Randomised Controlled Trial To Investigate The Effectiveness of The Self-Management After Radiotherapy (SMaRT) Intervention To Ameliorate Lower Urinary Tract Symptoms in Men Treated for Prostate Cancer


 Purpose

To evaluate the effectiveness of the self-management after radiotherapy (SMaRT) intervention to improve urinary symptoms in men with prostate cancer.
Methods

The randomised controlled trial (RCT) recruited men from one radiotherapy centre in the UK after curative radiotherapy or brachytherapy and moderate urinary symptoms defined as the International Prostate Symptom Score (IPSS) ≥ 8. 63 men were randomised either to SMaRT, a 10-week self-management intervention including group support, education, pelvic floor muscle exercises, or care-as-usual. The primary outcome was the IPSS at 6 months. Secondary outcomes were IPSS at 3 months, and International Continence Society Male Short Form (ICS), European Organisation for Research and Treatment of Cancer Quality of Life prostate scale (EORTC QLQ-PR25), EORTC QLQ-30 and Self-Efficacy for Symptom Control Inventory (SESCI) at 3 and 6 months. Analysis of covariance (ANCOVA) was used to analyse the effect of the intervention.
Results

SMaRT did not improve urinary symptoms as measured by IPSS at 6 months. The adjusted difference was − 2.5 [95%CI -5.0 to 0.0], p = 0.054. Significant differences were detected at 3 months in ICS voiding symptoms (-1.1 [-2.0 to -0.2], p = 0.017), ICS urinary incontinence (-1.0 [-1.8 to -0.1], p = 0.029) and SESCI managing symptoms domain (13.5 [2.5 to 24.4], p = 0.017). No differences were observed at 6 months.
Conclusions

SMaRT provided short-term benefit in urinary voiding and continence, and helped men manage symptoms but was not effective long-term. Face-to-face and supervised approaches may provide more benefit.


Introduction
Prostate cancer (PCa) is one of the most commonly diagnosed cancers in men and accounts for 26% of all new UK male cancer cases (1). It is estimated that 1.3 million men worldwide are diagnosed per year (2) and with earlier detection and better treatments more men are living with and beyond a PCa diagnosis (3). Although quantity of life has improved, quality of life may be reduced compared to those without cancer because of side effects after treatment (4). Improving symptom management post prostate cancer treatment is therefore a priority for research and clinical practice (5).
Quality-of-life in men living with and beyond PCa can be impacted by long-term side-effects post treatment, with prevalence of erectile dysfunction (87%,) urinary symptoms (20%) and bowel disturbance (14%) occurring up to 12 years after PCa treatment (6). Two years after initial PCa treatment distress in relation to urinary problems was experienced by 7% of men after radical prostatectomy and 11-16% of men after radiotherapy (6). In a USA study of Medicare claims the adjusted risk of grade 2-4 (moderate to severe) urinary symptoms after radiotherapy for PCa was OR 2.49 (95% CI: 2 to 3.11) times that of men without treatment at 10 years (7). Additionally a recent UK population study exploring self-reported symptoms and quality of life in 13,097 men 18-42 months post PCa diagnosis, found 13.5% of men reported moderate to severe bother with urinary symptoms and those with urinary bother were more likely to have poorer mental health OR 2.89 (2.54 to 3.27) and severe psychological distress OR 3.69 (3.12-4.38) (8). Whilst interventions are available for acute symptoms, long term urinary symptoms after PCa are often poorly addressed reducing men's ability to socialise and impacting men's daily activities (9).
Regardless of the type of radiotherapy (external beam radiotherapy or brachytherapy) the close proximity of the genitourinary tract to the prostate means urinary symptoms are relatively common during and shortly after radiotherapy (10). Acute urinary symptoms are often transient, long term symptoms can continue for 3-6 months, and late side-effects can be newly occurring up to 2 years after external beam radiotherapy (11). Adverse effects are more severe in those who are older, have poorer physical function and greater urinary symptoms at baseline (12)(13)(14). External beam radiation (EBRT) utilises high-energy photon beams and is shaped and conformed to the pro le of the prostate gland such as conformal radiotherapy (CFRT) or delivered through intensity-modulated radiotherapy (IMRT) minimising surrounding normal tissue damage (15), however lower doses of radiation can cover a wider eld across the pelvis impacting on additional pelvic structures.
Radiation alters bladder contractility through the effect of ionisation on the mucosal-detrusor communication, which impacts on stability of the bladder and voiding symptoms (16). Urothelial cells are very radiosensitive and pelvic radiotherapy has both direct as well as bystander affects that result in in ammation, vascular damage and brosis (17) causing urinary frequency, bleeding and urinary obstruction (18). Pelvic oor muscle structures are also affected by radiation with changes in muscle activity and contractility that all impact on urinary function (19). There is a paucity of studies on conservative intervention approaches for radiation induced urinary symptoms (10). Dieperink et al (20) tested the e cacy of a nurse-physiotherapist intervention, including pelvic oor muscle exercises (PFME), for men during and after external beam radiotherapy. Men in the intervention compared to men in the care-as-usual, showed signi cant improvements in urinary and hormonal symptoms at 20 weeks post intervention and improved men's physical quality-of-life. However, one-to-one intervention can be time consuming, require more clinical resources than group interventions and not provide opportunity for peer support that can be found in self-management programs. Self-management support ensures people develop the con dence and skills they need to look after their ongoing physical and mental health (21). Systematic reviews of the effectiveness of cancer self-management support for cancer survivors have consistently led researchers to call for focused, disease-speci c and patient targeted programmes (22)(23)(24). Previous to the study reported here, our feasibility work found that an augmented self-management intervention including coaching, bladder retraining and PFME instruction delivered at 3-6 months post radiotherapy treatment for PCa, was feasible within the clinical setting (25). We hypothesised that in comparison with care-asusual, at six months post intervention men who took part in the SMaRT intervention would report signi cantly less urinary symptoms, have better symptom-related quality-of-life, less emotional distress and improved con dence to deal with PCa and its associated problems.

Materials And Methods
This study was a two-armed, parallel-group randomised controlled trial. Participants were from one radiotherapy unit, serving four hospitals within NHS England, UK. They had received external beam radiotherapy (EBRT) with neo-adjuvant or adjuvant androgen deprivation therapy (ADT) or low dose-rate brachytherapy (BT).

Setting and participants
Men starting EBRT were asked to participate in the trial during on-treatment physician review. BT patients were invited by letter from their clinical nurse specialist (CNS) after treatment. All participant consent forms were returned by post. To allow for recovery of acute symptoms after treatment, men were screened for urinary symptoms at 3 months after EBRT with the International Prostate Symptom Score (IPSS) questionnaire and 6 months after BT. Men with IPSS scores ≥ 8 (moderate to severe symptoms) i.e., 70 of the 137 men, were entered into the trial and after baseline assessment they were randomised to receive either the SMaRT intervention plus care-as-usual, or only care-as-usual. Care-as-usual was de ned as hospital appointments for surveillance and symptom management with the clinical oncologist and/or telephone support with the CNS. Eligibility criteria are summarised in Table 1. Men were strati ed for type of radiotherapy treatment (EBRT vs BT) and randomisation was provided by a registered clinical trials unit. To ensure balance in group sizes, participants were randomly allocated to control or intervention in blocks of 12. Information about treatment, medication, TNM staging, and comorbidity was obtained from the medical records. Table 1 SMaRT study eligibility criteria Inclusion Patients who had: • Locally con ned prostate cancer disease (up to stage T3BNO) • Received neoadjuvant hormonal therapy (to control for standardised practice as recommended in the EAU Guidelines).
• Completed external beam radiotherapy three to four months prior to the intended commencement of the intervention.
• Or LDR brachytherapy six months prior to the intended commencement of the intervention.
• Moderate to severe urinary symptoms de ned as a score of ≥ 8 on the International Prostate Symptom Score (IPSS).
• Su cient understanding of written and spoken English.

Exclusion
Patients who had: • A urinary tract infection.
• A current psychiatric referral.
• A current referral for memory issues/ever been referred to a memory clinic/taking prescribed medication to help with memory.
• Required an interpreter.

Intervention
The SMaRT intervention was based on the framework that to be effective, self-management must address three core tasks namely, medical management (taking medications and treatment exercises), role management (adapting lifestyle or life roles) and emotional management (26). Having the con dence or belief to perform a given course of action is also a key mechanism whereby self-management can lead to changes in health behaviours and outcomes (26). To re ect this, our intervention also aimed to promote participant modelling, a key requirement for enhancing self-e cacy (27). A theory-based, 15-minute motivational lm was produced by the research team and shown in the rst group session to promote group dialogue and peer support (28).
The programme was delivered by an experienced nurse trained in teaching PFME and self-management techniques. PFME were taught both standing, sitting and laying down with 30 minutes of muscle strength training which included muscle endurance and strength with 10 repetitions for each muscle group for both.
Discussions were conducted on bladder retraining techniques, uid management, medication as well as the impact of symptoms on their wellbeing. Modules ran over 10 weeks and comprised four small group sessions (with 5/6 participants), one individual session with the CNS, and two telephone sessions with the CNS (Table 2.) This was followed by four months of at-home self-management. The group sessions were provided within a community leisure facility; face-to-face individual sessions were conducted at a clinical centre. Information booklets were provided in all the group sessions and set homework was discussed at the following group session. Outcome measures were completed at three time points: two weeks prior to the intervention at randomisation (baseline), 3 months and 6 months. Table 2 Self-Management after Radiation Therapy (SMaRT) intervention and assessment time points

minutes
Group session Introduction to the programme.
Short motivational peer support lm Exploration of experiences and emotional impact of prostate cancer Demonstration and group practice of PFME

Information provision
Promotion of daily home exercise (homework) Week 2:

minutes
Individual face-toface session One-to-one discussion Individual problem assessment and goal setting

Review of 7-day bladder diary
Guidance and information around other pelvic late effects (bowel and sexual issues)

Addressing personal and relationship issues
Physical assessment and personal training for PFME  (25).
SESCI questionnaire measures three dimensions: i) con dence to perform daily activities; ii) con dence to cope with urinary symptoms; and iii) con dence to manage (change) urinary symptoms. Cronbach's alpha for total scale 0.97 Cronbach's alpha for each subscale 0.94 (32).

Sample size calculations and statistical methods
Based on our feasibility study data, a two-sided signi cance level of 5%, and 85% power, a sample size of 21 evaluable participants per arm was considered su cient to detect a mean difference of change in IPSS score of 4 points between intervention and control, considered clinically signi cant. The calculation assumed a standard deviation for change from baseline in IPSS scores of 4.2. To account for possible attrition (withdrawal/loss-tofollow-up) of up to 30%, randomisation was planned to include a minimum of 60 participants.
The primary statistical analysis was undertaken using regression methods (analysis of variance, ANCOVA) to estimate the difference in IPSS scores between groups (intervention vs control) at six months from randomisation together with a two-sided 95% con dence interval, adjusting for baseline IPSS scores and type of radiotherapy which was included as covariate. Where 95% con dence intervals (CIs) do not span zero, the results would be regarded as signi cant.
For secondary outcomes, the differences between the two groups (intervention vs control) were analysed using regression estimates and 95% CIs obtained through the ANCOVA approach outlined above at both the three and six-months follow-up points.
The analysis was performed as a complete case analysis. To retain the validity of the randomisation, analyses were undertaken according to the intention-to-treat principle and included all consented and randomised patients for whom outcomes were available.

Baseline characteristics
Demographic, disease and treatment characteristics and screened IPSS scores for the SMaRT and care-as-usual groups at baseline are given in Table 3. The SMaRT group participants were slightly younger than the care-asusual group, socioeconomic status was high in both groups. Baseline median age score for the sample was 71 Page 9/22 (IQR 67 to 76). One or more comorbidities was common with more than 33.  Box plots (Fig. 2) illustrate a decrease in IPSS scores for both groups from T1 to T2 and T3; there was a trend for reduction in IPSS with SMaRT at both T2 and T3 time points, but it was not signi cant which may be partly due to the small sample size. However, there was a large overlap in observed values between the groups. We found no signi cant differences in our primary outcome between the SMaRT and care-as-usual groups in scores on the IPSS at 3 or 6 months even when adjusted for pre-intervention IPSS baseline scores and adjustment of radiotherapy type (Table 4).   Table 4). ICS incontinence symptoms did not differ signi cantly at 6 months. There were no observed differences in quality-of-life (EORTC QLQ-C30) or urinary domain scores (EORTC QLQ-PR25) between groups.
Self-E cacy for managing symptoms measured by the SESCI improved by 11.0 points (95% CI: 3.2 to 18.9) in the SMaRT group and decreased by -5.9 points (-14.7 to 2.9) in the care-as-usual group, a signi cant adjusted difference of 13.9 points (2.5 to 24.4) favouring the SMaRT group (p = 0.017) ( Table 4). Self-e cacy for managing symptoms did not differ signi cantly between the groups at 6 months. We noted no signi cant differences between the care-as-usual and SMaRT groups in self-e cacy for performing daily activities or selfe cacy for coping with symptoms at either 3 months or 6 months.

Discussion
We found that self-management after radiotherapy intervention (SMaRT) had no signi cant difference on IPSS outcomes in men who had received radiotherapy for PCa, compared to care-as-usual, at 3 and 6 months, but did provide signi cant differences in domain speci c urinary symptoms on ICS voiding and incontinence at 3 months. Our intervention improved urinary symptoms in ICS voiding by -1.9 and when adjusted for baseline scores a change of -1.1 and urinary incontinence by -0.9. As secondary outcomes we observed signi cant bene t in reported self-e cacy for men in managing symptoms at 3 months with a 13.5 (2.5 to 24.4) adjusted point difference in the SMaRT group compared to -5.9 (-14.7 to 2.9) care-as-usual. The intervention effect was not able to be sustained beyond 3 months as seen in the follow up scores where there was little difference between groups.
Contrary to our ndings, Dieperink et al.(20) in their study of multidisciplinary rehabilitation, found a 5.8 point (Cohen's d = 0.40; p0.011) difference in urinary sum scores for irritative symptoms between those receiving the intervention and care-as-usual recorded at 6 months post radiotherapy. In this study the usual care group had 1 physician visit face to face 4 weeks after radiotherapy whereas our care-as-usual group saw the physician at 6 months and had ongoing contact with a CNS. Despite this difference the change in urinary scores were not at the same level as that found by Dieperink (20) or in our feasibility study (25). The distinct difference between these studies is the intervention intensity, SMaRT was primarily group based and may not have provided the individualised approach provided by Dieperink (20) in the face-to-face multidisciplinary rehabilitation setting.
This dosing effect is important in PFME as variation in delivery such as the muscle targeted intensity of the programme and the position in which pelvic oor muscle contraction is taught, are in uential factors and contribute to variation in intervention outcomes (33). There is a need to focus more on the mechanistic science underpinning interventions for managing pelvic radiotherapy late effects. Damage to pelvic oor vasculature and brosis all contribute to lower urinary tract symptoms (18). One retrospective study of men with PCa who underwent MRI before and after EBRT or BT showed signi cant reductions in urethral length, increased signal intensity of the obturator internus muscle and peri-urethral part of the levator ani, suggestive of brotic changes (16). Diepernick et al. (34) in a follow-on study found that that pelvic oor muscle strength of men in their intervention study diminished over the 3 years post intervention but that men still had better LUTS than men in their control group.
In cancer populations, the evidence for self-management and lifestyle interventions is growing (24, 35) but is not consistent and negative trends in psychological distress for instance, have also been reported in some systematic reviews (23). Furthermore, whilst a recent systematic review (36) has classi ed the important components of benign LUTS self-management, the active components or behavioural interventions that contribute to these are far from clear. Skolarus et al. (37) reported a RCT of a self-management programme for long-term prostate cancer survivors and found no signi cant differences between intervention and control groups. However, like our study coping appraisal was higher (2.8 vs 2.6 p = 0.02) in men who had received the intervention. This highlights the problems with heterogeneity of the needs of men, speci city of intervention and how best to measure the clinical signi cance of any bene ts of self-management i.e., is it the symptoms that are the primary aim or the self-e cacy? In our study, men had a high level of self-e cacy across domains from the start of the study but clearly the participant modelling and information helped them manage symptoms and feel more con dent post treatment.

Strengths and limitations
A strength of SMaRT was we targeted men with long-term symptoms 3-6 months from completion of treatment, compared to other self-management intervention studies that occur during treatment. Differences we found may re ect a more di cult population that as urinary symptoms continue after radiotherapy, they can become more intractable (18). Men who have brachytherapy are much more likely to have issues with voiding due to swelling and in ammation which are probably less affected by PFME, however, this was adjusted for in the analysis. A limitation of our study is that we did not use, surface anal electromyography (EMG) to assess men's pelvic oor, or provide ongoing data on pelvic oor changes, or participant diaries to record adherence to PFME. Given EMG assessment is invasive in a group setting, it may have been useful to use it in the one-to-one session with the CNS to assess the effectiveness of the individuals' exercises. Studies of PFME in men with PCa have focused mainly on the surgical setting and have shown that pelvic oor muscle exercises pre-and post-treatment can improve symptom outcomes (38) and this evidence is re ected in NICE UK (39) prostate cancer guidelines.
Studies show that men who continue to have LUTS after radiotherapy have signi cant reductions in quality-oflife (40). In a systematic review of 13 studies, post radiotherapy pelvic oor muscle changes were found to occur between 2 and 26 months after radiation, showing the wide range of individual response in men with PCa (19).
Some of this variance may be due to prior LUTS (14), however, we adjusted for this as part of our analysis.

Conclusions
The study showed that the SMaRT intervention helped men feel more con dent in managing symptoms and created small changes in LUTS but was not clinically signi cant or sustained. Evidence for conservative interventions that augment self-management post pelvic radiotherapy are limited, therefore this RCT provides important evidence that contributes to improving treatment pathways for those living with and beyond prostate cancer. The growing number of men now surviving and requiring long-term symptom management for consequences of PCa has contributed to the growth in supported self-management programs to address longterm survivorship care (41-43) but the outcomes of these studies are varied partly because self-management requires targeted interventions to improve not only self-e cacy but personalised management strategies to improve symptoms. Although the intervention was not effective, some of the elements show promise and that a more targeted one-to-one approach is needed to address the more complex LUTS as a result of radiotherapy.

Declarations
Data availability: The data can be requested by contact the corresponding author. The access will be granted subject to a reasonable request and data sharing agreement.  Figure 1