The male synthetic sling (male sling) is an alternative to the artificial urinary sphincter (AUS) for men with urodynamic stress incontinence after prostate surgery, but there is limited evidence of relative effectiveness and cost-effectiveness to guide choice. We aim to resolve this by directly comparing the rate of incontinence at 12 months in a non-inferiority randomised controlled trial (RCT) powered on the basis that men would accept up to 15% lesser effectiveness in return for easier device operation and possible reduced adverse effects. We will recruit patients who have decided, with their clinicians, that surgery is needed. To address feasibility of recruitment, we have devised a schedule to give early indication of our ability to recruit to target but avoiding any disruptive pause if we are successful.
Scale of the problem in the UK and use of NHS resources
Men undergoing radical prostatectomy for prostate cancer frequently report the troublesome symptom of stress urinary incontinence (SUI). Prevalence estimates vary widely between 5% and 57% depending on definition, timing of assessment after surgery, and population characteristics. The rate of recovery of continence plateaus at around 12 months after surgery. This was confirmed in a recent large HTA-funded RCT of pelvic-floor muscle training (PFMT) in patients who suffered incontinence 6 weeks after radical prostatectomy. Subsequently, 40% had persistent UI at 1 year, with half of these (20%) having severe UI needing containment (incontinence pads or appliances) which then did not improve further during the second 12 months up to 24 months after the original surgery [
1,
2].
This means that of the 6000 patients currently undergoing radical prostatectomy in the UK each year, 1200 will be using additional treatments for resultant stress incontinence beyond 12 months. UI has a major impact on quality of life, including profound loss of self-esteem together with restrictions on work, social interaction and personal relationships including sexual life. The utility value associated with a person with UI is 0.72 compared to 0.93 in a comparable age-matched population [
3]. This is particularly devastating for men undergoing radical prostatectomy since they were typically without any urinary problems prior to the surgery, are fit for their age, and have a long life expectancy having generally been cured of their prostate cancer.
Unfortunately conservative treatment with one-to-one PFMT has been shown to be ineffective [
1,
2], drug treatment is unproven, and men mostly cope by using containment products. Other treatments, such as injectables and inflatable balloons, have been reviewed, but there was insufficient evidence to support their use.
Surgery for persistent bothersome SUI is traditionally by artificial urinary sphincter (AUS) as the ‘gold standard’ treatment [
4]. However, this is invasive, expensive and involves manipulation of a pump located in the scrotum to enable voiding. Analogous to surgery for SUI in women, synthetic slings for men have recently been developed to elevate the urethra. This is thought by some as less invasive, more acceptable to some men, and less expensive, but there is no clear evidence for its comparative effectiveness against the standard AUS. Current NHS guidance states that the male synthetic sling should only be used in RCTs against the AUS [
5].
Approximately 350 men were implanted with an AUS in the UK NHS during 2010 at a cost of £9000 per procedure; £3.2 million in total. The male sling was implanted in 30 men during 2010 at a cost of £6000 per procedure; £180,000 in total.
Evidence for surgical management for men with urinary incontinence after prostate surgery
There are no published RCTs comparing male slings with AUS. A Cochrane review found only one small, poor-quality RCT of surgery which suggested that implantation of artificial urinary sphincter (AUS) was better than an injectable bulking agent [
6]. In this RCT, the men treated with AUS were more likely to be cured (18/20, 82%) than those who had the injectable treatment (11/23, 46%, OR 5.67, 95% CI 1.28 to 25.10). All other evidence comes from case series which were recently summarised by the WHO-sponsored 4th International Consultation on Incontinence [
4]. This reported that the median (range) cure rate after AUS was 82% (59 to 90%, 12 series) and for male sling was 63% (13 to 86%, 20 series) [
7]. A more recent review of the academic literature looked at six case series of men implanted with the AdVance® brand of male sling and reported a cure rate of 60% [
8]. More recently sub-group analysis from a large case series showed that at 3 years after sling implantation, men categorised on the basis of pad usage as having ‘mild/moderate’ incontinence, had a cure/improved rate of 82% and those arbitrarily categorised as having severe incontinence had a cure/improved rate of 67% [
9]. These similar cure rates, which lie within the previously reported range for all degrees of incontinence, support our intention of not using the degree of incontinence as an eligibility criterion. Results from a further recent case series suggest that the outcome of implantation of AUS is not compromised by previous insertion of a male sling [
10]. As it is likely that some men in our trial, randomised to sling, may require subsequent repeat surgery, it is reassuring that their ultimate outcome is unlikely to be worse than those randomised to AUS.
We have analysed long-term follow-up data from men approached for the Men After Prostate Surgery (MAPS) trial and found that around 70% of men still reported some urine leakage 4 to 6 years after a radical prostatectomy (N = 579), and 39% after a transurethral resection of prostate (TURP) (N = 1413) (unpublished data). Of this cohort, 25% and 5% of men respectively were using pads, and 8% and 2% had leakage several times a day of a moderate or large amount of urine. A further 15 men had already had an AUS operation (of whom one required a second AUS operation), and six a male sling (of whom one required re-intervention by implantation of an AUS). In addition to these, a further 5% and 3% of men were considering surgery for incontinence.
Evidence explaining why this research is needed now
The most recent Cochrane review showed that the efficacy of conservative treatment with PFMT was still unclear [
11] and the addition of other evidence [
1,
2] did not change this conclusion. As a result, a large proportion of men (around 8% after radical prostatectomy and 2% after TURP) are left with disabling incontinence which ruins their quality of life and many have no option but to continue with containment measures (27% and 6%, respectively) (unpublished data from 4-6 year follow up of MAPS responders). Surgery is, therefore, currently the only option for active management of the problem. As such, the proposed trial will provide unique robust evidence, for patients, clinicians and healthcare policy-makers, on which to base treatment and healthcare provision decisions.
The number of men undergoing radical prostatectomy for localised prostate cancer is increasing (from 2500 in 2008, to 3200 in 2010 to 5600 in 2011). This trend may continue, as localised prostate cancer case-finding using PSA testing increases, potentially leading to more men subsequently requiring surgery for prostate-cancer-treatment-related urinary incontinence. As an indication, if 50 more men required an AUS each year, this would cost the NHS an additional £450,000. While treatment with the male sling appears to be less expensive, the harms, further treatment and revision surgery needs to be taken into account to determine full comparative cost-effectiveness.
Currently, the male sling is being offered to men seeking treatment with the NHS on a haphazard basis according to surgeon enthusiasm and local arrangements. Both clinicians and patients lack the evidence required to make an informed choice between the two options and NHS policy-makers lack information on cost-effectiveness to plan service provision. The MASTER trial will fulfil the research need identified by the recent Cochrane Review [
7] for adequately powered comparative RCTs of the surgical options for these men. The proposed trial will determine whether men can be confidently informed about whether implantation of the male sling gives equivalent effectiveness for cure of incontinence to the standard AUS. This will allow men and their clinicians to make an informed decision regarding the individual suitability of either option, taking into account other factors such as the relative need for subsequent re-intervention, the need to operate a control pump, and speedier recovery. As part of the trial design, we will take into account the different clinical characteristics of the men, such as type of prostate surgery, and identify factors which may influence comparative effectiveness, such as degree of incontinence. Affected men, clinicians and the NHS should benefit from the reliable evidence from the trial, to guide the choice of treatment and healthcare provision decisions, in terms of effectiveness, cost-effectiveness and adverse effects.
At present the design and function of the AUS appears optimal, as, despite attempts to improve on the existing device there are no signs of significant innovations that would have to be considered prior or during this trial. Sling technology, however, is less mature and we anticipate that during the trial recruitment period, there may be a choice of implants from different manufacturers. For that reason we will not specify which brand of sling should be used. However, it should be of the sub-urethral trans-obturator type, as currently, almost all implanted slings are of this type, and the available outcome data are chiefly for this type of sling. We feel that this research is timely since a robust examination of the comparative effectiveness of this new surgical option should provide high-quality evidence to determine whether or not it should be adopted widely in the NHS.
For a urologist to join the MASTER study, they must be uncertain regarding the best operative technique for correcting the man’s incontinence, and hence be willing to randomise the majority of patients. All the urologists must be able to perform one or both of the two operations, and be willing to randomise between them. Urologists must consider themselves competent (beyond the learning curve) and in equipoise regarding their relative merits. If surgeons only perform one procedure, they will be teamed with a surgeon who can perform the other.
The questions which this study will address
The aim of the trial is to determine whether the male sling is non-inferior to implantation of the AUS for men who have UI after prostate surgery (for cancer or benign disease), judged primarily on clinical effectiveness but also considering relative harms and cost-effectiveness. In order to determine whether the male sling or AUS is cost-effective for the NHS in the UK, the interventions will be compared in terms of: incontinence in men after prostate surgery; the relative harms of the interventions; costs to the patients, and to the NHS, including the need for repeat surgery in both groups; and overall patient satisfaction.
Principal objectives
1.
What is the clinical effectiveness of implantation of the male sling compared with AUS in terms of self-reported incontinence at 12 months?
2.
What is the cost-effectiveness of a policy of primary implantation of the male sling compared with AUS, measured by incremental cost per quality-adjusted life-year (QALY) at 24 months?
In the long term there is a need to capture the consequences of both devices. We consider the primary outcome of the trial to be a non-inferiority comparison on rate of incontinence at 12 months. Our reason for this approach is that if the male sling is inferior (by at least the agreed margin) in the short term, then male slings will highly likely not be introduced throughout the NHS, irrespective of longer-term costs and consequences. However, if the difference in effectiveness is within the non-inferiority margin, the cost-effectiveness analysis, using outcomes over 24 months, will be required to decide on the relative worth of the interventions to the NHS.
Secondary objectives
3.
What are the harms of each type of surgery?
4.
What are the costs of the benefits and harms of each treatment policy?
5.
What subsequent NHS services (including repeat surgery) are needed for men with persistent or recurrent problems?
6.
What are the differential effects of the operations on other outcomes such as quality of life and general health?
7.
How satisfied are the participants with each procedure?
In addition, a qualitative component has been embedded within the trial to establish patient-perceived importance of different outcomes, explore patients’ and surgeons’ perspectives on experiences of procedures and acceptable inferiority margins, and determine reasons for failure resulting in crossover to alternative surgery.