Patients and study design

This single group feasibility pilot study was approved by the Comitato Etico dell’Area Vasta Emilia Nord (23 June 2020, Number 520/2020/SPER/IRCCSRE). This study protocol adheres to the recommendation for clinical trials (Standard Protocol Items: Recommendations for Interventional Trials) guidelines (online supplemental file 1), and the study registration data set is shown in table 1.28 Eligible patients are adult men (≥18 years) with a histological diagnosis of prostate cancer who are currently treated with ADT and RT and are able to communicate in the Italian language. Participants with musculoskeletal, cardiovascular, psychiatric or neurological disorders that contraindicate exercise will be excluded. All patients referred to RT which are also candidate to receive ADT will be assessed for eligibility. If confirmed, written informed consent will be obtained from all participants, who will be invited to participate in a 20-week structured, supervised and unsupervised, multicomponent physical exercise programme. Patients will be assessed at baseline (T0), at the end of the intervention (T1) and at follow-up, which will occur 12 months from recruitment (T2).

So, the experimental physical exercise intervention will start concomitantly with RT, which lasts about 2 months. As regard to ADT, its duration can vary from 6 to 36 months, and it can begin up to 3 months before patient’s enrolment in this study and RT commencement.

Recruitment strategies

Between September 2020 and September 2021, eligible patients treated by the Radiotherapy Unit of Santa Maria Nuova Hospital of Reggio Emilia (Italy) will be given brief, written information about the study by their attending physician (radiotherapist or oncologist). On written consent, patients willing to receive more information will be referred to the Physical Medicine and Rehabilitation Unit and will receive a phone call by a research staff member (physiotherapist), who describes the study aim and modalities to them in detail. Patients who confirm their interest in participating will receive written information and consent forms to participate in the study to be filled out and signed. They will also make the first appointment to provide written consent and to perform the baseline assessment. The patient recruitment process is shown in figure 1, and the example of the patient consent form is provided in online supplemental file 2.

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Figure 1

Schematic study flow diagram. PMRU, Physical Medicine and Rehabilitation Unit.

Baseline assessment

In the baseline assessment, demographic, anthropometric, clinical data and physical function data will be collected. Clinical data include the date of diagnosis, tumour stage, time since receiving ADT and RT, and the presence of comorbidities assessed through the Charlson Comorbidity Index.29 Physical function will be measured using a 6 min walk test (6MWT)30 to calculate the intensity of aerobic exercise.

Experimental physical exercise intervention

The multicomponent experimental physical exercise intervention will last 20 weeks and consists of supervised and unsupervised exercise sessions held three times per week. Following a step-down approach, during the first 8 weeks, all physical exercise sessions will be supervised by a physiotherapist, while during the following 4 weeks, only 1 weekly session will be supervised, whereas the other two will be unsupervised; finally, during the last 8 weeks of experimental physical exercise, all sessions will be unsupervised. Supervised sessions will be conducted in small groups or individually at the Municipal Athletics Field in Reggio Emilia according to scheduled appointments, whereas the unsupervised sessions can be completed by participants in times, modalities and places of their convenience, providing for them the possibility to access the Municipal Athletics Field.

The multicomponent physical exercise intervention meets the dictates for exercise components, posology (frequency, sets, repetitions, intensity) and progression recommended for healthy adults.31 Its components are aerobic, resistance, core muscle stabilisation and neuromotor exercises associated with cognitive tasks. In addition, exercise intervention will include impact-loading exercise to provide an effective bone osteogenic stimulus. This type of exercise has been considered an effective strategy to prevent loss of bone mineral density in elderly patients32 33 and has been applied in patients with prostate cancer receiving ADT in previous studies.14 Altogether, the components of this intervention should preserve muscle strength and improve fatigue, balance, and cognitive function,32 and eventually, it should prevent accidental falls and fractures.

The intervention is tailored to individual general health, functional capacity and, as far as possible, preferences.

Supervised physical exercise sessions

Supervised sessions last 1 hour and 15 min and include a period of warm up and cool-down and a combination of the following physical exercise components:

• Aerobic exercise consists of 20–30 min of aerobic activity at moderate-high intensity, from 60% to 80% of maximum heart rate (% HRmax), previously determined through the 6MWT,30 which is conducted according to the current guidelines.34 To obtain the greatest effects on bone health, the proposed aerobic exercise activities are walking or jogging, depending on individual capacity and habitual or previous experiences of physical activity. The perceived effort will be monitored by the Borg’s Rate of Perceived Exertion (RPE) scale to maintain it between fairly light to hard, which corresponds to RPE scores 11–15.35 To ensure that participants reach the target HR, we will use HR monitors.

• Progressive resistance exercise consists of strength activity of the major lower and upper extremity muscle groups, using body weight as a load and free weights (resistance bands, dumbbells, anklets with weight, medicine ball). During each session, the goal is to perform four to eight exercises targeting different muscle groups by performing two to four sets of 8–15 repetitions for each exercise. The perceived effort will be measured by the individual using the Borg RPE scale36 (score between 11 and 15). The progression of intensity will be provided, starting the exercises with body weight and gradually increasing the load using free weights.37 Adjustments to load will be made when participants can complete the highest number of specified repetitions (≥15 repetitions, see also table 2). Thus, the number of exercises, dose progression (sets, repetitions) and related difficulties (eg, squat depth and/or duration, double task exercises) will be changed during the weeks based on the patient’s compliance and performance (see also table 2). For isometric exercises, dose will be incrementally increased by adding free weights, further limb exercise or asking for double task exercise, and/or increasing the duration of exercise from 20 to 60 s.

• Core muscle stabilisation exercise consists of postural and trunk stability exercises (eg, strengthening of transverse abdominis and pelvic floor muscles). Participants will perform two core exercises per session in two-four sets of 8–15 repetitions. Sets, repetitions, additional free weights, additional upper body and/or lower body movements and time of exercise from 20 to 60 s will be used to increase the intensity of exercises.

• Neuromotor exercise consists of balance and functional (coordination) exercises associated with cognitive tasks (eg, counting, adding, subtracting, saying day of weeks) and includes fit ball exercises (eg, knee and contralateral upper limb extension sitting on fit ball), standing balance activities (eg, stand on one leg) and dynamic functional tasks (eg, stop walking balanced on one foot, walking backward). Participants will be asked to complete two to four static and dynamic exercises per session. Static exercises are performed in two-four sets of 20–60 s, while dynamic exercises are performed in two-four sets of 8–15 repetitions. To provide progression, exercises are modified by introducing difficulties (eg, closing eyes, reducing base of support, introducing unstable support, adding free weights, or adding a second cognitive or manual task).

• Impact-loading exercise consists of jumping, leaping, jumping rope, hopping on one leg, going up and down steps, etc, in other words, exercises that provide impact with the ground using the body weight as a load. Two to four exercises per session will be performed. Training intensity is increased by adding repetitions, additional free weights, introducing multidirectional movement, and raising the exercise speed. To provide a large number of stimuli, several tools will be used.

Also, for core muscle stabilisation, neuromotor and impact-loading exercises, adjustments to load will be made when participants can complete the highest number of repetitions (≥15 repetitions) at the target exertion (RPE score between 11 and 15).

A detailed description of exercises, posology, tools and progressivity is available in table 2. Altogether, progressive resistance, core muscle stabilisation, neuromotor and impact-loading exercises are performed for 30–40 min each session.

Unsupervised physical exercise sessions

Unsupervised sessions also consist in all exercise components. In addition to walking or jogging, aerobic exercise can also be performed using bikes, stationary bikes or other aerobic activities based on individual availability and preferences. Regarding the progressive resistance, core muscle stabilisation, neuromotor and impact-loading exercise components, exercises that trade on body weight or with resistance bands that will be provided to patients are taught and suggested to overcome the possible unavailability of appropriate tools. Each activity and exercise will be explained to participants and practised by them during the supervised sessions. Furthermore, written educational material with instructions and pictures of the exercises will be provided to maximise accuracy of the unsupervised execution. The physiotherapist provides individualised indications regarding the activities to be performed during unsupervised sessions but also supports participants in progressively increasing the exercise workload when the individual perceives an improvement in their functional capacity.

Outcome measures

Muscle strength

The strength of the major lower and upper extremity muscle groups will be measured with the 10-RM test (extensor muscle group). The 10-RM test assesses the maximum weight that can be lifted for 10 repetitions while maintaining the correct technique. Prior to attempting this test, participants will complete 5 min of aerobic warm-up and 1–2 sets of 15–20 repetitions with a light load. Then, the load will be progressively increased while the number of repetitions will decrease accordingly until only ten repetitions can be completed. A recovery period of 2 min will be provided between each set.39 40

Fatigue

Fatigue will be measured using the Fatigue Severity Scale, a 9-item questionnaire on how fatigue interferes with activities and that rates its severity. The item is scored on a 7-point Likert scale with 1=strongly disagree and 7=strongly agree. The minimum score=9, and the maximum score=63. A higher score indicates greater fatigue severity.41

Cognitive function

Cognitive function will be measured using the Mini Mental State Examination (MMSE), a brief cognitive test designed to assess the overall cognitive status of patients. The MMSE tests five areas of mental status (orientation; registration; attention and calculation; recall; language) and is scored on a scale of 30, with adequate cognition for most adults indicated by scores from 24 to 30.42

Balance

Balance will be measured using the Tinetti Performance Oriented Mobility Assessment (POMA). The Tinetti POMA scale is a clinical test used to measure balance and gait abilities. The balance section (POMA-B) consists of 9 items, while the gait section (POMA-G) consists of 8 items. Each item can receive an ordinal score from 0 to 2, where ‘0’ indicates the highest level of impairment and ‘2’ indicates individual independence. The maximum possible total score for POMA-T is 28, for POMA-B is 16, and for POMA-G is 12. A POMA-T cut-off score <19 indicates a high risk of falling.43 44

Quality of life

Quality of life will be measured using the Short Form-12 questionnaire, which consists of twelve items measuring different physical and mental health parameters. Higher scores indicate better physical and mental health.45

Anxiety and depression level

Anxiety and depression level will be measured using the Hospital Anxiety and Depression Scale (HADS), a 14-item scale equally distributed across anxiety and depression states. The total score ranges from 0 to 21, with higher scores indicating greater levels of mood disturbances. In patients with cancer, a cut-off score of >9 for the HADS-A and >7 for the HADS-D indicates clinically relevant anxiety and depression levels, respectively.46

Accidental falls and fractures

During the intervention, accidental falls and fractures were recorded directly by the physiotherapist who supervised the sessions and performed the weekly phone call and thereafter at the 12month follow-up.

Participant satisfaction

Patient satisfaction will be assessed through a simple structured interview. At the end of the intervention, each participant will be invited to answer the following four open-ended questions that investigate its acceptability:

• How do you assess the overall experience you have had by participating in this study?

• Which activities did you like the most?

• Which activities did you like least?

• What can be improved in your opinion, or what would you have liked to have been offered?

A summary of the outcome measures and their assessments at follow-up is shown in table 3.

Sample size calculation

No formal sample size requirement is needed for this single-group, pilot, feasibility study. At the Santa Maria Nuova Hospital of Reggio Emilia, nearly 30 patients/year undergo ADT and RT, and we aim to recruit 25 patients during the 12-month recruitment period.

Data analysis

All statistical analyses will be performed by the local Clinical Trials and Statistics Unit of the AUSL-IRCCS of Reggio Emilia. The SAS System or R software will be used according to their availability at the time of data analyses. Descriptive statistics will be reported for feasibility and safety outcomes. For each percentage, the exact two-sided CI will be calculated according to the Clopper-Pearson approach, ensuring a confidence level of at least 95%. In fact, since it is an exact technique, the confidence level typically does not coincide with 95%, the discrepancy for small samples being more noticeable. Adverse events will be described and grouped into homogeneous classes. The data regarding patient satisfaction will be analysed to identify patterns of response and grouped into categories emerging from the data.

Descriptive statistics for secondary outcomes will be reported to inform potential future studies in terms of clinical health outcome measures. For all variables, percentiles, minimum, maximum, mean and SD will be calculated. For the mean, a 95% two-sided CI will be calculated assuming a t distribution. The changing over time of the secondary outcomes will be studied by the analysis of variance for repeated measures.

Concerning the number of accidental falls and fractures, as counts, the CI for the mean will be calculated according to the Poisson distribution. No missing data imputation techniques have been planned, therefore only the available data will be analysed. However, missing data will be appropriately described in their distributional aspects of relevance.

Data management and archiving

The dataset will be stored on a password-protected computer and managed by the Information and Technologies Service (STIT) of the Azienda USL-IRCCS of Reggio Emilia to protect patient privacy and data.

Patient and public involvement

Patients will participate in the study design so that the time and spaces necessary for the home-based intervention can be adapted according to their availability and discretion. Participants may suggest changes related to the frequency and intensity of the sessions and inform the study team about which type of exercises they prefer.

Ethics and dissemination

This study was approved by the Area Vasta Nord Local Ethics Committee of Azienda USL-IRCCS of Reggio Emilia (23 June 2020, Number 520/2020/SPER/IRCCSRE), which will also review potential modifications, if any. All patients will provide consent prior to participation. Results will be disseminated through scientific peer-reviewed journals and conference presentations. The expected impact for this study is the development of a useful and acceptable physical exercise programme integrated into the daily routine of patients with prostate cancer receiving ADT and RT.

These results will inform which type of physical exercise is required to improve adherence to the recommended exercise guidelines for cancer survivors and will help researchers plan feasible physical exercise interventions whose efficacy on bone health is to be verified through well-designed RCTs.