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Solifenacin Is Able to Improve the Irritative Symptoms After Transurethral Resection of Bladder Tumors
Ambulatory, Office-based, and Geriatric Urology Solifenacin Is Able to Improve the Irritative Symptoms After Transurethral Resection of Bladder Tumors Zhensheng Zhang, Zhi Cao, Chuanliang Xu, Haifeng Wang, Chao Zhang, Anyin Pan, Rongchao Wei, Song Peng, Fei Guo, Lei Wang, and Yinghao Sun OBJECTIVE METHODS
RESULTS
CONCLUSION
To evaluate the efficacy and safety of solifenacin in the management of irritative symptoms after transurethral resection of bladder tumors (TURBTs) with subsequent intravesical chemotherapy. A total of 116 patients undergoing TURBT were randomly allocated into 2 groups, 58 patients in each group. Group 1 patients received solifenacin 5 mg, 6 hours before surgery and 5 mg per day, after surgery for 2 weeks, whereas group 2 patients received a placebo. Patients with low-risk nonemuscle-invasive bladder cancer received immediate postoperative instillation of epirubicin. Patients with medium- or high-risk nonemuscle-invasive bladder cancer received postoperative instillation twice within 2 weeks, once immediately following the operation and once on the eighth postoperative day. All patients completed bladder diaries before surgery, on the 1st, 7th, and 14th days after removal of the catheter with overactive bladder symptom scores completed preoperatively, and on the 7th and 14th days. Additionally, the incidence and severity of catheter-related bladder discomfort were recorded at 6, 12, 24, 48, and 72 hours after the surgery. The incidence and the severity of catheter-related bladder discomfort in group 1, compared with group 2, were significantly reduced (P <.05). There was a significant difference in overactive bladder symptom scores between the 2 groups (5.67 vs 7.86; P <.001). Episodes of daytime, frequency, nocturia, urgency, and urge urinary incontinence in group 1 were also significantly lower than in group 2 (P <.05). This study demonstrates that solifenacin can be beneficial for the management of irritative symptoms after TURBT with subsequent intravesical chemotherapy. UROLOGY -: -e-, 2014. 2014 Elsevier Inc.
B
ladder carcinoma is the fourth most common cancer in men and the eighth most common cancer in women. Approximately 73,510 new cases of bladder cancer were diagnosed in 2012 in the United States, which accounted for roughly 14,880 deaths.1 When initially diagnosed, most bladder cancers are nonemuscle-invasive,2 for which transurethral resection of bladder tumors (TURBTs) is still the gold standard.3 To prevent or delay the recurrence of bladder cancer, intravesical chemotherapy or immunotherapy is used worldwide for adjunctive management after TURBT.2 However, irritative symptoms are common in patients who receive TURBT with subsequent intravesical therapy4,5; these symptoms are similar to those of overactive Zhensheng Zhang, Zhi Cao, and Chuanliang Xu contributed equally. Financial Disclosure: The authors declare that they have no relevant financial interests. From the Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, P. R. China Reprint requests: Yinghao Sun, Ph.D., M.D., Department of Urology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, P. R. China. E-mail: [email protected] Submitted: October 17, 2013, accepted (with revisions): February 28, 2014
ª 2014 Elsevier Inc. All Rights Reserved
bladder (OAB), that is, urgency, frequency, and nocturia, with or without urge urinary incontinence.6 During catheterization, it manifests as catheter-related bladder discomfort (CRBD), the incidence of which approaches 90% after TURBT.7 Additionally, it has been noted that intravesical chemotherapy lengthens the duration and increases the severity of irritative symptoms and can result in painful chemical cystitis.8 It is widely accepted that the irritative symptoms mentioned earlier negatively affect patients’ recovery, sequential therapy, and daily living. Muscarinic antagonists have been widely used for the management of OAB, and tolterodine has been tried for the prevention of CRBD with variable success.9 Solifenacin, as a newly developed muscarinic antagonist, was reported to have greater selectivity for the bladder over the salivary glands and less potent antimuscarinic action than tolterodine.10-12 Previous studies have confirmed the safety and efficacy of solifenacin for OAB compared with placebo.13,14 However, the efficacy of solifenacin for the management of irritative symptoms after TURBT with subsequent intravesical chemotherapy has not been reported. 0090-4295/14/$36.00 http://dx.doi.org/10.1016/j.urology.2014.02.034
1
In this randomized, single-blind controlled study, we evaluated the efficacy and safety of solifenacin in the management of irritative symptoms in patients receiving TURBT with subsequent intravesical chemotherapy, compared with a placebo.
MATERIALS AND METHODS This study was a prospective, randomized, single-blind, placebocontrolled clinical trial of solifenacin, which was conducted in the Department of Urology of Changhai Hospital over a 6month period. Crossover design was not applied in the study. This study was approved by our institutional medical ethics review committee, and informed consent was provided by all the patients. Men and women, aged 18-80 years and with diagnoses of nonemuscle-invasive bladder cancer (NMIBC), were eligible for inclusion. Patients with obstruction of the bladder outlet, neurogenic bladder, bladder stones, previous pelvic irradiation therapy, glaucoma, any psychiatric diseases, uncontrolled urinary tract infections, end-stage renal disease (urine output <500 mL/ 24 h), morbid obesity, chemical substance abuse, chronic pain, and cardiovascular disease were excluded, as well as patients who were taking any anticholinergic agents. The randomization method was described as follows: the participants were numbered from 1 to 124 according to the order in which they entered into the study. SPSS 18.0 (SPSS Inc) was used for the generation of 124 random numbers, which were realigned so that the first 62 random numbers were labeled as group 1 and the rest as group 2. The group 1 patients received solifenacin 5 mg with a sip of water, 6 hours before the administration of spinal anesthesia, whereas the group 2 patients received a placebo with similar anesthesia. Spinal anesthesia consisted of 2.5 mL of 0.5% hyperbaric bupivacaine, which was administered at a rate of 1 mL/10 s without barbotage. TURBT was performed by 2 experienced surgeons, who acted strictly according to the quality control specifications of our center: (1) resecting all visible tumors, (2) resecting apparently normal mucosa approximately 1 cm from the border of the tumor, (3) resecting the muscle layer at the base of the tumor until normal muscle fibers were visible, and (4) another surgeon inspecting the bladder lumen to confirm that there were no remaining tumors after the aforementioned procedures are completed. With regard to relatively small tumors, both the tumor and the tissue at the tumor base, down to the superficial muscle layer, were simultaneously resected. For relatively larger tumors, we adopted a 2-stage resection, with the first resection exposing the lower level of the mucosa and the second resection removing that lower mucosal layer. After surgery, all the patients received antibiotics until 3 days after the removal of the catheter and group 1 patients received solifenacin 5 mg per day for 2 weeks, whereas group 2 patients received the placebo for 2 weeks. The study drug and placebo tablets were similar in size, color, smell, and appearance. In addition, patients with low-risk NMIBC received immediate postoperative instillation of epirubicin, whereas patients with medium- or high-risk NMIBC received postoperative instillation of epirubicin twice within 2 weeks, once immediately after the operation and once on postoperative day 8. After the trial, intravesical epirubicin instillation was maintained once per week for 8 weeks and then once per month for 12 months.15 The catheterization time depended on the doctor’s judgment. 2
All patients completed OAB symptom score (OABSS)16 and 3-day bladder diaries before surgery, to obtain baseline values. CRBD was recorded at 6, 12, 24, 48, and 72 hours after the surgeries. The severity of CRBD was recorded on a 4-point scale (0, no discomfort; 1, mild discomfort reported on questioning only; 2, moderate discomfort, urge to pass urine reported by the patient without questioning; and 3, severe discomfort, urge to pass urine accompanied by behavioral responses, such as flailing limbs, strong vocal responses, or attempts to pull the catheter out).7,17 Hyoscine butyl bromide 20 mg or pethidine hydrochloride100 mg was administered intramuscularly as rescue therapy in cases of severe and intolerable CRBD. Participants completed OABSS on the 7th and 14th days after the removal of the catheter and bladder diaries on the 1st, 7th, and 14th days after the removal of the catheter to record daytime frequency, nocturia, urgency episodes, and urge urinary incontinence episodes. In accordance with good clinical practice principles, adverse events were recorded at each visit. The data collectors were trained and unaware of the grouping situation of the patients. The primary study outcome was the difference in OABSS between the 2 groups on the seventh day after the removal of the catheter. On the basis of a published standard deviation of 3.0 for the OABSS,18 and a 2-sided alpha value of 0.05, 102 people were required to have a statistical power of 90% to detect difference between groups of 2.0 on the OABSS. And, the number was increased to 124 to account for potential dropouts. Other efficacy measurements included the degree of CRBD, daytime frequency, nocturia, urgency episodes, and urge urinary incontinence episodes. The primary study outcome was analyzed by repeated measures analysis of covariance with a linear regression model and baseline values as covariates, as well as univariate analysis of covariance at different times. The incidence and severity of CRBD were compared between the groups using generalized estimating equations, which were also compared among groups using the Wilcoxon rank-sum test at different times. We used analysis of repeated measures covariance with a linear regression model to test for daytime frequency, nocturia, urgency episodes, and urge urinary incontinence episodes, which were also analyzed by analysis of covariance at different times. The baseline values were included as covariates. The comparability of patients’ characteristics and duration of surgery was assessed by t-test and Chi-square test. SPSS, 18.0 was applied in the analysis, all the statistical comparisons involved 2-sided tests at a significance level of a ¼ 0.05.
RESULTS A total of 153 patients were evaluated, of which 29 were excluded from the study because the inclusion criteria were not met or the patients were unwilling to participate. Therefore, 124 patients were included in the study and received study medication after randomization. Eight patients (4 from each group) dropped out of the study because of adverse events or were lost to follow-up, and 116 patients completed the study (58 in each group; Fig. 1). The patients with tumors located in the bladder trigone numbered 13 (22.4%) in group 1 and 11 in group 2 (20.0%; P ¼ .819). There were no significant differences with regard to the patients’ characteristics in terms of age, gender, risk stratification of bladder cancer, stage of bladder tumor, histologic grade of bladder tumor, UROLOGY
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Table 1. Patients’ characteristics and duration of surgery Solifenacin Placebo Group (n ¼ 58) Group (n ¼ 58) Age (y) 59.26 9.73 59.72 8.97 Sex ratio (M:F) 43:15 40:18 Risk stratification 7:38:13 10:37:11 LR:MR:HR Stage of bladder tumor 4:18:36 3:16:39 Tis:Ta:T1 31:17:10 30:19:9 Histologic grade of bladder tumor G1:G2:G3 Number of bladder tumor 2.28 1.33 2.64 1.33 Duration of surgery (min) 36.33 8.76 37.38 7.81 Catheterization time 3.2 0.48 3.3 0.58 F, female; G1, grade 1; G2, grade 2; G3, grade 3; HR, high risk; LR, low risk; M, male; MR, mediate risk.
statistical analysis at different times; the details are presented in Table 2. Adverse events were also recorded, which were anticholinergic in nature and of mild or moderate severity. The most common treatment emergent adverse events were dry mouth (10.3% and 6.9%; P ¼ .743), constipation (8.6% and 3.4%; P ¼ .438), headache (1.7% and 0%; P ¼ 1.000), and dizziness (1.7% and 0%; P ¼ 1.000) with solifenacin and placebo, respectively. Discontinuations due to adverse events numbered 2 with solifenacin and 0 with placebo, 1 patient dropped out because of unbearable headaches and another for dizziness. Figure 1. Flow randomization.
chart
of
patient
enrollment
and
number of bladder tumors, and duration of surgery (P >.05; Table 1). In most cases, the catheterization time was 3 days; durations of >5 days were not observed in the trial. Furthermore, the catheterization times were comparable between the 2 groups (P ¼ .492). For the primary efficacy variable, at day 7, the OABSS in group 1 was significantly lower than in group 2 (5.67 vs 7.86; P <.001). The repeated measure covariance indicated that there was a significant difference in OABSS between the 2 groups (P <.001; Table 2). And, there was no interaction between the treatment type and time (P ¼ .341), which was confirmed by analysis at different times. The incidence of CRBD at 6 hours after TURBT decreased from 93.1% (placebo group) to 67.2% (solifenacin group; P ¼ .001); the severity of CRBD was also significantly reduced in group 1 compared with group 2 (P ¼ .008), and no interaction between the treatment type and time was observed (P ¼ .174), which was also confirmed by analysis at different times. The incidence and severity of CRBD are presented in Table 3. Furthermore, there were also significantly fewer episodes of daytime frequency, nocturia, urgency, and urge urinary incontinence in group 1 than in group 2 (P <.05), which were indicated by both repeated measures analysis and UROLOGY
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COMMENT This study concludes that solifenacin 5 mg significantly benefits patients with irritative symptoms who have undergone TURBT with subsequent intravesical chemotherapy. Damage to the bladder mucosa, exposure of the detrusor to urine, catheterization, bladder irrigation, and instillation of intravesical chemotherapy agents can stimulate the afferent nerves of the bladder, leading to release of acetylcholine, which can bring about involuntary contractions of detrusor mediated by muscarinic receptors. Additionally, intravesical instillation can result in chemical cystitis. A previous report showed that the incidences of cystitis resulting from doxorubicin, epirubicin, thiotepa, and mitomycin were, respectively, 20%-40%, 10%-30%, 10%-30%, and 30%-40%.8 Irritative symptoms can obviously affect patients’ daily lives; 3 health-related outcomes—health-related quality of life, mental health, and quality of sleep—have been reported to be negatively affected by OAB symptoms.19 In addition, irritative symptoms can reduce the compliance of patients with intravesical instillation. In a multicenter, prospective, randomized phase 3 trial of intravesical epirubicin instillation therapy, the incidence of chemical cystitis reached 30%, with 5% of patients either requiring temporary delays or discontinuation.20 Antimuscarinic therapy, by suppressing involuntary bladder contractions, has been the mainstay of the 3
Table 2. Results of OABSS and bladder diary
OABSS (score) Preoperation 7th day 14th day Daytime frequency (episode per day) Preoperation 1st day 7th day 14th day Nocturia (episode per day) Preoperation 1st day 7th day 14th day Urgency (episode per day) Preoperation 1st day 7th day 14th day Urge urinary incontinence (episode per day) Preoperation 1st day 7th day 14th day
Solifenacin Group (mean SD)
Placebo Group (mean SD)
2.03 2.83 5.67 2.94 3.26 2.37
1.98 2.62 7.86 2.55 4.79 2.65
6.86 9.76 9.06 7.60
2.27 2.88 2.47 1.95
6.94 12.01 10.36 8.93
2.29 4.13 2.34 2.59
0.48 1.36 0.79 0.59
0.84 1.10 0.87 0.68
0.50 1.85 1.33 0.97
0.71 1.07 0.86 0.75
0.43 2.24 1.53 0.81
0.73 1.22 1.03 0.78
0.43 3.10 2.24 1.17
0.65 1.86 1.11 0.94
0.29 1.24 0.79 0.33
0.56 0.96 0.77 0.51
0.24 1.93 1.17 0.59
0.54 1.11 0.99 0.73
P(group)
P(group*time)
<.001 .919 <.001 .001 <.001 .839 .001 .005 .002 <.001 .905 .021 .001 .005 <.001 1.000 .004 .001 .026 <.001 .614 <.001 .023 .028
.341
.246
.689
.150
.057
OABSS, overactive bladder symptom scores; P(group*time), the P value for the interaction between group and time; SD, standard deviation.
Table 3. Incidence and severity of catheter-related bladder discomfort, data presented as number of patients Solifenacin Group, N (%) Time (h) 6 12 24 48 72
0 19 22 25 30 39
(32.8) (37.9) (43.1) (51.7) (67.2)
1 20 24 18 16 12
(34.5) (41.4) (31.0) (27.6) (20.7)
Placebo Group, N (%)
2 17 12 15 11 7
(29.3) (20.7) (25.9) (19.0) (12.1)
3 2 0 0 1 0
(3.5) (0) (0) (1.7) (0)
management of OAB. Solifenacin specifically blocks M3 receptor and, to a lesser extent, the M2 receptor, so it is 40 times less potent than oxybutynin and 79 times less potent than tolterodine in inhibiting salivary secretion.21 It also demonstrates greater affinity for the bladder because its inhibition of the detrusor is 3.6 times greater than its inhibition of salivary glands.11 Previous studies have demonstrated that solifenacin significantly reduced episodes of urgency in more than 60% of patients (with complete resolution of urgency in approximately 40%) and secondarily reduced other symptoms related to OAB symptoms.13,22 Additionally, in a group of patients with residual OAB symptoms after tamsulosin monotherapy, solifenacin significantly decreased urgency episodes after 12 weeks of management.23 In our study, the incidence of CRBD at 6 hours after TURBT decreased from 93.1% (placebo group) to 67.2% (solifenacin group; P ¼ .001), a finding that is similar to the report of Agarwal,17 which stated that tolterodine 2 mg administered 1 hour before surgery reduced the incidence of CRBD by 19%. 4
0 4 10 12 22 30
(6.9) (17.2) (20.7) (37.9) (51.7)
1 27 19 21 15 11
(46.6) (32.8) (36.2) (25.9) (19.0)
2 23 27 25 21 17
P
3
(39.7) (46.6) (43.1) (36.2) (29.3)
4 2 0 0 0
(6.9) (3.4) (0) (0) (0)
.002 <.001 .003 .041 .024
Our analysis concludes that solifenacin can significantly improve irritative symptoms after catheter removal by reducing OABSS, daytime frequency, nocturia, episodes of urgency, and episodes of urge urinary incontinence. Although the OABSS has been demonstrated to be highly sensitive to treatment-related changes in OAB symptoms, bladder diaries can provide more detailed information.18 It is commonly believed that nocturia reduces quality of sleep and quality of life. At the end of this study, the number of patients who had more than 1 episode of nocturia in the solifenacin group and placebo group was 4 and 10, respectively. Solifenacin was well tolerated in this study, with the most common adverse events being dry mouth, most cases of which were mild. In a pooled analysis of relevant studies, rates of dry mouth were 23.4% and 60.8% for tolterodine extended release 4 mg and oxybutynin extended release 5-30 mg, respectively.24 In the Overactive Bladder Judging Effective Control and Treatment study, which compared tolterodine 2 mg twice daily with oxybutynin extended release 10 mg daily, tolterodine was UROLOGY
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associated with dry mouth in 33.2% of patients, whereas oxybutynin was associated with dry mouth in 28.1% of patients.25 In a report of darifenacin outcomes in OAB, dry mouth was reported by 18.8% (7.5 mg) and 31.3% (15 mg) of treated patients.26 Thus, there are sound reasons to believe that the incidence of dry mouth of 10.3% seen in this study with solifenacin 5 mg daily compares favorably with the data for other agents. However, this study has some potential limitations. First, the study was a single-blind and not double-blind trial, which may bring bias to the results. Second, the trial was conducted in 1 center, the patients of which are all of Asian descent and Chinese. The efficacy of solifenacin in other races and nations was not evaluated. Third, the sample size of the trial was small, so larger studies are warranted to investigate further the impact of solifenacin on irritative symptoms after TURBT. Fourth, the administration of hyoscine butyl bromide or pethidine hydrochloride might bring important bias to the study. Fifth, the application of antibiotic was not strictly conducted according to the European Association of Urology guidelines on urologic infections. Sixth, we did not use the detrusor activity index in the study, which is a good diagnostic model with high accuracy to evaluate OAB.27
8. 9.
10. 11.
12.
13.
14.
15. 16.
CONCLUSION
17.
The incidence of irritative symptoms after TURBT is high. Our study demonstrated that solifenacin is a beneficial and safe agent for the management of irritative symptoms after TURBT with subsequent intravesical chemotherapy.
18.
19.
Acknowledgment. All authors appreciate Dr. Robert Stein at Cleveland Clinic for assistance with the writing of the manuscript.
References
21.
1. American Cancer Society. Cancer Facts and Figures 2011. Atlanta: American Cancer Society; 2012. 2. American Urological Association. Hall MC, Chang SS, Dalbagni G, et al. Guideline for the Management of Nonmuscle Invasive Bladder Cancer (Stages Ta, T1, and Tis): 2007 Update. Available at: https:// www.auanet.org/education/guidelines/bladder-cancer.cfm. Accessed February 18, 2010. 3. Furuse H, Ozono S. Transurethral resection of the bladder tumour (TURBT) for non-muscle invasive bladder cancer: basic skills. Int J Urol. 2010;17:698-699. 4. Alan JW, Louis RK, Andrew CN, et al. Campbell-Walsh Urology. 9th ed. Philadelphia: Elsevier Inc; 2007:9790. 5. Thrasher JB, Crawford ED. Complications of intravesical chemotherapy. Urol Clin North Am. 1992;19:529-539. 6. Abrams P, Andersson KE, Birder L, et al. Fourth International Consultation on Incontinence Recommendations of the International Scientific Committee: evaluation and treatment of urinary incontinence, pelvic organ prolapse, and fecal incontinence. Neurourol Urodyn. 2010;29:213-240. 7. Bala I, Bharti N, Chaubey VK, et al. Efficacy of gabapentin for prevention of postoperative catheter-related bladder discomfort in
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patients undergoing transurethral resection of bladder tumor. Urology. 2012;79:853-857. Alan JW, Louis RK, Andrew CN, et al. Campbell-Walsh Urology. 9th ed. Philadelphia: Elsevier Inc; 2007:9832. Agarwal A, Dhiraaj S, Singhal V, et al. Comparison of efficacy of oxybutynin and tolterodine for prevention of catheter related bladder discomfort: a prospective, randomized, placebo-controlled, double-blind study. Br J Anaesth. 2006;96:377-380. Abrams P, Andersson KE. Muscarinic receptor antagonists for overactive bladder. BJU Int. 2007;100:987-1006. Ohtake A, Ukai M, Hatanaka T, et al. In vitro and in vivo tissue selectivity profile of solifenacin succinate (YM905) for urinary bladder over salivary gland in rats. Eur J Pharmacol. 2004;492: 243-250. Ohtake A, Saitoh C, Yuyama H, et al. Pharmacological characterization of a new antimuscarinic agent, solifenacin succinate, in comparison with other antimuscarinic agents. Biol Pharm Bull. 2007; 30:54-58. Chapple CR, Cardozo L, Steers WD, et al. Solifenacin significantly improves all symptoms of overactive bladder syndrome. Int J Clin Pract. 2006;60:959-966. Chapple CR, Martinez-Garcia R, Selvaggi L, et al. A comparison of the efficacy and tolerability of solifenacin succinate and extended release tolterodine at treating overactive bladder syndrome: results of the STAR trial. Eur Urol. 2005;48:464-470. Chinese Urological Association. Guidelines on Urological Diseases. Beijing: People’s Medical Publishing House; 2011:29. Homma Y, Kakizaki H, Yamaguchi O, et al. Assessment of overactive bladder symptoms: comparison of 3-day bladder diary and the overactive bladder symptoms score. Urology. 2011;77:60-64. Agarwal A, Raza M, Singhal V, et al. The efficacy of tolterodine for prevention of catheter-related bladder discomfort: a prospective, randomized, placebo-controlled, double-blind study. Anesth Analg. 2005;101:1065-1067. Zaitsu M, Mikami K, Ishida N, et al. Comparative evaluation of the safety and efficacy of long-term use of imidafenacin and solifenacin in patients with overactive bladder: a prospective, open, randomized, parallel-group trial (the LIST Study). Adv Urol. 2011;2011:854697. Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003;20:327-336. Hendricksen K, Witjes WP, Idema JG, et al. Comparison of three schedules of intravesical epirubicin in patients with non-muscleinvasive bladder cancer. Eur Urol. 2008;53:984-991. Nabi G, Cody JD, Ellis G, et al. Anticholinergic drugs versus placebo for overactive bladder syndrome in adults. Cochrane Database Syst Rev. 2006;18:CD003781. Haab F, Cardozo L, Chapple C, et al. Long-term open-label solifenacin treatment associated with persistence with therapy in patients with overactive bladder syndrome. Eur Urol. 2005;47:376-384. Kaplan SA, McCammon K, Fincher R, et al. Safety and tolerability of solifenacin add-on therapy to alpha-blocker treated men with residual urgency and frequency. J Urol. 2009;182:2825-2830. Rovner ES, Wein AJ. Once-daily, extended-release formulations of antimuscarinic agents in the treatment of overactive bladder: a review. Eur Urol. 2002;41:6-14. Appell RA, Sand P, Dmochowski R, et al. Prospective randomized controlled trial of extended-release oxybutynin chloride and tolterodine tartrate in the treatment of overactive bladder: results of the OBJECT study. Mayo Clin Proc. 2001;76:358-363. Haab F, Stewart L, Dwyer P. Darifenacin, an M3 selective receptor antagonist, is an effective and well-tolerated once-daily treatment for overactive bladder. Eur Urol. 2004;45:420-429. van Waalwijk van Doorn ES, Ambergen AW. Diagnostic assessment of the overactive bladder during the filling phase: the detrusor activity index. BJU Int. 1999;83(Suppl 2):16-21.
5
RESULTS
CONCLUSION
To evaluate the efficacy and safety of solifenacin in the management of irritative symptoms after transurethral resection of bladder tumors (TURBTs) with subsequent intravesical chemotherapy. A total of 116 patients undergoing TURBT were randomly allocated into 2 groups, 58 patients in each group. Group 1 patients received solifenacin 5 mg, 6 hours before surgery and 5 mg per day, after surgery for 2 weeks, whereas group 2 patients received a placebo. Patients with low-risk nonemuscle-invasive bladder cancer received immediate postoperative instillation of epirubicin. Patients with medium- or high-risk nonemuscle-invasive bladder cancer received postoperative instillation twice within 2 weeks, once immediately following the operation and once on the eighth postoperative day. All patients completed bladder diaries before surgery, on the 1st, 7th, and 14th days after removal of the catheter with overactive bladder symptom scores completed preoperatively, and on the 7th and 14th days. Additionally, the incidence and severity of catheter-related bladder discomfort were recorded at 6, 12, 24, 48, and 72 hours after the surgery. The incidence and the severity of catheter-related bladder discomfort in group 1, compared with group 2, were significantly reduced (P <.05). There was a significant difference in overactive bladder symptom scores between the 2 groups (5.67 vs 7.86; P <.001). Episodes of daytime, frequency, nocturia, urgency, and urge urinary incontinence in group 1 were also significantly lower than in group 2 (P <.05). This study demonstrates that solifenacin can be beneficial for the management of irritative symptoms after TURBT with subsequent intravesical chemotherapy. UROLOGY -: -e-, 2014. 2014 Elsevier Inc.
B
ladder carcinoma is the fourth most common cancer in men and the eighth most common cancer in women. Approximately 73,510 new cases of bladder cancer were diagnosed in 2012 in the United States, which accounted for roughly 14,880 deaths.1 When initially diagnosed, most bladder cancers are nonemuscle-invasive,2 for which transurethral resection of bladder tumors (TURBTs) is still the gold standard.3 To prevent or delay the recurrence of bladder cancer, intravesical chemotherapy or immunotherapy is used worldwide for adjunctive management after TURBT.2 However, irritative symptoms are common in patients who receive TURBT with subsequent intravesical therapy4,5; these symptoms are similar to those of overactive Zhensheng Zhang, Zhi Cao, and Chuanliang Xu contributed equally. Financial Disclosure: The authors declare that they have no relevant financial interests. From the Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, P. R. China Reprint requests: Yinghao Sun, Ph.D., M.D., Department of Urology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, P. R. China. E-mail: [email protected] Submitted: October 17, 2013, accepted (with revisions): February 28, 2014
ª 2014 Elsevier Inc. All Rights Reserved
bladder (OAB), that is, urgency, frequency, and nocturia, with or without urge urinary incontinence.6 During catheterization, it manifests as catheter-related bladder discomfort (CRBD), the incidence of which approaches 90% after TURBT.7 Additionally, it has been noted that intravesical chemotherapy lengthens the duration and increases the severity of irritative symptoms and can result in painful chemical cystitis.8 It is widely accepted that the irritative symptoms mentioned earlier negatively affect patients’ recovery, sequential therapy, and daily living. Muscarinic antagonists have been widely used for the management of OAB, and tolterodine has been tried for the prevention of CRBD with variable success.9 Solifenacin, as a newly developed muscarinic antagonist, was reported to have greater selectivity for the bladder over the salivary glands and less potent antimuscarinic action than tolterodine.10-12 Previous studies have confirmed the safety and efficacy of solifenacin for OAB compared with placebo.13,14 However, the efficacy of solifenacin for the management of irritative symptoms after TURBT with subsequent intravesical chemotherapy has not been reported. 0090-4295/14/$36.00 http://dx.doi.org/10.1016/j.urology.2014.02.034
1
In this randomized, single-blind controlled study, we evaluated the efficacy and safety of solifenacin in the management of irritative symptoms in patients receiving TURBT with subsequent intravesical chemotherapy, compared with a placebo.
MATERIALS AND METHODS This study was a prospective, randomized, single-blind, placebocontrolled clinical trial of solifenacin, which was conducted in the Department of Urology of Changhai Hospital over a 6month period. Crossover design was not applied in the study. This study was approved by our institutional medical ethics review committee, and informed consent was provided by all the patients. Men and women, aged 18-80 years and with diagnoses of nonemuscle-invasive bladder cancer (NMIBC), were eligible for inclusion. Patients with obstruction of the bladder outlet, neurogenic bladder, bladder stones, previous pelvic irradiation therapy, glaucoma, any psychiatric diseases, uncontrolled urinary tract infections, end-stage renal disease (urine output <500 mL/ 24 h), morbid obesity, chemical substance abuse, chronic pain, and cardiovascular disease were excluded, as well as patients who were taking any anticholinergic agents. The randomization method was described as follows: the participants were numbered from 1 to 124 according to the order in which they entered into the study. SPSS 18.0 (SPSS Inc) was used for the generation of 124 random numbers, which were realigned so that the first 62 random numbers were labeled as group 1 and the rest as group 2. The group 1 patients received solifenacin 5 mg with a sip of water, 6 hours before the administration of spinal anesthesia, whereas the group 2 patients received a placebo with similar anesthesia. Spinal anesthesia consisted of 2.5 mL of 0.5% hyperbaric bupivacaine, which was administered at a rate of 1 mL/10 s without barbotage. TURBT was performed by 2 experienced surgeons, who acted strictly according to the quality control specifications of our center: (1) resecting all visible tumors, (2) resecting apparently normal mucosa approximately 1 cm from the border of the tumor, (3) resecting the muscle layer at the base of the tumor until normal muscle fibers were visible, and (4) another surgeon inspecting the bladder lumen to confirm that there were no remaining tumors after the aforementioned procedures are completed. With regard to relatively small tumors, both the tumor and the tissue at the tumor base, down to the superficial muscle layer, were simultaneously resected. For relatively larger tumors, we adopted a 2-stage resection, with the first resection exposing the lower level of the mucosa and the second resection removing that lower mucosal layer. After surgery, all the patients received antibiotics until 3 days after the removal of the catheter and group 1 patients received solifenacin 5 mg per day for 2 weeks, whereas group 2 patients received the placebo for 2 weeks. The study drug and placebo tablets were similar in size, color, smell, and appearance. In addition, patients with low-risk NMIBC received immediate postoperative instillation of epirubicin, whereas patients with medium- or high-risk NMIBC received postoperative instillation of epirubicin twice within 2 weeks, once immediately after the operation and once on postoperative day 8. After the trial, intravesical epirubicin instillation was maintained once per week for 8 weeks and then once per month for 12 months.15 The catheterization time depended on the doctor’s judgment. 2
All patients completed OAB symptom score (OABSS)16 and 3-day bladder diaries before surgery, to obtain baseline values. CRBD was recorded at 6, 12, 24, 48, and 72 hours after the surgeries. The severity of CRBD was recorded on a 4-point scale (0, no discomfort; 1, mild discomfort reported on questioning only; 2, moderate discomfort, urge to pass urine reported by the patient without questioning; and 3, severe discomfort, urge to pass urine accompanied by behavioral responses, such as flailing limbs, strong vocal responses, or attempts to pull the catheter out).7,17 Hyoscine butyl bromide 20 mg or pethidine hydrochloride100 mg was administered intramuscularly as rescue therapy in cases of severe and intolerable CRBD. Participants completed OABSS on the 7th and 14th days after the removal of the catheter and bladder diaries on the 1st, 7th, and 14th days after the removal of the catheter to record daytime frequency, nocturia, urgency episodes, and urge urinary incontinence episodes. In accordance with good clinical practice principles, adverse events were recorded at each visit. The data collectors were trained and unaware of the grouping situation of the patients. The primary study outcome was the difference in OABSS between the 2 groups on the seventh day after the removal of the catheter. On the basis of a published standard deviation of 3.0 for the OABSS,18 and a 2-sided alpha value of 0.05, 102 people were required to have a statistical power of 90% to detect difference between groups of 2.0 on the OABSS. And, the number was increased to 124 to account for potential dropouts. Other efficacy measurements included the degree of CRBD, daytime frequency, nocturia, urgency episodes, and urge urinary incontinence episodes. The primary study outcome was analyzed by repeated measures analysis of covariance with a linear regression model and baseline values as covariates, as well as univariate analysis of covariance at different times. The incidence and severity of CRBD were compared between the groups using generalized estimating equations, which were also compared among groups using the Wilcoxon rank-sum test at different times. We used analysis of repeated measures covariance with a linear regression model to test for daytime frequency, nocturia, urgency episodes, and urge urinary incontinence episodes, which were also analyzed by analysis of covariance at different times. The baseline values were included as covariates. The comparability of patients’ characteristics and duration of surgery was assessed by t-test and Chi-square test. SPSS, 18.0 was applied in the analysis, all the statistical comparisons involved 2-sided tests at a significance level of a ¼ 0.05.
RESULTS A total of 153 patients were evaluated, of which 29 were excluded from the study because the inclusion criteria were not met or the patients were unwilling to participate. Therefore, 124 patients were included in the study and received study medication after randomization. Eight patients (4 from each group) dropped out of the study because of adverse events or were lost to follow-up, and 116 patients completed the study (58 in each group; Fig. 1). The patients with tumors located in the bladder trigone numbered 13 (22.4%) in group 1 and 11 in group 2 (20.0%; P ¼ .819). There were no significant differences with regard to the patients’ characteristics in terms of age, gender, risk stratification of bladder cancer, stage of bladder tumor, histologic grade of bladder tumor, UROLOGY
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Table 1. Patients’ characteristics and duration of surgery Solifenacin Placebo Group (n ¼ 58) Group (n ¼ 58) Age (y) 59.26 9.73 59.72 8.97 Sex ratio (M:F) 43:15 40:18 Risk stratification 7:38:13 10:37:11 LR:MR:HR Stage of bladder tumor 4:18:36 3:16:39 Tis:Ta:T1 31:17:10 30:19:9 Histologic grade of bladder tumor G1:G2:G3 Number of bladder tumor 2.28 1.33 2.64 1.33 Duration of surgery (min) 36.33 8.76 37.38 7.81 Catheterization time 3.2 0.48 3.3 0.58 F, female; G1, grade 1; G2, grade 2; G3, grade 3; HR, high risk; LR, low risk; M, male; MR, mediate risk.
statistical analysis at different times; the details are presented in Table 2. Adverse events were also recorded, which were anticholinergic in nature and of mild or moderate severity. The most common treatment emergent adverse events were dry mouth (10.3% and 6.9%; P ¼ .743), constipation (8.6% and 3.4%; P ¼ .438), headache (1.7% and 0%; P ¼ 1.000), and dizziness (1.7% and 0%; P ¼ 1.000) with solifenacin and placebo, respectively. Discontinuations due to adverse events numbered 2 with solifenacin and 0 with placebo, 1 patient dropped out because of unbearable headaches and another for dizziness. Figure 1. Flow randomization.
chart
of
patient
enrollment
and
number of bladder tumors, and duration of surgery (P >.05; Table 1). In most cases, the catheterization time was 3 days; durations of >5 days were not observed in the trial. Furthermore, the catheterization times were comparable between the 2 groups (P ¼ .492). For the primary efficacy variable, at day 7, the OABSS in group 1 was significantly lower than in group 2 (5.67 vs 7.86; P <.001). The repeated measure covariance indicated that there was a significant difference in OABSS between the 2 groups (P <.001; Table 2). And, there was no interaction between the treatment type and time (P ¼ .341), which was confirmed by analysis at different times. The incidence of CRBD at 6 hours after TURBT decreased from 93.1% (placebo group) to 67.2% (solifenacin group; P ¼ .001); the severity of CRBD was also significantly reduced in group 1 compared with group 2 (P ¼ .008), and no interaction between the treatment type and time was observed (P ¼ .174), which was also confirmed by analysis at different times. The incidence and severity of CRBD are presented in Table 3. Furthermore, there were also significantly fewer episodes of daytime frequency, nocturia, urgency, and urge urinary incontinence in group 1 than in group 2 (P <.05), which were indicated by both repeated measures analysis and UROLOGY
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COMMENT This study concludes that solifenacin 5 mg significantly benefits patients with irritative symptoms who have undergone TURBT with subsequent intravesical chemotherapy. Damage to the bladder mucosa, exposure of the detrusor to urine, catheterization, bladder irrigation, and instillation of intravesical chemotherapy agents can stimulate the afferent nerves of the bladder, leading to release of acetylcholine, which can bring about involuntary contractions of detrusor mediated by muscarinic receptors. Additionally, intravesical instillation can result in chemical cystitis. A previous report showed that the incidences of cystitis resulting from doxorubicin, epirubicin, thiotepa, and mitomycin were, respectively, 20%-40%, 10%-30%, 10%-30%, and 30%-40%.8 Irritative symptoms can obviously affect patients’ daily lives; 3 health-related outcomes—health-related quality of life, mental health, and quality of sleep—have been reported to be negatively affected by OAB symptoms.19 In addition, irritative symptoms can reduce the compliance of patients with intravesical instillation. In a multicenter, prospective, randomized phase 3 trial of intravesical epirubicin instillation therapy, the incidence of chemical cystitis reached 30%, with 5% of patients either requiring temporary delays or discontinuation.20 Antimuscarinic therapy, by suppressing involuntary bladder contractions, has been the mainstay of the 3
Table 2. Results of OABSS and bladder diary
OABSS (score) Preoperation 7th day 14th day Daytime frequency (episode per day) Preoperation 1st day 7th day 14th day Nocturia (episode per day) Preoperation 1st day 7th day 14th day Urgency (episode per day) Preoperation 1st day 7th day 14th day Urge urinary incontinence (episode per day) Preoperation 1st day 7th day 14th day
Solifenacin Group (mean SD)
Placebo Group (mean SD)
2.03 2.83 5.67 2.94 3.26 2.37
1.98 2.62 7.86 2.55 4.79 2.65
6.86 9.76 9.06 7.60
2.27 2.88 2.47 1.95
6.94 12.01 10.36 8.93
2.29 4.13 2.34 2.59
0.48 1.36 0.79 0.59
0.84 1.10 0.87 0.68
0.50 1.85 1.33 0.97
0.71 1.07 0.86 0.75
0.43 2.24 1.53 0.81
0.73 1.22 1.03 0.78
0.43 3.10 2.24 1.17
0.65 1.86 1.11 0.94
0.29 1.24 0.79 0.33
0.56 0.96 0.77 0.51
0.24 1.93 1.17 0.59
0.54 1.11 0.99 0.73
P(group)
P(group*time)
<.001 .919 <.001 .001 <.001 .839 .001 .005 .002 <.001 .905 .021 .001 .005 <.001 1.000 .004 .001 .026 <.001 .614 <.001 .023 .028
.341
.246
.689
.150
.057
OABSS, overactive bladder symptom scores; P(group*time), the P value for the interaction between group and time; SD, standard deviation.
Table 3. Incidence and severity of catheter-related bladder discomfort, data presented as number of patients Solifenacin Group, N (%) Time (h) 6 12 24 48 72
0 19 22 25 30 39
(32.8) (37.9) (43.1) (51.7) (67.2)
1 20 24 18 16 12
(34.5) (41.4) (31.0) (27.6) (20.7)
Placebo Group, N (%)
2 17 12 15 11 7
(29.3) (20.7) (25.9) (19.0) (12.1)
3 2 0 0 1 0
(3.5) (0) (0) (1.7) (0)
management of OAB. Solifenacin specifically blocks M3 receptor and, to a lesser extent, the M2 receptor, so it is 40 times less potent than oxybutynin and 79 times less potent than tolterodine in inhibiting salivary secretion.21 It also demonstrates greater affinity for the bladder because its inhibition of the detrusor is 3.6 times greater than its inhibition of salivary glands.11 Previous studies have demonstrated that solifenacin significantly reduced episodes of urgency in more than 60% of patients (with complete resolution of urgency in approximately 40%) and secondarily reduced other symptoms related to OAB symptoms.13,22 Additionally, in a group of patients with residual OAB symptoms after tamsulosin monotherapy, solifenacin significantly decreased urgency episodes after 12 weeks of management.23 In our study, the incidence of CRBD at 6 hours after TURBT decreased from 93.1% (placebo group) to 67.2% (solifenacin group; P ¼ .001), a finding that is similar to the report of Agarwal,17 which stated that tolterodine 2 mg administered 1 hour before surgery reduced the incidence of CRBD by 19%. 4
0 4 10 12 22 30
(6.9) (17.2) (20.7) (37.9) (51.7)
1 27 19 21 15 11
(46.6) (32.8) (36.2) (25.9) (19.0)
2 23 27 25 21 17
P
3
(39.7) (46.6) (43.1) (36.2) (29.3)
4 2 0 0 0
(6.9) (3.4) (0) (0) (0)
.002 <.001 .003 .041 .024
Our analysis concludes that solifenacin can significantly improve irritative symptoms after catheter removal by reducing OABSS, daytime frequency, nocturia, episodes of urgency, and episodes of urge urinary incontinence. Although the OABSS has been demonstrated to be highly sensitive to treatment-related changes in OAB symptoms, bladder diaries can provide more detailed information.18 It is commonly believed that nocturia reduces quality of sleep and quality of life. At the end of this study, the number of patients who had more than 1 episode of nocturia in the solifenacin group and placebo group was 4 and 10, respectively. Solifenacin was well tolerated in this study, with the most common adverse events being dry mouth, most cases of which were mild. In a pooled analysis of relevant studies, rates of dry mouth were 23.4% and 60.8% for tolterodine extended release 4 mg and oxybutynin extended release 5-30 mg, respectively.24 In the Overactive Bladder Judging Effective Control and Treatment study, which compared tolterodine 2 mg twice daily with oxybutynin extended release 10 mg daily, tolterodine was UROLOGY
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associated with dry mouth in 33.2% of patients, whereas oxybutynin was associated with dry mouth in 28.1% of patients.25 In a report of darifenacin outcomes in OAB, dry mouth was reported by 18.8% (7.5 mg) and 31.3% (15 mg) of treated patients.26 Thus, there are sound reasons to believe that the incidence of dry mouth of 10.3% seen in this study with solifenacin 5 mg daily compares favorably with the data for other agents. However, this study has some potential limitations. First, the study was a single-blind and not double-blind trial, which may bring bias to the results. Second, the trial was conducted in 1 center, the patients of which are all of Asian descent and Chinese. The efficacy of solifenacin in other races and nations was not evaluated. Third, the sample size of the trial was small, so larger studies are warranted to investigate further the impact of solifenacin on irritative symptoms after TURBT. Fourth, the administration of hyoscine butyl bromide or pethidine hydrochloride might bring important bias to the study. Fifth, the application of antibiotic was not strictly conducted according to the European Association of Urology guidelines on urologic infections. Sixth, we did not use the detrusor activity index in the study, which is a good diagnostic model with high accuracy to evaluate OAB.27
8. 9.
10. 11.
12.
13.
14.
15. 16.
CONCLUSION
17.
The incidence of irritative symptoms after TURBT is high. Our study demonstrated that solifenacin is a beneficial and safe agent for the management of irritative symptoms after TURBT with subsequent intravesical chemotherapy.
18.
19.
Acknowledgment. All authors appreciate Dr. Robert Stein at Cleveland Clinic for assistance with the writing of the manuscript.
References
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