2008 The Authors; Journal compilation Original Article
2008 BJU International
BLADDER BOTULINUM TOXIN A INJECTION CHUANG et al.
BJUI
Bladder botulinum toxin A injection can benefit patients with radiation and chemical cystitis
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Yao-Chi Chuang, Dae Kyung Kim*, Po-Hui Chiang and Michael B. Chancellor† Department of Urology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan, *Department of Urology, Eulji University School of Medicine, Daejeon, Korea, and †Department of Urology, William Beaumont Hospital, Royal Oak, MI, USA Accepted for publication 31 January 2008
Study Type – Therapy (case series) Level of Evidence 4
sedation or local anaesthesia, BoNT-A was injected through a cystoscope into 20 sites submucosally in the trigone and floor of the bladder.
OBJECTIVE RESULTS To investigate the potential utility of botulinum toxin A (BoNT-A) bladder injections in patients with radiation cystitis and bacillus Calmette-Guérin (BCG)-induced chemical cystitis. PATIENTS AND METHODS In all, six patients with refractory radiation cystitis were treated with 200 U bladder BoNT-A injections and two patients with refractory cystitis after intravesical BCG therapy were treated with 100 U bladder BoNT-A injections. All the patients were refractory to anticholinergic agents. Under
INTRODUCTION Radiotherapy is inevitably associated with normal tissue side-effects. Pelvic radiotherapy is not infrequently complicated with radiation cystitis, which is characterized by dysuria and increased urinary frequency [1,2]. Similarly, intravesical BCG therapy for superficial bladder cancer often compromises bladder storage function [3,4]. Several different treatments have been proposed for severe cystitis, such as antimuscarinic agents, empirical antibiotic therapy, or NSAIDs. Nevertheless, the therapeutic effects are limited for these patients [4]. Botulinum toxin A (BoNT-A) was originally known to block acetylcholine release at neuromuscular junctions and have therapeutic effects on muscular hypercontraction [5,6]. The utility of
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There were no side-effects or retention after BoNT-A injection. In five of the six patients with radiation cystitis there was a moderate to significant improvement; the mean (SD) bladder capacity increased from 105 (25) mL to 250 (35) mL and the urinary frequency decreased from 14 (2) to 11 (1) episodes per day. In the two patients with BCG cystitis both reported significant symptomatic improvement; the mean (SD) bladder capacity increased from 110 (23) to 230 (23) mL, the urinary frequency decreased from 16 (1) to 12 (1) episodes per day, and using a 10-point visual analogue
BoNT-A, initially used in treating urological disorders including hyper-reflexic bladder and detrusor-sphincter dyssynergia due to spinal cord injury [7], has expanded to the treatment of patients with multiple sclerosis and non-neurogenic voiding and storage disorders [8,9]. Recent research has shown that BoNT-A blocks exocytosis of neurotransmitters including acetylcholine, sensory neuropeptides and inhibits transient receptor potential vanilloid subfamily 1 and P2X3 receptors [10–12]. BoNT-A may also inhibit cyclooxygenase-2 (COX-2) expression and suppress inflammatory reactions [13]. Persistent voiding symptoms after radiation and intravesical instillation of BCG can be difficult to manage. In the present study, our aim was to assess whether BoNT-A was safe, well tolerated and improved the quality of life in patients with radiation and chemical cystitis.
pain scoring system, the perceived pain score decreased from 8 to 2. Microscopically, the bladder tissue at 1 month after BCG injection showed marked acute and chronic inflammation with eosinophilic infiltration and focal granulomatous formation. At 2 months after BoNT-A injection, there was only a mild degree of chronic inflammation with few eosinophils. CONCLUSION These preliminary results suggest that BoNTA injected into the bladder is a promising treatment for patients with refractory radiation and BCG cystitis. KEYWORDS botulinum toxin, radiation cystitis, chemical cystitis
PATIENTS AND METHODS We conducted a retrospective review of eight patients, with a mean (SD) aged of 67.8 (3.1) years, who had moderate to severe storage symptoms, i.e. frequency, urgency, and/or bladder pain, and who had failed conventional therapy for at least 2 months, and then had undergone bladder BoNT-A injections. BoNT-A bladder injections were performed by injecting 100–200 U of BoNT-A diluted in 10–20 mL sterile saline into the bladder wall with a cystoscopic injection needle. Targeted sites included the posterior and lateral wall of the bladder. Care was taken to raise a 0.5–1.0 mL submucosal bleb with each injection, facilitating visualization of the targeted site, avoiding the risks of perforation, damage to surrounding structures, and wastage of toxin.
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FIG. 1. Bladder capacity (mL), before (pre) and after (post) BoNT-A injection in the radiated and BCG cystitis groups. Bladder capacity increased after BoNT-A injection.
FIG. 2. Voiding frequency (episodes/24 h) before (pre) and after (post) BoNT-A injection in the radiated and BCG cystitis groups. Voiding frequency decreased after BoNT-A injection.
tumour and the inflammatory changes were markedly diminished with only a mild degree of chronic inflammation with few eosinophils.
Bladder Capacity, mL
24 h Uriary frequency, n
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FIG. 3. Combined haematoxylin and eosin histology of BCG cystitis before (A) and after (B) BoNT-A injection. There is a dense inflammatory cell infiltrate composed of histiocytes, lymphocytes, neutrophils and lots of eosinophils in the fibrous stroma (A), these inflammatory effects was significantly reduced after BoNT-A injection (B). ×200.
Four men with refractory radiation cystitis after prostate radiation (two external beam, two interstitial seeds) and two women with external beam radiation for cervical cancer were treated with 200 U bladder BoNT-A injection. Two patients with refractory BCG cystitis after six courses of intravesical BCG for the treatment of bladder cancer were also treated with 100 U bladder BoNT-A injections. Under sedation or local anaesthesia, BoNT-A was injected through a cystoscope into 20 sites submucosally in the posterior and lateral wall of the bladder. Follow-up consisted of patient clinic visits with a voiding diary.
RESULTS There were no long-term or systemic complications in either group. No retention or side-effects were reported. Symptomatically, among the six patients with radiation cystitis one patient had no improvement, three had moderate improvement and two had significant improvement at 1 week after injection. The maintenance of the results lasted for up to 6 months. At 2 months after BoNT-A injection, the mean (SD)
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bladder capacity increased from 105 (25) to 250 (35) mL on the 3-day voiding diary (Fig. 1) and the urinary frequency decreased from 14 (2) to 11 (1) episodes per day. The residual urine volume, as determined by suprapubic ultrasonography, remained similar at 12 (16) mL before injection to 21 (10) mL after BoNT-A injection (Fig. 2). In the two patients with BCG cystitis, both reported significant symptomatic improvement. The bladder capacity increased from 110 (23) to 230 (23) mL, urinary frequency decreased from 16 (1) to 12 (1) episodes per day, and using a 10-point visual analogue pain scoring system, the perceived pain score decreased from 8 to 2. There was no significant difference in the residual urine volume before and after BoNT-A injection. Microscopically, the bladder tissue at 1 month after BCG injection had marked acute and chronic inflammation with eosinophilic infiltration and focal granulomatous formation. However, no acid-fast bacilli were identified by Ziehl-Neelsen staining (Fig. 3). At 2 months after BoNT-A injection, there was no evidence of local recurrence of bladder
Previously, bladder BoNT-A injections have been successfully used to relieve the symptoms of overactive bladder and interstitial cystitis [14–16]. Here we report the first clinical use of this toxin in patients with radiation cystitis and BCG cystitis with promising initial results. With a total dose of 100–200 U of BoNT-A injected into the bladder, seven of the eight patients who previously had severe storage symptoms had significant improvements. There were no adverse events after bladder BoNT-A injection in these challenging patients. Therefore, the present results support, that for selective patients with refractory radiation cystitis and BCG cystitis, botulinum toxin injection may be considered. Radiation cystitis tends to be a late complication of pelvic radiotherapy, which includes the symptoms of urinary frequency and urgency based on impairment of storage function of the organ, i.e. a decrease in bladder storage capacity. A previous study in a rat model showed that irradiation resulted in pronounced COX-2 dependent inflammatory changes in the bladder wall [17]. Similarly, intravesical BCG therapy for superficial bladder cancer often induces BCG cystitis and compromises bladder storage function. BCG cystitis typically consists of an acute inflammation of the bladder wall in conjunction with the formation of granulomas [4], and in the present study, such inflammatory changes were seen in the patients with BCG cystitis. Symptomatic treatment of radiation cystitis and BCG cystitis is challenging for clinicians. As any efferent signal from the reflex arc can be blocked, BoNT-A may be effective, regardless of the original aetiology, so long as the detrusor reflex is associated with symptom provocation. Also, recent research from a capsaicin-induced prostatitis model has shown that BoNT-A suppresses COX-2 expression and has analgesic and antiinflammatory effects [13]. The present study provides additional evidence for the therapeutic benefit of BoNT-A for the symptomatic relief from chronic inflammatory conditions of bladder.
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C H U A N G ET AL.
The benefit of bladder BoNT-A injection is that it has the potential to be an option for the treatment of storage symptoms of overactive bladder and chronic cystitis. However, theoretical risks of the injection procedure of BoNT-A, including haematuria, perforation, UTI, and injection-site pain, should be considered. Schurch et al. [18] reported the development of UTIs in ≈25% of patients receiving bladder BONT-A injections, but the incidence of other adverse events was minimal. In the present series, although no formal evaluation of VUR after injection was performed, there were no reported episodes of pyelonephritis. A recent meta-analysis examining the safety of BoNT-A injection across a wide range of therapeutic applications, reported that the overall rate of adverse events in patients treated with BoNTA was 25% (primarily focal weakness) compared with 15% in control groups. There were no serious or severe systemic adverse events reported in any of the 36 included trials [19]. In the present series, there were no acute or long-term systemic complications. In conclusion, the present series represents the first use of bladder BoNT-A injection for refractory radiation and BCG cystitis and the results are promising. However, the present study is limited by the few cases and formal clinical trials should be undertaken to address these refractory conditions. CONFLICT OF INTEREST Yao-Chi Chuang and Michael B. Chancellor are both Consultants to Allergan. REFERENCES 1
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Correspondence: Yao-Chi Chuang, 123, Ta-Pei Road, Niao-Song Hsiang, Kaohsiung Hsien, Taiwan. e-mail:
[email protected] Abbreviations: BoNT-A, botulinum toxin A; COX-2, cyclooxygenase-2.
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