia (storage symptom com- posites). Each question is scored separately from 0 to 5, with a higher score representing a worse outcome. The IPSS ranges from 0 to 35, with scores of 0, 1 to 7, 8 to 19, and 20 to 35 indicating absent, mild, moderate, and severe symptoms, respectively. The IPSS QoL score quantifies the QoL for specific LUTS, and is scored from 0 to 6, with a higher score indicating worse health. The urinary flow rates (only voids > 150 mL were in- cluded) and IPSS were recorded before and at each visit 12 months after RRP. Residual urine was determined by transabdominal ultrasonography. Out of 40 patients, 34 who desired further improvement of storage symptoms were medicated by anticholinergic drugs (solifenacin 5 mg, once daily) for 6 months. The urinary flow rates, IPSS, QoL, the International Consultation on Inconti- nence Questionnaire-Short Form (ICIQ-SF),(9) and the King’s Health Questionnaire (KHQ)(10) were recorded at 3 and 6 months after administration of medication. The ICIQ-SF and KHQ were self-completed by the patients. The ICIQ-SF assesses and scores frequency of urine loss (0–5), severity (0–6), and urine leakage interfering with daily life (0–10), and also includes an unscored self-diagnostic question. The scores are added (score range from 0 to 21), with a higher score indicat- ing a worse QoL. The KHQ is a measure of health-re- lated QoL that includes two single-item domains (gen- eral health perception and incontinence impact), seven multi-item domains (role limitations, physical limita- Voiding Patterns after Prostatectomy-Yang et al. Table 1. Clinical characteristics of the patients (n = 40). Characteristics Values Mean age (years) 66.5 ± 5.8 Age (years) < 60 6 (15) 60~69 18 (45) ≥ 70 16 (40) Mean PSA at diagnosis (ng/mL) 12.3 ± 8.5 PSA at diagnosis (ng/mL) < 4 2 (5) 4~10 18 (45) > 10 20 (50) Gleason score ≤ 6 19 (47.5) 7 14 (35) ≥ 8 7 (17.5) Clinical tumor classification T1 24 (60) T2 16 (40) Prostate volume (mL) < 20 4 (10) 20 - 40 32 (80) > 40 4 (10) Abbreviation: PSA, prostate-specific antigen. Values are presented as mean ± standard deviation and number (percent- age). Urological Oncology 2685 tions, social limitations, personal relationships, emo- tional problems, and sleep/energy disturbances), and a multi-item severity measure.(9) The two single item domains and the seven multi-item domains of the KHQ are scored on a scale from 0 (best) to 100 (worst). Re- ported adverse events during the treatment period were also analyzed. Statistical Analysis All statistical analyses were performed using Statistical Package for the Social Science (SPSS Inc, Chicago, Illi- nois, USA) version 18.0. Parametric numeric data were analyzed with the paired t-test and nonparametric data were assessed using the Wilcoxon’s signed rank test. Values are expressed as the mean ± standard deviation Table 2. Comparison of uroflowmetry and International Prostate Symptom Score prior to and 12 months after surgery (n = 40). Variables Before RRP After RRP P Value Maximal flow rate (mL/sec) 17.9 ± 5.3 18.6 ± 6.4 .162 Residual urine (mL) 31 ± 29.5 27 ± 19.1 .160 Total IPSS 10.9 ± 6.7 9.2 ± 5.7 .075 Voiding 6.7 ± 4.5 4.4 ± 3.6 b .003 Storage 4.2 ± 2.9 4.8 ± 2.8 .136 Incomplete emptying 1.4 ± 1.4 0.8 ± 1.0 a .010 Frequency 1.7 ± 1.2 1.6 ± 1.0 .618 Intermittency 1.8 ± 1.5 1.2 ± 1.2 a .033 Urgency 0.9 ± 1.2 1.5 ± 1.5 a .027 Weak stream 2.3 ± 1.5 1.4 ± 1.1 b .005 Straining 1.3 ± 1.5 1.0 ± 1.1 .208 Nocturia 1.6 ± 1.3 1.7 ± 1.2 .570 Quality of life 2.0 ± 1.3 2.5 ± 1.1 a .020 Abbreviations: IPSS, international prostate symptom score; RRP, radical retropubic prostatectomy. Values are presented as mean ± standard deviation. a P < .05, b P < .01 versus before RRP. Variables Baseline 3-Month 6-Month P Value a P Value b Maximal flow rate (mL/sec) 18.7 ± 6.7 18.5 ± 6.4 18.1 ± 4.8 .661 .439 Residual urine (mL) 26.8 ± 20.2 28.8 ± 17.9 28.5 ± 17.4 .256 .439 Total IPSS 9.7 ± 5.9 9.3 ± 5.3 9.0 ± 4.4 c .082 .026 Voiding 4.6 ± 3.6 4.7 ± 3.4 4.8 ± 2.8 .292 .353 Storage 5.2 ± 2.9 4.6 ± 2.4 d 4.2 ± 2.1 d .001 .001 Incomplete emptying 0.8 ± 1.0 0.8 ± 0.9 0.9 ± 0.7 .325 .254 Frequency 1.7 ± 1.1 1.6 ± 1.0 1.4 ± 0.8 c .160 .027 Intermittency 1.2 ± 1.2 1.2 ± 1.2 1.3 ± 0.9 .571 .414 Urgency 1.7 ± 1.5 1.4 ± 1.2 d 1.4 ± 1.1 d .006 .008 Weak stream 1.5 ± 1.1 1.5 ± 0.9 1.4 ± 0.9 .661 .254 Straining 1.1 ± 1.1 1.1 ± 1.1 1.2 ± 1.1 .160 .096 Nocturia 1.7 ± 1.2 1.5 ± 1.0 c 1.4 ± 1.0 d .017 .003 Quality of life 2.6 ± 1.2 2.6 ± 1.1 2.3 ± 1.0 c .325 .016 Abbreviation: IPSS, international prostate symptom score. Values are presented as mean ± standard deviation. a Compares values between the baseline and 3 months of therapy; b Compares values between the baseline and 6 months of therapy; c P < .05 versus baseline; d P < .01 versus baseline. Table 3. Comparison of uroflowmetry and International Prostate Symptom Score prior to administration of medication, and 3 and 6 months after med- ication (n = 34). Voiding Patterns after Prostatectomy-Yang et al. Vol 13 No 03 May-June 2016 2686 (SD), with P < .05 considered significant. RESULTS Characteristics of the 40 patients at the time of diag- nosis are presented in Table 1. At diagnosis the mean PSA value was 12.3 ng/mL (range 3.2 – 43.6 ng/mL) and the median prostate volume was 28.6 cm3 (range 16 – 56 cm3). The overall mean total IPSS, which was 10.9 ± 6.7 before RPP, decreased over time after RPP to 9.2 ± 5.7 at 12 months after surgery, a difference that did not reach the level of significance. The overall mean IPSS QoL score increased with time after RPP, and the difference reached the level of significance at 12 months after RRP, while the change in IPSS did not. In- dividual analysis of each question reflected in the IPSS demonstrated that the symptoms of incomplete empty- ing, intermittency, and weak stream were significantly relieved after surgery, while the symptom of urgency significantly worsened after RRP (Table 2). The over- all mean total IPSS in the patient population seeking medication to relieve LUTS, which was 9.7 ± 5.9 before medication, was reduced significantly to 9.0 ± 4.4 at 6 months after medication. The overall mean IPSS QoL score decreased with time after medication in parallel with the IPSS, and the difference from baseline reached the level of significance at 6 months after medication. No significant change was noted in any of the four void- ing symptom composites. However, all three of the stor- age symptom composites decreased significantly at 6 months after medication. The results of the uroflow test before and after medication showed that maximal uro- flow changed from 18.7 ± 6.7 mL/sec to 18.1 ± 4.8 mL/ sec, and residual urine changed from 26.8 ± 20.2 mL to 28.5 ± 17.4 mL, neither of which reached the level of significance (Table 3). The ICIQ-SF score improved from 4.9 ± 1.8 to 4.6 ± 1.4 at 6 months after medication, which did not reach the level of significance. The KHQ score significantly improved from 25.6 ± 7.1 to 23.5 ± 6.6 at 6 months after medication (Table 4). The overall incidence of adverse events was 35.3% (12/34 patients), and all were mild in intensity. No patients experienced severe hepatic dysfunction, renal failure, or cardio- vascular effects. Dry mouth was the most frequently reported adverse event (23.5% or 8/34), followed by constipation in 14.7% (5/34). No patients discontinued treatment due to adverse events (Table 5). DISCUSSION Prostate cancer is likely to remain one of the most im- portant issues in men’s health for the foreseeable future. Opinions differ regarding the optimal management of prostate cancer. In men > 70 years of age, or in those with appreciable co-morbidity, a conservative manage- ment approach is generally accepted. However, healthy younger men are more likely to live long enough to ex- perience disease progression; therefore, radical prosta- tectomy and radiotherapy, as well as "watchful waiting", are options in this group. Use of radical prostatectomy has been increasing in patients with early stage disease, and is indicated for men with a life expectancy of > 10 years.(11) The first surgical management of prostate can- cer was performed by Millin and colleagues in 1947.(12) Since then, several improved operative methods have been established. Surgical management of the dorsal vein complex and a procedure effective for preserving the neurovascular bundle were described by Walsh and colleagues(13) Consequently, the incidence of postopera- tive complications has been decreasing. However, post- operative LUTS continue to occur at a constant rate and negatively affect the QoL of the patients. Thus, QoL issues need to be considered when deciding on the best treatment option. Relief of obstruction by radical pros- tatectomy has been reported by several investigators to diminish LUTS. Schwartz and colleagues indicated, in patients with moderated or high degree symptoms, that radical prostatectomy significantly reduces the total IPSS and positively affects LUTS.(14) Our investigation further extended knowledge of the impact of RRP on LUTS, demonstrating that RRP provides major benefits for men with LUTS. Namiki and colleagues reported that storage symptoms, such as frequency and nocturia, do not improve after radical prostatectomy, or are exac- erbated in some cases.(15) Results from the present study were similar, in that overall urinary symptoms signif- icantly improved after operation, yet patients’ QoL progressively worsened. Specifically, progressively Table 4. Comparison of questionnaire scores prior to, and 3 and 6months after medication (n = 34). Variables Baseline 3-Month 6-Month P Value a P Value b ICIQ-SF score 4.9 ± 1.8 4.8 ± 1.4 4.6 ± 1.4 .404 .154 KHQ score 25.6 ± 7.1 24.8 ± 6.2 23.5 ± 6.6 c .263 .019 Abbreviations: ICIQ-SF, International Consultation on Incontinence Questionnaire-Short Form; KHQ, King’s Health Questionnaire. Values are presented as mean ± standard deviation. a Compares values between the baseline and 3 months of therapy; b Compares values between the baseline and 6 months of therapy; c P < .05 versus baseline. Voiding Patterns after Prostatectomy-Yang et al. Urological Oncology 2687 deteriorating storage symptom composites negated the improvements in voiding symptom composites, result- ing in worsened QoL. This information is important when counseling patients about treatment options for localized prostate cancer. The improvement of LUTS is probably mostly attrib- utable to obstruction relief by RRP. It is well known that benign prostatic hypertrophy can cause BOO, sec- ondary bladder overactivity, and reduction in function- al bladder capacity, which may result in storage symp- toms.(16) Conversely, these symptoms can be reversed with obstruction relief by prostatectomy.(17) Several in- vestigators have also reported IPSS improvement con- current with an increase in urinary flow rate after RRP in patients with moderate to severe LUTS.(18) Although our study lacked urodynamic data, these findings sug- gest an association between BOO relief by RPP and IPSS improvement. RRP increased urgency and noc- turia (not significantly) in our study. In contrast, Na- miki and colleagues(19) reported that nocturia did not return to the baseline level within 2 years after surgery. Gomha and colleagues(20) reported that, following rad- ical prostatectomy, a substantial proportion of patients were affected by detrusor overactivity, impaired detru- sor contractility, decreased compliance, and sphincter weakness. Bladder denervation during surgery has been suggested as one reason for these abnormalities. Wide anatomical dissection around the prostate and bladder neck may disrupt regional afferent and efferent inner- vation, causing outlet lethargy and partial denervation of the detrusor muscle.(21) Also, Jung and colleagues(22) demonstrated that leakage of urine into the proximal urethra could increase bladder activity by stimulating urethral afferents, which in turn modulate the micturi- tion reflex and induce detrusor instability. Thus, blad- der denervation during surgery and postoperative urine incontinence may be implicated in the deterioration of storage symptoms, even though recovery from urinary incontinence after RPP is considerable. For patients with LUTS, these adverse effects may exacerbate urgency or nocturia. The reversal of detrusor overactivity by relief of BOO might have been dampened by adverse effects such as bladder denervation or subtle urine leakage. In patients with preoperative LUTS, communicating that voiding symptoms can be improved after radical pros- tatectomy will be important to promoting QoL. In our study, bladder storage symptoms aggravated after pros- tatectomy. We believe that an irritated urethra caused by urine leakage due to nerve or sphincter injury during prostatectomy caused decreased bladder compliance and detrusor overactivity. Also, extensive incisions dur- ing prostatectomy can damage the efferent and afferent nerves of the bladder trigone, bladder neck, and detru- sor muscle. Therefore, storage symptoms may be ag- gravated as opposed to voiding symptoms after prosta- tectomy.(22) In general, storage symptoms are managed with anticholinergic drugs, since detrusor contractions are mediated by cholinergic receptor stimulation. The results of the current study show that anticholinergic drugs act not only on detrusor muscle but also on mus- carinic receptors located on bladder afferent nerve ter- minals and on urothelium.(23) Recent pharmacologic ad- vancements have produced anticholinergic drugs with an increased duration of action and fewer side effects, such as dry mouth and constipation. In our study, tak- ing anticholinergic drugs significantly improved stor- age symptoms after radical prostatectomy. Our findings supplement subjective questionnaire-based reports of decreased urgency and frequency reported in trials of solifenacin.(24,25) Our study will help clarify treatment options for patients with localized prostate cancer who consider refusing prostatectomy due to not wanting changes in LUTS. Limitations of our study are its small sample size and short follow-up period after medication, which allows for potential selection bias. Long-term follow-up data on this patient population is needed. To clarify the mechanism of LUTS improvement, further investi- gation including urodynamic studies and overactive bladder symptoms score, will be needed. Further large prospective studies and long-term follow-up will be re- quired to fully evaluate the drug efficacy results. CONCLUSIONS Postoperative LUTS is a common adverse effect of RRP, potentially leading to a significantly diminished QoL. However, the exact cause of postoperative LUTS was not determined. Although our study was relatively small, it provides important and detailed information about the impact of RRP on LUTS and LUTS-related QoL. It also supports the benefits of anticholinergic drugs as treatment for postoperative LUTS. We hope Table 5. Adverse events due to anticholinergic drugs (n = 34). Adverse Events 3-Month 6-Month Dry mouth 6 (17.6) 8 (23.5) Constipation 3 (8.8) 5 (14.7) Blurred vision 0 (0) 1 (2.9) Headache 2 (5.9) 1 (2.9) Dizziness 1 (2.9) 1 (2.9) Values are presented as number (percentage). Voiding Patterns after Prostatectomy-Yang et al. Vol 13 No 03 May-June 2016 2688 that our findings will assist patients, families, and doc- tors in their discussions about treatment expectations and outcomes. ACKOWLEDGEMENTS This work was supported by Chungnam, National Uni- versity Hospital Research Fund, 2011. CONFLICT OF INTEREST None declared. REFERENCES 1. Siegel R, Ma J, Zou Z, Jemal A. Cancer Statistics, 2014. CA Cancer J Clin. 2014;64:9-29. 2. Jani AB, Hellman S. 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