Randomised controlled trial of exercise to prevent shoulder problems in women undergoing breast cancer treatment: study protocol for the prevention of shoulder problems trial (UK PROSPER)

Musculoskeletal shoulder problems are common after breast cancer treatment. Early postoperative exercises targeting the upper limb may improve shoulder function. This protocol describes a National Institute for Health Research-funded randomised controlled trial (RCT) to evaluate the clinical and cost-effectiveness of an early supervised structured exercise programme compared with usual care, for women at high risk of developing shoulder problems after breast cancer surgery. Methods This pragmatic two-armed, multicentre RCT is underway within secondary care in the UK. PRevention Of Shoulder ProblEms tRial (PROSPER) aims to recruit 350 women from approximately 15 UK centres with follow-up at 6 weeks, 6 and 12 months after randomisation. Recruitment processes and intervention development were optimised through qualitative research during a 6-month internal pilot phase. Participants are randomised to the PROSPER intervention or best practice usual care only. The PROSPER intervention is delivered by physiotherapists and incorporates three main components: shoulder-specific exercises targeting range of movement and strength; general physical activity and behavioural strategies to encourage adherence and support exercise behaviour. The primary outcome is upper arm function assessed using the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire at 12 months postrandomisation. Secondary outcomes include DASH subscales, acute and chronic pain, complications, health-related quality of life and healthcare resource use. We will interview a subsample of 20 participants to explore their experiences of the trial interventions. Discussion The PROSPER study is the first multicentre UK clinical trial to investigate the clinical and cost-effectiveness of supported exercise in the prevention of shoulder problems in high-risk women undergoing breast cancer surgery. The findings will inform future clinical practice and provide valuable insight into the role of physiotherapy-supported exercise in breast cancer rehabilitation. Protocol version Version 2.1; dated 11 January 2017 Trial registration number ISRCTN35358984; Pre-results.


GENERAL COMMENTS
-The focus is on musculoskeletal shoulder problems, to which extent do you take into account neurological problems, e.g. sensory disturbances and neuropathic pain, and lymphoedema in the treatment protocol? -Can you specify what you changed in the protocol based on the pilot study? This may be interesting for other researchers and clinicians to take into account when they deliver an intervention.
-In the introduction you elaborate on the studies investigating exercise following breast cancer. Is this the only treatment modality of the intervention? Can you elaborate as well on the evidence for the other modalities?
-Rationale for the trial: can you include in this section with which intervention you will compare the 'structured physiotherapy intervention'?
-I believe the fact that you test the effectiveness of a 'structured' intervention compared to a 'free' program is important. You may emphasize this in the aims of the methods.
-Aim: if I understood well. Aim 1 en 2 are actually for the preparation of the trial. Can you make this more clear? Can you also specifiy of the pilot study has already finished?
-Can you explain more why pts with immediate reconstruction or bilateral sugery are exclude? What is different in the routine postop physiotherapy program for these patients? Wouldn't they benefit from your PROSPER exercise program as well since they are also at high risk?
-Why do you include so many stratification factors? You have a considerable large sample size so randomization should do its work and equally balance the groups? -Control arm: can you clarify if all pts in the control arm will receive the same (2?) brochures?
-Is it possible to provide more detailed information on the content, intensity, duration, frequency of the prosper exercise programme? On what is the progression based? In understand this is done pragmatically but can you specify bit more?
-To which extent do you take into account physiotherapy delivered by other physical therapists or other treatments for their shoulder problems?
-Can you elaborate more on the reliability and validity of the questionnaires? Are they all validated or are they self-developed? Will they be validated? The PASE is for eldery? What with younger participants?
- Figure 1: I would suggest to put the outcomes in a second table. Now it is confusing and not clear when assessments are performed, eg. Are all outcomes assessed at baseline (=enrolment), is this before or after surgery?
- Table 2: are women with SLNB and mastectomy not at high risk?
- Figure 2: can you specify what happens before and after surgery and the duration of the inteventions?
Note: I am not familiar with economic evaluations so I did not review this part.

GENERAL COMMENTS
This protocol is well written and organized. However, three issues should be considered. 1. Shoulder conditions, pain history, and shoulder functions (flexibility and strength) should be measured in screening process. Pre-existing shoulder pain and dysfunctions may affect outcome measures.

2.
Shoulder exercise comprises ROM exercise, strength exercise, and general physical activity. Exercises should be described in detail for readers. Assessment methods for measuring ROM and strength should be described, ex. Measurement tools et al. And ROM and strength data would be useful information for supporting result of study.

3.
Exercise will be performed at home. How authors can monitor compliance of exercise.

REVIEWER
Irene de la Rosa Diaz Alcala University, Spain.

GENERAL COMMENTS
Functional impairment following breast cancer treatment is an important target for physiotherapists nowadays, so I find the paper interesting and pragmatic.
Relating to methods, sample homogeneity is needed to avoid confusing factors, thus contralateral breast cancer or relapses should be excluded. Blinding techniques should be clarified. The PROSPER approach should be well-detailed as an exerciseperformance explanation is needed to enable study repetition. Likewise, number and duration of the physiotherapy sessions should be mentioned. About sample size calculation, pitot data is for calculating the sample size of the clinical trial. However, authors used data from other study instead. That issue should be justified. Concerning to outcomes, the assessment method of secondary variables and the instruments used should be detailed. In addition, the election of DASH questionnaire has to be justified since there are other more specific questionnaires to assess shoulder functions (i.e. SPADI or OSS). Relating to discussion section, it should be more explained and conclusions have to be added. Dr. Irene de la Rosa Diaz.

VERSION 1 -AUTHOR RESPONSE
Reviewer 1 1. The focus is on musculoskeletal shoulder problems, to which extent do you take into account neurological problems, e.g. sensory disturbances and neuropathic pain, and lymphoedema in the treatment protocol?
Response: Women randomised to the treatment arm are reviewed by the PROSPER physiotherapist during each face to face appointment and are assessed for signs of lymphoedema and painful symptoms. The PROSPER treatment protocol includes recommended pathways to follow based upon clinical findings e.g. consider referral to lymphoedema nurse if painful arm swelling or heaviness; refer to GP if pain intensity scores greater than 7/10 on visual analogue scale. We have limited the description of the exercise intervention in the trial protocol paper as we have written a separate detailed paper describing intervention development and content. No changes have been made to the manuscript.

2.
Can you specify what you changed in the protocol based on the pilot study? This may be interesting for other researchers and clinicians to take into account when they deliver an intervention.
Response: These were mostly minor changes to the wording on trial-related and patient-facing documents after feedback from qualitative interviews with newly-diagnosed breast cancer patients and breast cancer survivors. Overall, patients and recruitment staff were positive about the proposed study. We have edited the paragraph 'Internal Pilot Study' (page 11) by adding "Changes were made to patient-facing materials and to exercise intervention materials. Easy to use pocket-sized laminated cards with details of the PROSPER trial inclusion/exclusion criteria and shoulder screening criteria were produced for recruitment staff. Additional telephone or face-to-face appointments were added to the exercise intervention to allow for flexibility during ongoing cancer treatment". 3. In the introduction you elaborate on the studies investigating exercise following breast cancer. Is this the only treatment modality of the intervention? Can you elaborate as well on the evidence for the other modalities?
Response: This is a good point and we have elaborated on this in the trial intervention paper which is currently under review with BMC Health Services Research. In the intervention manuscript, we describe the evidence-base for behavioural strategies, including NICE guidance for behavioural changethus, how best to promote adherence to self-management interventions. The PROSPER intervention also implemented strategies from the NHS Health Trainer Manual, developed by behaviour change experts. We have not elaborated on this within the trial protocol paper which focuses on the rationale for the trial, aims, methods and study design issues etc.
4. Rationale for the trial: can you include in this section with which intervention you will compare the 'structured physiotherapy intervention'?
Response: Thank you for highlighting this. 'Compared to usual care' has been added to the first sentence under the 'Rationale for a trial' section, on page 6.
5. I believe the fact that you test the effectiveness of a 'structured' intervention compared to a 'free' program is important. You may emphasize this in the aims of the methods.
Response: The term 'structured' has been added to the Abstract (line 4) and under the second aim, within the Methods section on page 6.
6. Aim: if I understood well. Aim 1 and 2 are actually for the preparation of the trial. Can you make this more clear? Can you also specify of the pilot study has already finished?
Response: This is correct, the first two aims were to develop an exercise intervention and to establish whether the trial was acceptable to patients and feasible to deliver. The third aim was then to undertake a definitive RCT to examine the clinical and cost-effectiveness of an early supervised exercise programme compared to usual care for women at high risk of shoulder problems after treatment for breast cancer. These aims are published on the NIHR HTA website as the study was funded on this basis. Rather than restrict our description to the main trial only, we have been explicit and transparent by referring to all aims in this protocol paper. The pilot study was completed as planned; this has been clarified within the paragraph on page 11 -'Internal pilot study'. The sentence 'The pilot study was completed as planned, and the funder approved progression to full trial' has been added.
7. Can you explain more why patients with immediate reconstruction or bilateral surgery are exclude? What is different in the routine postop physiotherapy program for these patients? Wouldn't they benefit from your PROSPER exercise program as well since they are also at high risk?
Response: We very much agree that women undergoing reconstruction and/or bilateral breast surgery are at high risk of developing shoulder problems and could potentially benefit from an exercise programme. However it would be challenging to develop a 'one-size fits all' structured exercise intervention for non-reconstructive surgery and the many different reconstructive surgery procedures, which include implants or autologous tissue flaps, including abdominal (e.g. DIEM, SIEA TRAM), buttock and thigh flaps (e.g. GAP, TUG, PAP) and/or back muscle flaps (LAT). These would each require careful consideration of movement restrictions in the acute postoperative period.
Reconstructive breast surgery is classed as major surgery whereby patients are hospitalised for 7-10 days postoperatively; more drains are left in situ and these women are at greater risk of postoperative complications, including wound infection. These are a different clinical group to those admitted as day cases for mastectomy/WLE. The current UK model is for non-reconstructive breast surgery is discharge within a day, as per the 23hour Ambulatory Surgery model of care. The PROSPER intervention was designed specifically for these patients. It would be overly complex to design and test two or more exercise interventions for different clinical groups within the same trial framework. We do believe there is potential for a separate trial investigating the effectiveness of postoperative exercise for women undergoing reconstructive breast surgery.
Re. bilateral non-reconstructive surgery, this was a pragmatic decision. It is challenging to design data collection tools to capture outcomes from women having surgery on both breasts and both axilla. Our data collection tools were designed to record painful symptoms, swelling, functional problems etc. on the operated side only. This was based on our experience of previous studies investigating recovery after breast cancer surgery.
8. Why do you include so many stratification factors? You have a considerable large sample size so randomization should do its work and equally balance the groups?
Response: It is usual practice to stratify by site to account for potential variation in clinical care. We stratified by timing of entry to the study as a small proportion of women are eligible for the trial postoperatively, if referred for radiotherapy to the axilla. This decision is made after pathology reports are obtained. Also a small number of women will undergo repeat surgery, thus readmission for excision of surgical margins. Stratification was undertaken to ensure there was equal distribution across treatment arms for these treatment subgroups.
9. Control arm: can you clarify if all pts in the control arm will receive the same (2?) brochures?
Response: Yes, all participants receive the two information leaflets from Breast Cancer Care. This has been clarified on page 9 by adding 'All participants' in line 1 and 'These two information leaflets were given to all patients….' on line 8 of that paragraph.
10. Is it possible to provide more detailed information on the content, intensity, duration, frequency of the prosper exercise programme? On what is the progression based? In understand this is done pragmatically but can you specify bit more?
Response: Apologies to give the same response as before, but we have restricted the description of the exercise intervention in this protocol paper to the essential facts. We acknowledge that the reviewer is an experienced physiotherapy researcher and is understandably looking for more detailed information about frequency, duration, intensity, progression etc. We can certainly provide more information within this manuscript however seek guidance from the Editorial team on this matter. We have a separate intervention publication as per recommended guidance from the EQUATOR/CONSORT networkthe intervention paper adheres to the Template for Intervention Description and Replication (TiDIER) framework.
11. To which extent do you take into account physiotherapy delivered by other physical therapists or other treatments for their shoulder problems?
Response: We ask all trial participants to report any attendance with any other healthcare professionalthese data will also be used for health economic analysis. Participants complete questionnaires at six weeks, six months and 12 months, and report any contacts with GPs, physiotherapists and any other healthcare professionals. As the trial is pragmatic, we do not restrict contact and any patient can attend a non-PROSPER physical therapist at any time.
12. Can you elaborate more on the reliability and validity of the questionnaires? Are they all validated or are they self-developed? Will they be validated? The PASE is for elderly? What with younger participants?
Response: All of the questionnaires have been validated. We carefully considered a number of questionnaires to assess shoulder function. There is reasonable evidence of validity and reliability for the DASH scale. A review summarised the psychometric properties of nine commonly used instruments designed to measure symptoms and function of the shoulder (Angst et al, 2011). In summary, the DASH questionnaire was reported to be the most widely used and thoroughly tested instrument. This scale captures symptoms and function of the upper limb rather than the shoulder joint per se. This is important because there is good evidence to show that women experience problems with the upper limb after breast cancer treatment, not just the shoulder joint. Although surgery and radiotherapy target the breast and axilla area, treatment side effects can impact upon the hand, arm and shoulder e.g. potential trauma to the nervous and lymphatic systems, leading to arm swelling, problems with grip strength etc.
Re the other measures, we have experience of capturing pain outcomes after breast cancer treatment. The DN4 Neuropathic pain scale has been used in numerous population-based and surgical cohort studies, including breast cancer surgery. It is short, easy to complete and has reasonable correlation with objective tests of nerve dysfunction (hyperalgesia etc).
Re inclusion of items from the Physical Activity Scale for the Elderly (PASE). One component of the exercise intervention is to encourage physical activity throughout the recovery period. Again, we considered a number of different physical activity measuresmany of these questionnaires were too detailed and lengthy. We wanted a brief indicator of walking and physical activity to compare change from recruitment to follow-up. The PASE was originally developed for use in epidemiological surveys with people aged 65 years and older. Given that the mean age of our PROSPER pilot sample was 61 years, and that our PPI group felt that the PASE questions were easy and straightforward to answer, we opted to use items from this questionnaire.
13. Figure 1: I would suggest to put the outcomes in a second table. Now it is confusing and not clear when assessments are performed, eg. Are all outcomes assessed at baseline (=enrolment), is this before or after surgery?
Response: We used the template figure for trial protocol papers as per SPIRIT 2013. However we agree with the reviewer that this is not a very user-friendly figure! We have modified it from the recommended templateit has been split into Figure 1 and Table 3. This should be clearer for readers.
14. Table 2: are women with SLNB and mastectomy not at high risk?
Response: No, women having more extensive axillary surgery are at greater risk of shoulder problems than those having sentinel lymph node biopsy. Type of breast surgery is not a major independent factor for adverse postoperative outcomes of shoulder dysfunction or chronic postoperative pain. There is recent evidence demonstrating that other factors, including axillary clearance, are associated with onset and persistent of chronic pain e.g Meretoja et al (2017, J Clin Oncol).
15. Figure 2: can you specify what happens before and after surgery and the duration of the interventions?
Response: Patients are recruited and randomised before surgery. The first treatment appointment is booked for 7 to 10 days postoperatively, as described on page 9. The second appointment is booked for between four to six weeks postoperatively (page 10, line 4). The third appointment is recommended for between 12 and 16 weeks postoperatively (page 10, line 7). The pathway differs slightly for women with postoperative entry to the trial, but the exercise programme should commence