- Top of page
- PATIENTS AND METHODS
- CONFLICT OF INTEREST
- Supporting Information
BOO secondary to BPH with benign prostatic enlargement represents the most common cause of LUTS in older men . Major treatment goals are fast and sustained long-term relief of LUTS, improvement of health-related quality of life (HRQL), prevention of disease progression and complications, and as important, patient's satisfaction with treatment. Currently, BPH is commonly treated with pharmacological therapy including α-blockers, which reduce urethral resistance, and 5α-reductase inhibitors (5-ARIs), which reduce prostate volume. However, these drugs must be taken continuously, cannot always control the long-term urinary symptoms and progression, and are associated to several side-effects [2–4]. For patients with severe LUTS, prostate reduction can be obtained surgically by TURP or by minimally invasive surgical techniques. Each surgical option has specific adverse consequences and >20% of patients undergoing TURP do not have satisfactory long-term outcomes .
Botulinum toxin (BTX) is an emerging, non-invasive and potentially targeted therapy for BPH. BTX blocks the release of neurotransmitters, e.g. acetylcholine and norepinephrine, from pre-synaptic nerves [6,7]. The therapeutic benefit of intraprostatic BTX injection is based on its organ-specific, chemical denervation leading to inhibition of smooth muscle contraction and tissue atrophy [6,7]. Animal experiments have suggested that the mechanism of action in the prostate gland is induction of atrophy, diffuse apoptosis, reduced cell proliferation and decreased expression of α-adrenergic receptors [8–10]. As a result, BTX may have effects on both the dynamic and the mechanic component of BPH.
Several cohort and small randomised studies evaluating the effects of intraprostatic injection of BTX have been published and recently summarised in systematic reviews [11,12]. There is substantial agreement on the safety and effectiveness of BTX in improving both LUTS and BOO parameters. However, these studies focused mainly on objective measures and limited the evaluation of subjective health outcomes to the IPSS . The patients' opinions about the treatment were given little consideration for assessing treatment outcome. The value of patient-reported outcomes (PROs), such as patients' perceptions, preferences and satisfaction with therapy, is increasingly accepted as part of the clinical decision-making process, and has been increasingly acknowledged in clinical practice guidelines for the management of BPH [14–17]. Consequently, we considered it of interest to appraise the PROs of this investigational novel treatment for male LUTS, to provide researchers with pre-trial data relevant for the design of future randomised trials.
The purpose of the present study was to evaluate safety and efficacy of intraprostatic injection of OnabotulinumtoxinA (BTX-A) by assessing both objective and subjective health outcomes, including the impact on sexual function and patients perceptions about their treatment.
- Top of page
- PATIENTS AND METHODS
- CONFLICT OF INTEREST
- Supporting Information
In agreement with most published studies evaluating the efficacy of intraprostatic injection of BTX in patients with BPH [11, 12], in the present study there was a significant improvement in LUTS and HRQL at 3-months follow-up, without significant complications and side-effects. Compared with baseline, there was a statistically significant reduction in the IPSS and IPSS-HRQL score of 49% and 45%, respectively. Interestingly, both storage and voiding LUTS improved after treatment. This finding is of interest because storage LUTS are the most frequent patient-reported most bothersome symptoms and are often maintained after BPH treatments . The clinical efficacy of the treatment was also supported by an increase in Qmax and a reduction in PVR after treatment compared with baseline.
The first pioneering randomised control trial on intraprostatic injection of BTX-A was performed in 2003 by Maria et al.  on 30 patients who did not respond to conventional medical treatment and declined the surgical option. In 15 patients, both lobes of prostate were injected with 200 U BTX-A, diluted in 4 mL saline; the remaining 15 were injected with saline only. In the treatment group they reported at 2-months follow-up a significant improvement in the AUA Symptom Score of 65%, an increase of 52% in Qmax and a reduction of 82% in PVR in 13 of 15 treated patients. Of interest, a significant reduction in TPV (68%) was observed in this work. These results were replicated in an open-label study in the same institution by Brisinda et al.  that treated 77 patients with 200 U BTX-A. Compared with the present findings, these studies [20,21] reported more impressive results, although the outcome evaluation occurred earlier. There was also a reduction in PSA levels after therapy in these and other studies [22,23], in disagreement with the results of the present and other studies [24,25].
A few studies have evaluated treatment outcomes at 3-months follow-up, reporting results consistent with those of the present study [25–27]. In the work of Kuo , 10 patients with BPH were treated with 200 U BTX-A, injected transurethrally into 10 sites in the transitional zone of the prostate. The author reported a statistically significant increase in Qmax (31%) and a reduction in PVR (78%) and TPV (30%). Chuang et al.  used BTX-A in 41 patients with BPH refractory to medical treatment. A dose of 100 U BTX-A was used for prostates of <30 mL and 200 U for prostates of >30 mL, obtaining at 3 months a significant improvement in the IPSS (57%), IPSS-HRQL (49%), Qmax (59%), PVR (62.5%) and TPV (14%). Similar results were reported in the study conducted by Park et al.  in 30 patients, with a greater benefit in the IPSS-storage subscore than the voiding subscore.
None of the published studies assessed PROs, such as patient-perceived level of improvement and success of therapy, as well as the patient satisfaction with intraprostatic BTX-A therapy. BPH might be defined by the LUTS whose severity is not strictly related to objectively measurable parameters and whose impact on patients is heterogeneous and difficult to predict . As a result, evaluations from the patient's perspective, using information gathered directly from the treated patients, are of utmost importance in BPH research and management [14–17]. PROs, e.g. patient's satisfaction with treatment, have been showed to have significant implications in making a full assessment of overall treatment success in patients with BPH. Studying the patient-perceived efficacy of doxazosin, Cam et al.  reported that, after 1 year, the probability of surgery was significantly higher in patients who considered treatment ineffective than in the those who considered the treatment effective or reported no change (P < 0.05), and was also significantly higher in those who felt that their condition remained unchanged than in those who considered treatment effective (P < 0.05).
The present study is the first to provide data useful for gaining insight into the way patients perceive the effect that treatment with intraprostatic BTX has on their symptoms and HRQL. The assessment of patients' perception of treatment outcome, for patient-reported improvement, satisfaction and effectiveness, showed promising results, comparable with those reported in the studies on α-blockers and 5-ARIs [28–31]. A subjective improvement of LUTS was reported by more than half of the present patients and nearly two-thirds of them reported some degree of satisfaction and effectiveness.
In the present study, there were also a not negligible proportion of patients reporting no satisfaction or no improvement from the treatment or even a worsening of their LUTS. Considering that patients had to compare their clinical status at 3 months with that before treatment (when they were still on medical therapy), these results could be explained by an efficacy of BTX-A similar (in patients reporting no change) or lower (in patients reporting worse symptoms) than that of medical therapy in these patients. Based on the correlation analysis, these patients tended to have lower baseline IPSS and had lower reductions in the IPSS. However, an appropriate subgroup analysis would need a larger study population and the evaluation of more biological factors. Likewise, other studies on drug therapy of BPH reported comparable rates of no satisfaction [28,30]. Satisfaction with the α-blockers doxazosin (4 mg/day) was evaluated in 178 men in a 3-month open-label trial . Patients were asked ‘What is your opinion about the efficacy of the drug you have taken to relieve your urinary symptoms’? Doxazosin was considered effective by 44% of patients, ineffective by 23% and there was no change in 33%. Using the Patient Perception of Study Medication (PPSM), a questionnaire exploring patient-reported satisfaction with treatment and validated for use in men with BPH, Montorsi et al.  reported 36%, 24% and 24% of no satisfaction with improvement in urinary problems at 3 months after treatment with dutasteride, tamsulosin and combined therapy, respectively.
Some patients (11%) reported satisfaction with the treatment and judged the treatment as effective, although they reported no perception of symptoms improvement. This finding may be explained by the fact that these patients were satisfied by maintaining the same symptoms severity without taking continuous oral drug therapy.
In the present study, a correlation, although moderate, between the reduction in IPSS after treatment and more severe baseline symptoms is in agreement with the findings of some previous studies on the effect of tamsulosin [32–36] and dutasteride , and is worthy of further investigation.
We also tried to investigate what drove patient satisfaction. The present data showed an apparent positive correlation between satisfaction with treatment and both the baseline IPSS (moderate correlation) and IPSS reduction from baseline (strong correlation), indicating higher satisfaction in patients with increasing severity of baseline symptoms and more pronounced symptom reduction. Accordingly, a positive correlation between the IPSS reduction and the patient-perceived improvement and satisfaction score has been previously reported in patients treated with dutasteride, tamsulosin or combined therapy [30,38]. Conversely, in the present study there were no correlations between patient-reported satisfaction and baseline objective parameters, e.g. age, prostate volume, PSA level, Qmax and PVR. Overall, these findings suggest a clinical benefit with BTX-A therapy in all age ranges and also in patients with known risk factors for disease progression, e.g. severe LUTS, large prostate volume, low Qmax, high PVR and PSA level . Together with the quick relief of both voiding and storage symptoms and the improvement of HRQL reported in most studies [11,12], these findings may indicate, if confirmed in large randomised studies, that BTX therapy has the potential to be a treatment option capable of delivering a ‘total’ management approach for both low/intermediate and high-risk patients with BPH .
According to Silva et al. , we confirmed in the present study that intraprostatic BTX-A injection in patients with BPH does not impair erectile, orgasmic or ejaculatory functions and does not change libido. This is of utmost importance because sexual dysfunctions commonly occur in parallel with BPH  and are often associated with α-blockers and 5-ARIs.
The present study does have some limitations. The open-label/non-comparative design, the lack of a placebo arm, and the assessment of PROs with a non-validated questionnaire reduce the generalizability of the present findings and the level of evidence provided. Recall bias also has to be considered when asking patients to compare their present health status with a previous one. In the present study, it was not possible to study the biological effects of BTX-A on human prostate. This is an interesting issue, as little is known about the mechanism of action, which is hypothesised to be related to the induction of apoptosis [8,43]. The short follow-up of the present study did not allow elucidation of the long-term efficacy of BTX treatment and we plan to report the longer term results. According to international guidelines, the treatment strategy for BPH involves the sustained improvement of LUTS and HRQL, and the reduction of the risk of acute urinary retention and BPH-related surgery [16,17]. It would be very interesting to study the long-term effects of BTX therapy, not only on LUTS and HRQL of patients with BPH, but also on the risk of acute urinary retention and BPH-related surgery, especially because the available data suggest that patients are more worried about long-term risks of BPH and prefer therapies that affect long-term disease progression over those that provide short-term symptoms relief [14,31,44].
In conclusion, the present study confirmed that intraprostatic injection of BTX-A is a promising, safe and minimally invasive therapeutic option able to improve both objective and subjective outcomes in patients with LUTS due to BPH with unsatisfactory response to medical therapy.
The study also provided important outcome information from the patient's perspective by showing that most of the treated patients reported favourable subjective outcomes at 3-months follow-up. Noteworthy, PROs appeared not to be associated in this cohort with age and objective baseline parameters, but there was a moderate correlation between PROs and increasing severity of baseline LUTS. This could be explained by the subjective nature of both PROs and the IPSS.
The use of BTX-A in the setting of patients with BPH remains off-label in all countries and further basic research and randomised trials are necessary in order to: (i) identify predictive parameters clinically useful for a better selection of patients, (ii) achieve an adequate level of scientific evidence supporting the introduction of this treatment in clinical practice, and (iii) define the best treatment technique (dose, injection site, route of administration).