Exercise to prevent shoulder problems after breast cancer surgery: the PROSPER RCT

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 13/84/10. The contractual start date was in March 2015. The draft report began editorial review in March 2020 and was accepted for publication in June 2021. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Copyright statement

Copyright © 2022 Bruce et al. This work was produced by Bruce et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.

2022 Bruce et al.

Background

Breast cancer is the most common cancer in women in the UK, with over 55,000 new cases diagnosed each year. 1 Breast cancer incidence has increased by 20% since the early 1990s. 1 Despite increasing incidence, survival rates have improved dramatically as a result of advances in early diagnosis and treatment. 1 Breast cancer survival has doubled in the UK over the last 40 years; now, nearly 8 in 10 women (78%) treated for invasive breast cancer survive for ≥ 10 years. 1 Treatments are complex and can be toxic, causing side effects that persist in the long term. There is increased recognition of the benefits of providing supportive care for people living with and beyond cancer treatment. 2

Surgical treatment of breast cancer

Surgery is the mainstay of treatment for breast cancer, supplemented with chemotherapy, radiotherapy and biotherapy, with or without reconstruction surgery. 3 Treatment decisions are based on clinical criteria, tumour stage, lymphatic spread and patient preference. Surgery to the breast consists of either mastectomy or breast-conserving surgery (BCS), with newer oncoplastic conserving procedures increasingly being used. 4 Breast-conserving procedures, such as lumpectomy or wide local excision, combined with whole-breast radiotherapy, aim to achieve disease control with minimal morbidity. These breast-conserving treatments have been demonstrated to be as effective as mastectomy in increasing long-term overall survival in patients with early breast cancer. 5,6 Conservative surgery followed by radiation therapy allows for the preservation of the breast, which can improve patient quality of life (QoL) and satisfaction with treatment. 7 Sentinel lymph node biopsy (SLNB) has largely replaced axillary lymph node dissection (ALND) for disease staging, and also reduced the need for extensive axillary node clearance (ANC). There is good evidence that 10-year survival among women receiving SLNB only is equivalent to that among women receiving ANC after SLNB. 8,9

Treatment-related side effects

Although largely curative, breast cancer treatments have negative sequelae. Surgery and radiotherapy can affect the upper body, especially the shoulder joint and upper limb, causing restricted shoulder range of movement (ROM), impaired strength and functional limitations. Arm morbidity has been strongly associated with the extent of axillary node surgery. Although arm lymphoedema can affect up to 20% of women, systematic reviews report higher rates of lymphoedema after ALND than after SLNB up to 2 years after surgery [20%, 95% confidence interval (CI) 14% to 28%, n = 18 studies, n = 3599 participants, vs. 6%, 95% CI 4% to 9%, n = 18 studies, n = 3583 participants]. 10,11

A systematic review11 of upper limb problems after surgery and radiotherapy (32 observational studies) reported prevalence estimates for restricted shoulder ROM (up to 67%), arm weakness (< 28%) and shoulder/arm pain (< 68%). Prevalence estimates vary widely, in part because of differences in definitions, methods of measurement and timing of postoperative follow-up. Other common postoperative complications include wound infection, seroma and axillary web syndrome (cording) and chronic pain. 11,12

A nationwide Danish study13 of 2500 women undergoing breast cancer surgery found that over one-third of women reported persistent pain and half reported sensory disturbances up to 7 years after treatment. Persistent upper limb dysfunction and pain are debilitating, affecting sleep quality, QoL and physical and emotional function. These enduring adverse sequelae of cancer treatment are burdensome and associated with increased health-care utilisation.

Risk factors for persistent post-treatment complications

Research has examined patient- and treatment-related risk factors associated with upper body problems after breast cancer treatment. 11,14,15 Women undergoing mastectomy have higher odds of postoperative shoulder restriction than those undergoing BCS [odds ratio (OR) 5.67, 95% CI 1.03 to 31.2]. 11 More invasive axillary surgery is associated with greater impairments of abduction ROM and strength than SLNB, up to 7 years post treatment. 16 Radiotherapy to the axilla or chest wall, compared with no radiotherapy, slightly increases the odds of shoulder ROM restriction (pooled OR 1.67, 95% CI 0.98 to 2.86) and lymphoedema (pooled OR 1.46, 95% CI 1.16 to 1.84). 11 A higher body mass index (BMI) was found to be an independent risk factor for shoulder external rotation problems up to 7 years after treatment. 16 Higher BMI (overweight or obese) is also a known risk factor for lymphoedema10 and for development of chronic post-surgical pain (six studies, pooled OR 1.34, 95% CI 1.08 to 1.67). 17

Evidence for the effect of exercise on shoulder dysfunction

A Cochrane systematic review,12 published in 2010 [24 randomised controlled trials (RCTs), 2132 participants], reported that exercise and/or physiotherapy may help to prevent shoulder and arm morbidity after breast cancer treatment. This review12 found that physiotherapy, compared with usual care or control, improved shoulder flexion only within the first 2 weeks and at 3 and 6 months postoperatively. The timing of starting postoperative physiotherapy may also be important for shoulder ROM and upper limb function. Early exercise, started on the first postoperative day, was beneficial in improving flexion and abduction at 1 week postoperatively, and flexion at 4–6 weeks postoperatively, when compared with delayed exercise (exercise that started after the fourth postoperative day). 12

A more recent systematic review,14 published in 2015 (18 RCTs, 2389 participants), compared different exercise modalities (multifactorial therapy, passive mobilisations, stretching and exercise therapy) and the timing of application. 14 The overall findings were similar, suggesting that early exercise improved upper arm ROM in the short and long term after breast cancer treatment. However, exercising in the first postoperative week also increased the risk of greater wound drainage volume and seroma formation. 14 Regarding physiotherapy modalities, adding stretching to an exercise programme may improve postoperative ROM. 14

Although these reviews suggest that physiotherapy may prevent postoperative shoulder problems, the majority of trials conducted to date are small, methodologically weak and with short-term follow-up. Many trials investigated exercise delay prescription until after completion of adjuvant therapy. 12 Few fully report details of prescribed regimes; hence there is a lack of knowledge regarding the optimum content, frequency, intensity, timing or safety of exercise prescription. Another limitation is the exclusion of patients with existing shoulder problems, the very population who may benefit the most from targeted postoperative support. 18

Rationale for the PRevention Of Shoulder ProblEms tRial

We designed the PRevention Of Shoulder ProblEms tRial (PROSPER) to address the evidence gap and to investigate whether or not an early supervised exercise programme, compared with usual care, could prevent musculoskeletal shoulder conditions in patients undergoing treatment for breast cancer. This research was commissioned in 2013–14 by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme, with specifications to design an exercise intervention for women identified as being at higher risk of developing shoulder problems as a consequence of their breast cancer treatment. At the time of funding, the UK National Institute for Health and Care Excellence (NICE) recommended that all breast cancer patients should be provided with instructions on functional exercises to start doing from the first postoperative day. Each breast cancer centre should have written local guidelines for postoperative physiotherapy, but NICE recommended that patients be referred to physiotherapy services only if they experienced persistent shoulder restrictions after cancer treatment. 3

Literature update

We reviewed literature to identify new trials investigating exercise after breast cancer surgery published since the commissioned call in 2014. We sought RCTs comparing exercise and/or physiotherapy with standard or usual care (i.e. no active intervention), regardless of the type of outcome. Our search strategies were adapted from previous systematic reviews12,14 and applied to MEDLINE (via Ovid), EMBASE (via Ovid), PEDro (Physiotherapy Evidence Database) and LILACS (Latin American and Caribbean Health Sciences Literature). We also searched for trials registered on the World Health Organization (WHO) search portal, the European Union clinical trials register and www.clinicaltrials.gov (US National Library of Medicine). We searched for citations published from 1 January 2014 to 10 December 2019. Of 439 potentially eligible studies identified, after screening titles and abstracts, 12 trials were included, eight of which were published trials and four of which were registered as ongoing. One trial reported ROM and grip strength data across two separate publications. 19,20

Recent evidence: physiotherapy compared with usual care

Of eight published trials, four were pilot RCTs and all studies were single centred with small sample sizes (mean 79 participants), although one trial recruited 153 participants. 21 Type of exercise varied and included aquatic-based,22 aerobic23 and resisted exercises. 19–21,24–26 Interventions were delivered either in the clinic setting19–23,25,26 or using an online interface. 24 Exercise programmes varied widely in terms of duration and frequency, ranging from 3 to 9 months (Table 1). 23,26 Outcomes also varied, but the most commonly reported were health-related quality of life (HRQoL), function and lymphoedema. Five studies reported improvements favouring the intervention group for the majority of outcomes (n = 427 participants). Three studies reported no differences between groups for function19 (n = 59 participants), lymphoedema22 (n = 29 participants) or limb volume25 (n = 35 participants).

Forthcoming studies: registered trials

At the time of writing, we found four registered trials, all overdue for reporting, from Spain (n = 90 participants27 and n = 84 participants28), Brazil (n = 38 participants29) and the USA (n = 568 participants30) (Table 2). These trials have different primary outcomes and postoperative follow-up points: ROM at 1 month,28 pain and fatigue after 7 weeks of exercise sessions,29 functional capacity at 12 months27 and presence of lymphoedema at 18 months. 30 The American lymphoedema trial30 has provided interim data on the clinicaltrials.gov website suggesting early benefit on lymphoedema outcomes; final results are pending. We present an overview of findings regarding the content and safety of exercise interventions in Chapter 3, which describes the development of the PROSPER exercise intervention.

Aims and objectives of PROSPER

The overall aim of PROSPER was to investigate whether or not an early supervised exercise programme compared with best practice usual care was clinically effective and cost-effective for women at high risk of shoulder problems after breast cancer treatment on outcomes of upper limb function, complications and QoL.

The study objectives were to:

• develop and refine a complex intervention of physiotherapy-led exercises, incorporating behavioural strategies, for women at risk of developing musculoskeletal problems after breast cancer treatment

• assess the acceptability of the structured exercise programme and outcome measures, to optimise participant recruitment and refine trial processes during a 6-month internal pilot phase

• use findings from the internal pilot phase to undertake a definitive, full RCT in approximately 15 UK NHS breast cancer centres.

A health economic analysis and a qualitative substudy were embedded within the trial. Qualitative research was undertaken throughout to inform intervention development and gain insight into the experiences of both women and physiotherapists taking part in trial interventions.

Overview of report

The report is structured across seven subsequent chapters. We present the methods and describe intervention development and trial results, followed by separate chapters reporting the qualitative findings and the health economic evaluation. Finally, we present an overarching discussion and conclusion.

Trial design and setting

This trial was a two-arm, pragmatic RCT with an internal pilot study, an embedded qualitative evaluation and a parallel economic analysis. A detailed description of the trial protocol has been published. 31 The trial was undertaken in secondary care settings, in breast cancer centres within NHS trusts across England.

Participants

Participant recruitment and consent

Patients were identified from multidisciplinary cancer team meetings and preoperative oncology and radiotherapy clinics. Screening was undertaken by a member of the clinical team (a specialist breast nurse, surgeon, research nurse or facilitator trained in PROSPER screening and recruitment procedures). Eligible patients were given a patient information sheet while attending an oncology clinic and were given at least 24 hours to consider participation. In the case of those interested and willing to participate, written informed consent was obtained by the delegated site investigator after discussion and clarification of any queries. We sought consent for multiple levels of access to medical data, including medical records and routine data held by NHS Digital. At the time of trial launch, the wording of consent forms was appropriate for access to Hospital Episode Statistics (HES) data and approved by the Ethics Committee and relevant monitoring committees.

Trial setting and prespecified requirements

The trial was undertaken in secondary care settings in England, in NHS trusts with specialist breast oncology services. Any centre could take part as long as hospital physiotherapy services had the capacity to treat participants for the trial duration. We specified that a minimum of two physiotherapists per site attend intervention training. Any hospital providing routine preoperative or postoperative physiotherapy for non-reconstructive breast surgery could not take part. We also screened usual-care practices at hospitals expressing an interest in taking part. A specification was the agreement of centres to provide PROSPER usual-care leaflets for all trial participants.

Allocation sequence generation and randomisation

The unit of randomisation was the individual participant. Three stratification variables were used: the centre, whether it was the participant’s first or repeat surgery and whether or not the participant had been informed of the need for radiotherapy within 6 weeks of surgery. These stratification variables accounted for late-entry participants and for those having multiple surgical procedures, which can increase the risk of postoperative complications. We used a computer-generated randomisation algorithm held and controlled centrally within the Warwick Clinical Trials Unit (WCTU) by an independent programmer. Trial participants were registered after screening checks, then randomised to treatment. Treatment allocation was coded and unavailable to the trial management team.

Blinding

We adhered to the Consolidating Standards of Reporting Clinical Trials (CONSORT) statement. 32 Owing to the nature of the exercise intervention, it was not possible to blind participants or physiotherapists delivering the intervention. Data entry staff were unaware of treatment allocation, and we undertook data cleaning blind to treatment allocation. Senior members of the research team and the statistical team were blind to treatment allocation for the duration of the trial. Final statistical analysis was undertaken by a statistician independent of the core trial team.

Trial interventions

Full details of trial interventions are described in Chapter 3. In summary, all participants received best-practice usual care consisting of two information leaflets describing postoperative exercises and advice for recovery after surgery. 33,34 The control group participants received no further intervention other than usual clinical care. Participants randomised to the exercise intervention were then referred to physiotherapy. We designed a new exercise programme that was underpinned with evidence and co-developed with cancer rehabilitation specialists and breast cancer survivors. The newly developed intervention was a physiotherapist-led, individualised, structured exercise programme comprising shoulder-specific exercises, behavioural change strategies and physical activity. 35 Three face-to-face appointments with a trained physiotherapist were scheduled at specific postoperative time points, with up to three optional appointments at any time up to 12 months after randomisation. An overview of the PROSPER intervention is detailed in Figure 1.

FIGURE 1.

Overview of trial interventions.

Co-interventions

No restrictions were placed with regard to referral to other health-care providers or private physiotherapy during the trial. At trial closure, participants continued with their usual health care.

Data collection

Outcomes

Secondary outcomes

Data collection

Follow-up data were collected at 6 weeks, 6 months and 12 months postoperatively. We used postal questionnaires for all patient-reported outcomes with an explanatory cover letter. Questionnaire booklets were professionally printed, in colour, with a freephone number on the front page and a free-text section on the final page. Draft versions were modified after pilot testing and feedback from women treated for breast cancer. Core outcome data were collected by telephone if no response was received after one postal reminder. Clinical data on all surgeries and adjuvant treatment delivered over the study duration were gathered from medical records after completion of the 12-month follow-up.

Process evaluation

We measured a range of process evaluation indicators relating to intervention uptake and delivery. Data included time from randomisation to first appointment, participant uptake of the exercise intervention, number of contacts with physiotherapists and number of quality control (QC) assessments. We defined adherence to or compliance with the prescribed exercise programme as a participant having three or more contacts with the physiotherapist. Those having one or two contacts only were defined as partial compliers. We calculated ‘strength and work capacity’ for ROM and strength exercises, defined as the product of repetitions and sets prescribed at each appointment. The terminology ‘work capacity’ is used throughout to denote ‘strength and work capacity exercises’. For strength exercises, this was calculated using the product of resistance for Therabands [Paterson Medical, Cascade Healthcare Solutions, Tukwila, WA, USA (1.1 kg, 1.7 kg or 2.7 kg)] by repetitions and sets prescribed from the second appointment onwards. Theraband length was standardised, although physiotherapists spent time with each participant to demonstrate how to use the band correctly to ensure that the band length was suitable and to check their technique. If necessary, the bands could be shortened by adjusting the grip.

Monitoring of intervention delivery

Physiotherapists completed treatment logs to record information on attendance, exercise prescription, shoulder ROM, muscle strength, lymphoedema, wound healing, pain intensity and confidence in exercising for every participant. Completed treatment logs were returned to the co-ordinating centre after participants were discharged from physiotherapy. Chapter 3 describes quality assessment procedures for intervention fidelity.

Data management

Questionnaires were entered manually by the research team into a bespoke database, designed by the WCTU programming team. All data were checked for range, outliers, data missingness and date discrepancies. Any identified anomaly was checked against original data sources for rectification.

Data analyses

Introduction

This chapter presents a description of the PROSPER usual-care and exercise interventions. We developed an exercise intervention for the trial following Medical Research Council guidance for the design of complex interventions. 58 We present an overview of the evidence to inform the selection of core components and we describe the final intervention as per the Template for Intervention Development and Replication (TIDieR)59 recommendations and the Consensus on Exercise Reporting Template (CERT). 60

Control group: information leaflets

Participants allocated to the control group received best-practice usual care. At the time of trial set-up, usual NHS care was to provide newly diagnosed breast cancer patients with information leaflets describing cancer treatments and advice for postoperative recovery. 61 Specialist breast cancer nurses or oncology teams gave leaflets preoperatively. Patients undergoing non-reconstructive surgery were not routinely referred to physiotherapy services unless for a specific postoperative musculoskeletal problem. In 2005, a review61 of patient materials from 105 UK oncology departments across England was undertaken to identify usual clinical practice for postoperative shoulder mobilisation after breast cancer surgery. This survey61 found that half of the responding centres used materials published by Breast Cancer Care (now Breast Cancer Care/Breast Cancer Now; London, UK). We undertook a scoping survey of information leaflets used in breast cancer units across England and evaluated materials published by breast cancer charities. The content and design of hospital leaflets varied widely, although many were adapted or photocopied from charity materials. Most recommended restricted arm movement in the first postoperative week. We reviewed all materials, in collaboration with patient representatives and clinical rehabilitation experts, to select leaflets for best-practice usual care. We selected two well-designed, colourful leaflets produced by the charity Breast Cancer Care: Exercises After Breast Cancer Surgery33 and Your Operation and Recovery. 34 These leaflets describe exercises to do after breast surgery, lymph node removal and/or radiotherapy. Recommendations were to start upper body exercises from the first postoperative day, with instructions for warm up, basic arm exercises restricted to 90° of shoulder elevation, and a cool-down (BCC633). More advanced exercises, such as wall climbing, arm lifts and elbow pushes, were recommended from the second postoperative week onwards. The surgical recovery leaflet (BCC15134) covered generic postoperative advice and common complications, including wound infection, pain, cording, seroma and lymphoedema. These leaflets were provided to the study team free of charge by Breast Cancer Care. All participants were given a copy of each leaflet on recruitment to the trial; these were given out by the surgical oncology teams.

Overview of exercise intervention development

We designed a new exercise programme specifically for testing within PROSPER. We followed multiple steps to develop and refine the intervention before testing in the main trial. The key stages of development included:

1. an exploratory phase incorporating a literature review to identify evidence of effectiveness and harm from exercise interventions and of behaviour change techniques, a survey of postoperative materials used in the NHS, a patient and public involvement (PPI) focus group with breast cancer survivors and consultation with cancer rehabilitation experts

2. production of a draft intervention protocol for agreement at an intervention development consensus day, hosted by the WCTU, attended by 20 clinical rehabilitation experts and two breast cancer survivors

3. assessment of feasibility and acceptability of the prototype exercise programme with women attending a community-based support group for breast cancer patients, testing the intervention with 15 newly diagnosed breast cancer participants recruited to the internal pilot study from three NHS trusts

4. final refinement of the exercise programme based on patient and therapist feedback during the internal pilot study.

The final PROSPER exercise intervention was a physiotherapist-led, early, progressive, home-based postoperative programme that incorporated three components: shoulder-specific exercises, physical activity and behavioural support strategies to encourage adherence. The PROSPER programme was designed to be adaptable and flexible to allow for prolonged cancer treatment schedules and cancer-related fatigue. The evidence and rationale for inclusion of core components are given below.

Overview of evidence for exercise after breast cancer surgery

We undertook a literature review to identify systematic reviews and clinical trials investigating the effectiveness and potential adverse effects from exercise interventions for breast cancer patients. We also reviewed national and international breast cancer clinical guidelines62–64 and the types of exercises reported to be prescribed within the UK survey of physiotherapy and oncology departments. 61 We considered the content, timing, duration and setting of delivery of exercises.

A Cochrane systematic review,12 published in 2010, investigated the effectiveness of exercise interventions in preventing, minimising or improving upper limb dysfunction due to breast cancer treatment (24 trials; 2132 participants). Exercise type was broadly classified as active, active-assisted, passive, manual stretching and resistance. The review compared interventions on outcomes of ROM, strength, lymphoedema and pain. Subgroup analyses compared the timing of exercise in relation to cancer treatment (10 trials; 1304 participants) and the effect of postoperative exercise to usual care (six trials; 354 participants). Authors defined early exercise as that commencing from days 1 to 3 postoperatively; in contrast ‘delayed’ exercise was defined as starting from day 4 onwards. This definition differed from that used in the UK survey,61 which defined delayed exercise as starting after 1 week. Only one of the 24 trials in the Cochrane review was considered at low risk of bias:65 the remainder were of low to moderate quality and with small sample sizes (mean 44 participants per treatment arm). Included trials were published between 1979 and 2008 and older trials examined rehabilitation after extensive breast surgery, such as modified radical mastectomy. These procedures have since been replaced with less invasive surgeries; therefore, some rehabilitation practices, such as wearing a sling, are no longer indicated.

We summarise findings from the literature review in relation to the core components considered for the PROSPER intervention. The Cochrane review12 informed intervention development, although the findings are now outdated as other trials of exercise interventions have been published or registered since publication of the Cochrane review in 2010. To date, however, only two trials have ever been undertaken in the UK NHS: a small trial examining wound drainage, conducted in 197966 (n = 69 radical mastectomy), and a single-centre trial67 examining lymphoedema after breast surgery with ALND (n = 116).

Evidence for early postoperative exercises

Axillary surgery and radiotherapy increase the risk of shoulder ROM restrictions, in particular flexion, abduction and abduction with external rotation. 14 Breast cancer treatments can damage the lymphatic system, causing secondary lymphoedema. Patients may benefit from ROM exercises as active and active-assisted ROM exercises can improve fluid drainage and lymphatic flow. These exercise modalities activate physiological mechanisms as a result of muscle contraction, and they can also increase blood flow to the joints and soft tissues. 14,68

The Cochrane review12 found some evidence that early ROM exercises were more beneficial than delayed exercise for shoulder flexion ROM in the short term, within 4–6 weeks postoperatively [mean difference (MD) 12.12°, 95% CI 0.35° to 23.88°; I² = 89%; three studies, 608 participants]. 12 However, there was no evidence of a difference up to 2 years after surgery (MD 3.00°, 95% CI –0.65° to 6.65°; one study, 181 participants). 12 Early exercise was beneficial for shoulder abduction ROM at 1 week (MD 11.65°, 95% CI 2.93° to 20.38°; I² = 85%, three studies, 677 participants), with meta-analysis suggesting some increased benefit at 6 months compared with delayed exercising (MD 4.31°, 95% CI 1.38° to 7.25°; I² = 0%; two studies, 549 participants). 12

Evidence for harm or adverse events after early postoperative exercise

Early ROM exercises, when compared with delayed exercises, did not increase the risk of seroma after surgery (OR 1.52, 95% CI 0.82 to 2.82; five studies), delay wound healing (OR 1.30, 95% CI 0.82 to 2.31; four studies), increase the number of wound aspirations (weighted mean difference 0.11, 95% CI –0.23 to 0.45; three studies), increase postoperative pain at 6 months (OR 1.87, 95% CI 0.70 to 4.96; one study) or increase lymphoedema incidence at 6 months (OR 1.24, 95% CI 0.45 to 3.41; three studies). 12 However, early ROM did increase volume of wound drainage (SMD 0.31, 95% CI 0.13 to 0.49; seven studies, 912 participants) and extended duration of wound drainage by 1 day (weighted mean difference 1.15; 95% CI 0.65 to 1.65; five studies, 725 participants) compared with delayed exercises. In a sensitivity analysis excluding older surgical trials published pre 1995, these findings did not change: early ROM increased the volume of postoperative wound drainage. 12

The single-centre UK trial,67 published since the Cochrane review,12 found that introducing ROM exercises limited to 90° shoulder elevation in the first week after ALND did not increase the risk of AEs compared with starting exercises after 1 week. 67 As programmes incorporating ROM exercises were known to be safe, we included shoulder ROM from the first week onwards while recommending restriction of shoulder ROM below 90° in the first postoperative week. Early restriction of shoulder ROM was also recommended in hospital information leaflets and cancer charity materials.

Evidence for stretching exercises

Surgery to the axilla and radiotherapy to the supraclavicular and infraclavicular nodes can lead to structural and functional problems as a result of tissue inflammation and damage. 69 Treatments can lead to tightening and contracture across the shoulder and chest area. 70 Studies report that the pectoralis muscles can atrophy after treatment. 71 Stretching exercises may contribute to remodelling injured connective tissues and may prevent negative physiological adaptations to the muscle spindles. 72,73 Stretching may prevent the shortening of muscle fibres. 74 Few trials provided details of the included exercises, but, in those that did, stretching of the pectoral muscles was most commonly reported. 65,75,76 Although study findings were largely inconclusive in terms of ROM improvement, there was no evidence to suggest that exercise regimes incorporating pectoral muscle stretching increased the risk of arm comorbidity. 65,75 Some studies found evidence of benefit when stretching was combined with other ROM exercises. 14,77 Another consideration was the arm position required for radiotherapy, which requires flexibility and adequate ROM of the shoulder joint. A minimum range of 90° of shoulder abduction and lateral rotation is required for radiotherapy targeting the lateral side of the breast and chest wall. 61 Owing to the pectoralis major insertion on the humerus, a shortened pectoralis will affect the ability to place the arm into the required position for radiotherapy. 78 Given that we aimed to recruit women already considered at risk of shoulder problems, the PROSPER exercise intervention included a daily ‘stretch and hold’ exercise for the pectoralis muscles.

Evidence for strengthening exercises

Patients undergoing cancer treatment are at an increased risk of loss of muscle mass and reduced muscle strength as a consequence of treatment-related pathophysiological changes. 79,80 Older age is also a risk factor for reduced muscle mass and strength. Muscle strength is greatest in our younger years, with maximum strength peaking at age 20–40 years. 81 Breast cancer is more common in women aged > 50 years, when 10% of muscle mass is already lost. The rate of muscle decline then accelerates,81 although this decline is thought to be, in part, due to decreasing levels of physical activity. Strengthening exercises can prevent the loss of muscle and bone mass. 82 The physiological stimulus from strengthening exercises can improve muscle mass and strength even during active treatment, as demonstrated in studies of cancer populations. 82 Targeted strength training can stimulate other changes, including improvements in insulin action, bone density and energy metabolism. 81 One systematic review found some evidence for improved HRQoL in adult cancer survivors participating in resistance training compared with usual care or alternative exercise regimes (SMD –0.17, 95% CI –0.34 to 0.00; I² = 0%; six studies, 548 participants). 83

Another systematic review84 investigated the impact of low- to moderate-intensity resistance training on outcomes of muscle function, body composition and fatigue in cancer survivors (nine trials, 752 participants). Seven of the nine trials included breast cancer patients. 84 A meta-analysis revealed that resistance training improved upper limb muscle strength up to 1 year after cancer treatment (weighted mean difference ≥ 6.9 kg, 95% CI 4.78 to 9.03 kg; I² = 79%; nine studies, 752 participants). 84 Improvements in lower limb strength and percentage body fat were also observed, but with weaker evidence of an improvement in cancer-related fatigue [weighted mean difference 1.86 Functional Assessment of Cancer Therapy – Fatigue, 95% CI –0.03 to 3.75; I² = 0%; four studies, 437 participants]. 84

One trial82 included in the systematic review84 directly compared strengthening exercises to a stretching only programme for breast cancer patients (n = 106). 82 Those randomised to do strengthening exercises three times per week for 1 year maintained their bone and muscle mass throughout cancer treatment, in contrast to those following the stretching-only protocol. 82 Given the evidence for the benefits of strengthening exercises, we included progressive and individually tailored strengthening exercises to the PROSPER intervention. We specified that strengthening exercises should start only after the first postoperative month, to allow time for wound and tissue healing.

Evidence for physical activity

The American Cancer Society recommends that cancer patients should complete at least 150 minutes of moderate activity and at least two sessions of strength training per week. 85 This is in line with Department of Health and Social Care recommendations for physical activity for adults. 86 The American College of Sports Medicine recently recommended that cancer survivors should undertake aerobic and resistance training for approximately 30 minutes, for three sessions per week. 87 Physical activity during and after cancer treatment is safe, and has been associated with improved survival, reduced cancer recurrence and improvement in cancer-related side effects, with some studies reporting beneficial effects on fatigue, anxiety and depression. 83,88,89 Despite these benefits, only a small proportion of people achieve the recommended activity levels. One systematic review90 found that up to 70% of cancer survivors did not achieve the recommended activity targets. Cancer survivors are twice as likely to be physically inactive as the general population. 91

A Cochrane review,92 published since we developed the PROSPER intervention, found moderate-quality evidence that exercise during adjuvant treatment for breast cancer improved physical fitness (SMD 0.42, 95% CI 0.25 to 0.59; 15 studies, 1310 participants) and slightly reduced fatigue (SMD –0.28, 95% CI –0.41 to –0.16; 19 studies, 1698 participants), although there was weaker evidence for physical activity improving cancer-specific QoL or depression. 92 Given international recommendations to increase physical activity and evidence for improved outcomes during cancer treatment, without incurring risk of AEs, we incorporated physical activity guidance as a core component within the PROSPER intervention. 85

Evidence for behavioural change strategies

Early engagement with our lay representatives highlighted the need for a supported self-management approach to rehabilitation. National guidelines93 recommended that behaviour change strategies should be incorporated into any self-management interventions to support adherence and to achieve long-term behaviour change. 93 Adherence to any exercise intervention is essential to achieve the expected positive outcomes. However, there are numerous barriers to adherence and engagement with exercise, particularly during cancer treatment, when symptom burden can be overwhelming. 94 Psychological factors play a key role, particularly fear of cancer recurrence and fear of being active during treatment. 94–96

We referred to the NHS Health Trainer Manual,93,97 which was developed by health psychology experts in behaviour change. This practical guide summarises evidence-based strategies to promote positive health-related behavioural change. We selected the most relevant techniques to meet the needs of our patient population, while also considering demands placed on physiotherapy teams working in NHS clinics. Our aim was to increase motivation to exercise and to encourage adherence to the PROSPER programme. We recommended and trained physiotherapists in the motivational interviewing mode of communication. Motivational interviewing uses techniques to encourage compliance and participation. It has been found to be an effective technique for facilitating change in other lifestyle behaviours leading to improved health outcomes, such as weight loss and increased physical activity, and also for addressing the psychosocial needs of cancer survivors. 98 We incorporated the motivational interviewing approach into the PROSPER programme, along with other evidence-based psychological techniques. These included working with participants to set short- and long-term goals, promoting confidence to exercise, developing strategies to solve problems and reduce barriers and encouraging motivation and sustaining exercise adherence.

Intervention refinement with clinicians and patients

We refined the draft intervention to produce a long menu of exercises after discussion with 20 cancer rehabilitation specialists, upper limb physiotherapists and patient representatives who attended our 1-day consensus event at the WCTU in March 2015. We refined the menu of exercises after the consensus meeting and applied a colour-coded classification framework to each movement direction (e.g. flexion, abduction, external rotation with abduction). We described each exercise using lay-friendly terminology: for example, one shoulder abduction and external rotation movement was named ‘the woodchopper’ exercise. We developed patient manuals using colour photographs with clear instructions for each exercise. Qualitative interviews were held with seven women who had been recently treated for breast cancer and recruited from the lead hospital site, University Hospitals Coventry and Warwickshire (UHCW) NHS Trust. The women were positive about draft trial materials, preferring photographs to cartoon diagrams commonly used in NHS materials; they also preferred the term ‘physiotherapy’ to ‘exercise’ on patient-facing materials.

We also attended a community-based breast cancer support group for feedback on the almost finalised version of trial intervention materials before testing in the pilot study. This support group was attended by women with a recent breast cancer diagnosis, but also by cancer survivors who had been treated years previously. Feedback on materials was again positive, and the only recommendation was that more information on lymphoedema should be included.

Pilot study

We tested pragmatic implementation of the intervention by testing the PROSPER intervention with the first 15 women with newly diagnosed primary breast cancer recruited from three hospital sites within the pilot study. The qualitative study (see Chapter 5), with feedback from participants and physiotherapists, informed refinement of trial-related procedures and paperwork. Minor edits were made to the wording of participant materials. We reviewed treatment pathways and algorithms for the management of postoperative complications including pain, cording, wound infection, lymphoedema and cancer-related fatigue.

Overview of exercise programme

The aim of the exercise intervention was to prevent shoulder problems, caused by breast cancer treatments, by improving shoulder function through a physiotherapist-led, early, progressive, home-based postoperative exercise programme. It used behavioural strategies to encourage exercise adherence and support participants to be more physically active (see Table 5). Although several of the upper body exercises were familiar to physiotherapists and used in clinical practice, the PROSPER exercise programme was packaged as a new intervention to be prescribed and delivered as a whole. The intervention was delivered by NHS physiotherapists with musculoskeletal expertise.

Exercise quality control assessments

All intervention sites were visited by one of the research physiotherapists (HR/BM) to undertake QC assessments. These visits were scheduled shortly after completion of training and after the physiotherapist had undertaken one or more assessments with participants referred to the intervention group. The aim of the QC assessment was to ensure that the intervention was delivered in a standardised manner, according to the trial protocol and training. At least one appointment, either the first or follow-up appointment, was observed. It was a requirement for all physiotherapists to demonstrate competency in the intervention. We used a standardised checklist during the visit to monitor exercise prescription, to ensure safe delivery of the programme and to check that the intervention was delivered according to the intervention manual. Checks were also made of all trial-related documentation, including prescription logs, treatment forms, withdrawal forms and electronic appointment spreadsheets. Each physiotherapist received a written graded report at the end of the assessment, graded as satisfactory, minor concerns or serious concerns. Follow-up visits were arranged if any concerns were identified. The chief investigator was notified if any serious concerns were identified. The research physiotherapists provided regular supervision and support to all physiotherapists over the duration of the trial.

Study timeline

The first trial participant was recruited in January 2016 and recruitment continued until July 2017. Postal follow-up completed in August 2018 and NHS Digital data were received in October 2019. We made no substantial changes to interventions from pilot to main trial other than minor adaptations to physiotherapy treatment logs.

Recruiting centres

We recruited participants from 17 breast cancer units across England, from Lancashire to Cornwall. These ranged from high-volume cancers centres within major teaching hospitals to smaller units serving more rural localities. All hospitals had access to physiotherapy services. Appendix 1 provides details of participating hospitals by NHS trust. The trial recruitment graph is displayed in Report Supplementary Material 1.

Participant flow

Screening

The CONSORT flow diagram (Figure 2) illustrates the overall flow of participants through the study from screening to the 12-month follow-up. A total of 951 breast cancer patients were screened. Of these, 761 out of 951 (80%) were eligible for invitation to the study and 662 out of 761 (87% of those eligible) patients were approached by clinical teams; 99 (13%) were not approached by clinical staff owing to limited time to recruit. Of those invited, 392 out of 662 (59%) were consented and were randomised to interventions (392/761; 52% of eligible patients). Table 6 reports screening by hospital code and by treatment allocation. The mean number of participants randomised per recruiting centre was 23 (range 7–73). The main reasons for not participating in the study included lack of transport or car parking issues, having ‘too much going on’ or feeling overwhelmed with cancer treatment.

FIGURE 2.

The CONSORT flow diagram of trial participants. Adapted with permission from Bruce et al. 102 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/.

Adapted with permission from Bruce et al. 102 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/.

TABLE 6 - Screening and randomisation by hospital site

Per cent randomised of number screened.

Site code	Screened, n (N = 951)	Randomised, n (%)a
		Usual-care group (N = 191)	Exercise group (N = 191)	Total (N = 392)
UHCW	89	36	37	73 (82.0)
DCH	68	19	19	38 (55.9)
OUH	92	18	18	36 (39.1)
HH	89	18	17	35 (39.3)
NCH	57	16	17	33 (57.9)
CRH	97	14	14	28 (28.9)
BCH	58	11	12	23 (39.7)
WMH	72	12	10	22 (30.6)
HCH	53	7	8	15 (28.3)
MKH	23	7	8	15 (65.2)
RCH	35	7	8	15 (42.9)
RSH	45	7	7	14 (31.1)
MDH	16	5	7	12 (75.0)
BTH	93	5	4	9 (9.7)
MPH	10	6	3	9 (90.0)
GEH	11	4	4	8 (72.7)
QAH	43	4	3	7 (16.3)

Participant baseline outcome measures

We present a summary of baseline outcome measures in Table 9. All outcome measures were similar across treatment groups at baseline as expected, owing to randomisation, and there was no difference in mean DASH score at baseline (mean 18.8; SD 20.5). In relation to the sample size, we anticipated that our pooled SD for the DASH score would be 19.5 at baseline. Of those returning baseline questionnaires, completion of the DASH scale was good (338/350; 97%); this equated to 338/392 (86%) of those randomised (Table 10). Approximately 10% (36/350) women reported some arm heaviness and swelling, indicative of lymphoedema symptoms on recruitment, possibly as a consequence of preoperative biopsy or investigative procedures. A similar proportion reported preoperative neuropathic pain in the area of breast or armpit (33/350; 9%). QoL scores were comparable at baseline, with mental health scores being slightly lower than physical health scores on recruitment.

Outcomes and analyses

Primary outcome: upper limb function

For the primary ITT analysis, we found evidence of a difference in upper limb function at 12 months, with those randomised to the exercise programme having better upper limb function scores than those in the usual-care group (Table 12). The unadjusted mean difference in DASH scores for usual care versus exercise was –7.34 (95% CI –12.23 to –2.44; p = 0.003) and the adjusted mean difference was –7.81 (95% CI –12.44 to –3.17; p = 0.001). Given that the primary outcome data were skewed, we also examined non-parametric models, with similar findings of an improvement in the exercise group compared with usual care for both unadjusted (median –4.89, 95% CI –7.84 to –1.58); p = 0.002) and adjusted models (median –7.87, 95% CI –12.01 to –2.66; p = 0.01).

We also examined recovery trajectory in upper limb function over time (see Table 12). At 6 months, DASH scores had improved from baseline in the exercise group but declined in those receiving usual care, resulting in a statistically significant difference in the mean change from baseline to 6 months between groups, for both unadjusted and adjusted comparisons (adjusted MD 4.60, 95% CI 0.31 to 8.90; p = 0.04) (see Table 12).

Primary outcome: complier–average causal effect analysis

Using our compliance definition of at least three physiotherapy contacts, 143 out of 196 participants (73%) fully complied with the intervention. For the CACE analysis, we found a statistically significant difference in upper limb function at 12 months by compliance status (adjusted MD –8.74, 95% CI –13.71 to –3.77; p = < 0.001) (Table 13).

We also carried out multiple imputation as detailed in the statistical analysis plan. Owing to low missingness, the imputation chained equation procedure was not valid for implementation. We replaced this with imputation of the total DASH score, where some items were missing, to assess the impact. The results for multiple imputation were similar to those presented for the CACE (see Table 13).

Secondary outcomes

Health-related quality of life over time by intervention

We assessed HRQoL over time by treatment group. Findings for EQ-5D-5L HRQoL outcomes are presented in Chapter 6. Table 20 presents SF-12 scores and missingness for PCS and MCS scores. Among participants returning 12-month questionnaires (274/392; 70%), item missingness for the SF-12 was low (17/274; 6%). We found differences in mean physical HRQoL scores at 6 and 12 months, with higher physical HRQoL scores observed in the exercise group than in the usual-care group (adjusted MD at 12 months, 4.84; 95% CI 2.06 to 7.63; p < 0.001). In the usual-care group, mean scores for physical HRQoL were lower at both 6 and 12 months than baseline scores (mean PCS score of 47.6 at baseline vs. PCS score of 43.2 and 43.8 at 6 and 12 months, respectively). We found no differences in mental HRQoL scores between groups at 6 or 12 months.

Process evaluation

Exercise progression over time: range of movement

We assessed progression in ROM by comparing exercise difficulty at each physiotherapy session. We analysed exercises according to movement direction: forward/flexion (clasp hand raise and forward wall slide exercises), abduction/sideways (morning stretch and sideways wall slide), and abduction and external rotation exercises/open chest (back broom lift and surrender). We present ROM data for compliers and partial compliers with the exercise progression in Table 23. We also present ROM data by movement direction by number of participants across up to six appointments in Figures 3–6. We calculated work capacity for ROM by calculating the product of total sets and repetitions, as recorded by physiotherapists at each contact.

TABLE 23 - Progression in ROM exercises by intervention compliance

Calculated as sets × number of repetitions per set.

Movement direction	Compliers, mean (SD) work capacitya			MD (95% CI)	p-value	Partial compliers, mean work (SD)a		MD (95% CI)	p-value
	First appointment (N = 152)	Second appointment (N = 150)	Third appointment (N = 147)			First appointment (N = 32)	Second appointment (N = 19)
Flexion	10.1 (4.7)	10.3 (5.4)	10.3 (6.2)	0.17 (–1.45 to 1.14)	0.80	10.2 (2.9)	10.0 (2.8)	0.16 (–1.56 to 1.87)	0.86
Abduction	9.7 (4.6)	10.1 (5.3)	10.3 (6.2)	0.59 (–1.89 to 0.70)	0.37	8.6 (3.4)	8.4 (3.3)	0.17 (–1.80 to 2.15)	0.86
Abduction and external rotation	9.7 (4.3)	9.8 (4.9)	9.6 (5.6)	–0.07 (–1.12 to 1.25)	0.91	9.2 (3.6)	8.9 (2.6)	0.27 (–1.65 to 2.19)	0.78

FIGURE 3.

Range of movement progression: flexion exercises.

FIGURE 4.

Range of movement progression: abduction exercises.

FIGURE 5.

Range of movement progression: abduction and external rotation exercises.

FIGURE 6.

Mean work capacity by movement direction in exercise compliers (n = 143).

At the first appointment, most participants (approximately 65%) started off at the easiest level for all ROM exercises for flexion, abduction, and abduction and external rotation movements (Appendix 2). We observed ROM progression across the second and third appointments: by the third appointment, fewer than half of participants were still doing ‘easy’ exercises for flexion, abduction, and abduction with external rotation (27%) (see Figures 3–5). For abduction ROM exercises, participants progressed to advanced or very advanced ROM movements (Figure 5). We observed a small increase in mean (SD) work capacity for flexion and abduction exercises, but this was not statistically significant (Table 23).

Progression over time: strength exercises

Strength exercises were prescribed only from 1 month postoperatively, corresponding to the second physiotherapy appointment. We examined strength progression over time by calculating mean (SD) work capacity (resistance × repetitions × sets), as presented in Table 24 and Figure 6. We observed an increase in mean strength over time among exercise compliers for each of the movement directions: flexion (t-test, p = 0.003), abduction (t-test, p = 0.01) and abduction and external rotation (t-test, p = 0.004). As strength was prescribed from the second appointment, we had data for one time point only for partial compliers (n = 19 participants). Although this was a very small sample, the partial compliers had good baseline strength compared with the full compliers who attended the second appointment of their programme (Table 24).

TABLE 24 - Mean (SD) work capacity for strength exercises by intervention compliance

Calculated as Theraband resistance × repetitions × sets.

t-test with assumption of equal variances.

Movement direction	Mean (SD) work capacity,a compliers			p-valueb	Mean (SD) work capacity,a partial compliers
	Second appointment (N = 152)	Third appointment (N = 138)	Fourth appointment (N = 81)		Second appointment (N = 19)
Flexion	11.1 (14.9)	16.4 (19.1)	18.2 (19.1)	0.003	12.2 (13.1)
Abduction	13.3 (17.9)	16.7 (20.0)	20.0 (21.4)	0.01	12.6 (12.4)
Abduction and external rotation	13.3 (17.0)	18.7 (20.1)	20.7 (19.7)	0.004	14.7 (15.0)

Figure 7 is a graphical representation of strength progression by Therabands prescribed across follow-up appointments. For each of the three movement directions, most participants were started on either the tan (1.1 kg resistance) or red bands (1.7 kg). By the third appointment, a large proportion of participants had progressed to the more advanced blue bands (2.6 kg). In the case of those attending four physiotherapy appointments (85/181; 47%), the blue band was the most commonly prescribed band across all three movement directions (Figures 6 and 7).

FIGURE 7.

Progression over time of band strength for abduction exercises among exercise compliers (n = 143).

Introduction

Qualitative research was undertaken in parallel with the trial to inform recruitment processes and the refinement of intervention materials, and to understand experiences of the trial interventions from the perspective of both participants and physiotherapists. Qualitative research can be used alongside RCTs to achieve varying objectives, such as informing recruitment processes, developing interventions that are acceptable and appropriate to the population of interest (and thus more likely to be taken up) and understanding the context in which a complex intervention is introduced. 104 In this study, qualitative research was important to refine aspects of the intervention and trial processes, and to understand the experiences of receiving and delivering the complex intervention.

This chapter reports on the qualitative research we conducted. First, we undertook pre-pilot interviews with seven newly diagnosed breast cancer patients and two breast care nurses (BCNs) to refine our procedures to approach and consent newly diagnosed patients. We also received early feedback on draft information materials before launching the internal pilot study. We then completed interviews with 10 participants randomised to usual care and 10 randomised to the exercise intervention to understand experiences of each trial intervention. We aimed to interview a sample of patients who declined participation in the trial: one patient agreed to interview. Finally, interviews were completed with 11 physiotherapists to investigate experiences of delivering the intervention. Selected findings from the qualitative research have been submitted for publication. 105

Aims of qualitative study

The aims of the qualitative study were to:

• understand patients’ and BCNs’ perspectives of the trial materials and processes to refine these materials and processes

• understand the acceptability of the exercise intervention to participants

• explore how the trial interventions affected experiences of recovery after cancer treatment

• investigate the experiences of physiotherapists delivering the exercise intervention

• explore participants’ and physiotherapists’ perspectives on issues related to the PROSPER programme to inform future plans for implementation.

Methodology

Sampling for qualitative study

Recruitment and consent procedures

Overview of interviewees

Findings

An overview of the qualitative objectives and the key findings are summarised in Table 27.

Overview of health economic analysis

We conducted a within-trial economic evaluation to estimate the cost-effectiveness of the PROSPER exercise programme compared with usual care after breast cancer surgery. The primary health economic analysis took the form of a cost–utility analysis, expressed in terms of cost per quality-adjusted life-year (QALY) gained and incremental net monetary benefit. The analysis adopted the ITT principle. In line with NICE guidance,126 the analysis was based on an NHS and Personal Social Services (PSS) perspective. The price year adopted for the analysis was 2015, which was when the trial intervention materials were developed. The health economic analysis used a 12-month time horizon and consequently no discounting of costs or outcomes was required. Multiple imputation was used to address missing data. Hierarchical linear models were used to analyse the single cost and QALY end points, whereas a hierarchical net benefit regression framework was used to jointly examine costs and consequences. Uncertainty around cost-effectiveness was characterised through the use of net benefit plots and cost-effectiveness acceptability curves (CEACs), in addition to multiple sensitivity analyses.

Aim

We aimed to estimate the cost-effectiveness of the PROSPER exercise intervention compared with usual care.

Methods

Outcomes

In line with NICE guidelines,126 QALYs were the primary outcome for the economic evaluation.

Missing data and multiple imputation

Although resource use/cost component data are presented in their raw form, for the cost-effectiveness analysis that combined multiple cost components and multiple EQ-5D-5L scores across time points, multiple imputation was necessary to avoid the pitfalls associated with complete-case analysis with substantial missing data. Multiple imputation avoids many of the issues encountered with simpler imputation methods (e.g. last observation carried forward), which have been criticised for underestimating uncertainty. 134 Missing data were assumed to be missing at random. To maximise the use of available data, multiple imputation was conducted at the component level (e.g. for each health-care cost variable and EQ-5D-5L) at each time point. Costs and EQ-5D-5L scores were imputed jointly using chained equations and predictive mean matching; the imputation model included age, ethnicity, marital status, employment status and recruiting site as co-variates. For 15 participants lacking covariate data, these were dropped from the multiple imputation analysis. Given that approximately 30–35% of data were missing for each cost component, a total of 35 imputations were calculated to produce 35 complete data sets. Multiple imputation procedures were conducted in Stata 16.

Analyses of resource use, cost and quality-adjusted life-years

Resource use between trial groups was examined using standard statistical methods: descriptively and using t-tests for continuous variables and chi-squared tests for categorical variables. Regression models using the multiple imputation data were used to examine the impact of the intervention on the single cost and QALY end points. The data were hierarchical, that is we expected participants within each site to be more similar to each other than to individuals in different sites. Consequently, multilevel linear models that accounted for clustering by including random-effect parameters were used to estimate end points. Following recommendations, it was necessary to adjust for baseline differences between the two groups when examining differences in QALYs. 126 Consequently, the baseline EQ-5D-5L score was included within the incremental analysis of QALYs as a covariate.

Results

Health-care cost components

Utility values by time point

Health utility at each time point is reported in Table 36 and Figure 8. At baseline, there was a very slight imbalance between the two groups, with the usual-care group having a mean utility score of 0.666 and the exercise group a score of 0.683. The period from baseline to 6 months was associated with a small decrease in health utility in both groups, with the mean utility score falling to 0.648 in the usual-care group and to 0.673 in the exercise group. Between 6 months and 12 months the utility scores diverged, with that in the exercise group increasing to 0.705 while, in contrast, the score in the usual-care group fell to 0.633. Thus, by 12 months, utility scores had improved compared with baseline in the exercise group, but in the usual-care group were worse than at baseline. The utility scores that use the multiple imputation data show a very similar picture. Imputed utility scores at all time points are nearly identical to the complete case data; however, uncertainty surrounding those estimates is reduced, as is reflected in the slightly narrower CIs.

FIGURE 8.

The EQ-5D-5L profile by group (multiple imputation data).

Analysis of costs

Table 37 presents the incremental costs associated with intervention resulting from the multilevel regression of NHS and PSS costs. There was an incremental cost difference of –£387 (95% CI –£2491 to £1718) in favour of the exercise group. This represents a cost saving. However, the wide CI shows that there is a high degree of uncertainty surrounding this estimate. The cost difference using the complete-case analysis also shows exercise to be cheaper than usual care; however, the difference is slightly smaller (–£258.56). Reflecting the large numbers of missing data in the complete-case analysis, the uncertainty (95% CI –£3609 to £3092) surrounding this estimate is much greater than in the multiple imputation data set.

Analysis of quality-adjusted life-years

The analysis of QALYs is shown in Table 38. Using the multiple imputation data and controlling for baseline imbalance, the intervention group accrued 0.029 (95% CI 0.001 to 0.056) more QALYs than the usual-care group. This is a statistically significant increase (p = 0.04). The results of the complete-case analysis reflect the multiple imputation results, with the intervention group accruing 0.030 QALYs (95% CI 0.002 to 0.059), a statistically significant difference (p = 0.04).

Cost-effectiveness analysis

To examine cost-effectiveness, incremental costs and QALYs were analysed simultaneously. From the analysis of costs and QALYs it is evident that exercise dominated usual care. The results combining costs and QALYs within a net benefit framework are shown in Figures 9 and 10. As seen in Figure 9, net benefit was positive at all levels of WTP including zero; this reflects the domination of exercise over usual care. That is, even if we are not willing to pay any money for health gains, the intervention group still provides a greater net benefit to society because of the lower health-related costs. As can be seen by the lower 95% CI for net benefit being below zero, there is uncertainty surrounding the results. This aligns with the previous finding of a high degree of uncertainty surrounding the incremental cost estimate.

FIGURE 9.

Primary analysis: net benefit by WTP.

FIGURE 10.

Primary analysis: cost-effectiveness acceptability curve.

To examine the levels of uncertainty around the results, a CEAC (presented in Figure 10) was created. This shows the probability that the intervention is cost-effective at different levels of WTP for QALYs. Even at a WTP of £0 there is still a 61% chance that exercise is more cost-effective than usual care. The CEAC is upwards-sloping because of the positive coefficient associated with incremental QALYs in the intervention group. That is, as the WTP for health benefits increases, so does the probability that the intervention is cost-effective. At the NICE-specified WTP threshold values of £20,000 per QALY and £30,000 per QALY, there is, respectively, a 78% and 84% probability that exercise is more cost-effective than usual care. Given that EQ-5D-5L utility scores were diverging at the final time point it is reasonable to conclude that this probability would increase if the time horizon were extended beyond the trial, as the exercise group would continue to accrue more QALYs than the usual-care group.

Secondary analyses

Discussion

This economic evaluation examined the costs and outcomes associated with the PROSPER exercise intervention in comparison with usual care. A multilevel net benefit regression framework was used to assess the cost-effectiveness of the intervention and to estimate the uncertainty surrounding the results. The results found that the exercise intervention was cost-effective compared with usual care, with the exercise intervention in the primary analysis having a 78% chance of being the more cost-effective option at the NICE cost-effectiveness threshold of £20,000 per QALY. 126 The results were robust to a range of sensitivity analyses. Given that the EQ-5D-5L utility scores were diverging at the final time point, it is reasonable to assume that these estimates are conservative. This is reinforced by secondary analysis 5, which found that there was a 97% chance of cost-effectiveness when excluding likely non-attributable costs (e.g. high-cost cancer treatments and inpatient surgery), which drove much of the uncertainty around the cost estimates in the other analyses.

There were a number of challenges in conducting this economic analysis. First, the hierarchical nature of the data resulting from being a cluster RCT provided methodological challenges. To account for this, a multilevel net benefit framework that adjusted for baseline differences in addition to clustering was used. Although the number of missing EQ-5D-5L data as relatively small, a significant number of data for health-care usage were missing, as is common within trials. To address this, multiple imputation was used to make the most of available data while retaining uncertainty. Although the cost-effectiveness estimates were favourable, there was a large uncertainty surrounding incremental cost estimates. This is probably because of the high cost and variable nature of breast cancer treatments, whereby certain cancer treatments unrelated to the rehabilitation of the shoulder post surgery account for the vast majority of costs. Consequently, to focus on costs that are more likely to be attributable to shoulder pain and its rehabilitation, we conducted a secondary analysis that included only those costs that might plausibly be related to shoulder pain and discomfort. In this analysis, there was much less uncertainty around cost estimates, which resulted in a very high probability of the intervention being cost-effective (97%).

This chapter has reported the results for the trial-based analysis. A limitation to this is that the EQ-5D-5L utility scores had not converged by the final time point. Given that participants in the exercise group were still in a better health state at the final time point than those in the usual-care group, and costs were incurred largely upfront, it is likely that the strength of evidence for cost-effectiveness would be stronger still if longer-term follow-up was conducted. This is an avenue for future research and as part of this study we are conducting an additional beyond-trial time point outcome data collection. A further limitation was that linear interpolation was specified as the method for calculating QALYs, as the time between each follow-up was significant and trajectories may not follow a linear pattern. Given the prolonged nature of treatment in this cohort, we, however, felt that this was the best approximation with the data we had. Finally, there is still debate about the validity of the EQ-5D-5L. 137 At the inception of the study this measure was recommended by NICE126 and hence was chosen to ‘futureproof’ results. The use of the three-level version, however, may have given slightly different results. Given the difference in QALYs between the two groups, we do not anticipate that this would have meaningfully changed the results.

Study findings and key messages

To our knowledge, this is the first large-scale, multicentre, pragmatic, definitive trial to investigate the clinical effectiveness and cost-effectiveness of an early structured exercise programme for women at higher risk of shoulder problems after breast cancer surgery. We delivered the trial in an NHS setting, across 17 breast cancer centres within secondary care services. Treatments were delivered by physiotherapists independent of multidisciplinary oncology teams. We aimed to provide evidence of whether or not early postoperative physiotherapy, currently not offered to women undergoing non-reconstructive breast surgery, is a clinically effective and cost-effective use of NHS resources.

We found evidence that the exercise programme led to greater intermediate and longer-term benefits on upper limb function, postoperative pain, arm symptoms and QoL than information leaflets only. Exercises started within 10 days of surgery were not associated with increased risk of wound-related AEs at 6 weeks or chronic AEs, such as lymphoedema, over 1 year. Overall, our results suggest that physiotherapy-supported exercise is a cost-effective intervention for women undergoing invasive cancer treatments, particularly treatments targeting the axilla, which can increase the risk of shoulder problems.

Key findings from the trial are discussed below. We consider issues relating to recruitment, uptake and retention, and also potential threats to the internal and external validity of the study. We also consider the characteristics of trial participants, the implications of losses to follow-up, and intervention adherence and fidelity. We then discuss our findings in relation to the current literature. Finally, we consider the clinical implications of our findings on recommendations for breast cancer care.

Recruitment uptake

A total of 951 patients were screened in the clinical setting and, of these, 190 (20%) were deemed ineligible for the trial. The main reasons for ineligibility were not being at higher risk of shoulder problems and opting for immediate breast reconstruction surgery. Current UK guidance62 now recommends that all women undergoing mastectomy should be offered either immediate or delayed breast reconstruction and rates of immediate implant-based reconstruction surgery have doubled in England since 2005. 138 Of those eligible to participate, a proportion of women were given study materials but had limited time to consider the information (43/761; 6%). Recruitment staff did not always record the specific reason for non-participation (77/761; 10%). Time from diagnostic testing of breast cancer to surgery can be rapid, within weeks, as per recommended NHS cancer referral and treatment guidelines. 3 Evidence from the US139 suggests that fewer than 1 in 20 cancer patients approached to take part in clinical trials are actually enrolled, although a recent meta-analysis suggested uptake to cancer clinical trials was nearer 8%. 140 Enrolment and uptake into prevention trials and trials testing exercise interventions can present additional challenges, such as the discounting of future perceived benefits,141 particularly when faced with a distressing diagnosis. Other known barriers to participation in cancer clinical trials include structural (e.g. access), clinical and attitudinal (physician and patient) factors. 140

Of those eligible and approached, 270 out of 761 (35%) women declined to participate. Before starting PROSPER, we considered the findings of a single-centre RCT67 conducted in the NHS in England, in which two exercise programmes were compared after ANC surgery. The authors reported low recruitment, with 64% of 345 women invited declining participation. 67 Timing of invitation was cited as a key issue, with women being distressed or more concerned with their immediate cancer treatment or pending surgery when approached preoperatively. 67 These authors recommended approaching women to participate in research after breast cancer surgery.

For PROSPER, we incorporated pre-pilot interviews with patients and BCNs specifically to inform our recruitment procedures and development of trial materials. Based on the literature and interview findings, we opted to screen and recruit women preoperatively. Most breast cancer surgery is undertaken as short-stay or day-case surgery, as per the NHS 23-hour ambulatory care model; thus, postoperative recruitment would be challenging. Consequently, uptake to PROSPER was good, with 59% (392/662) of women actually approached by clinical/research staff about the study agreeing to take part. Our materials explained equipoise, but also that, if allocated to the exercise intervention, participants would then be supported by a trained physiotherapist with flexible appointments arranged around routine clinical follow-ups.

Participant retention

Although uptake was good, eight participants were randomised in error and two allocated to the exercise group declined when notified of their treatment allocation. In all cases, errors in randomisation or declining to participate occurred on the day of randomisation and no further data were collected. An additional 8% of randomised participants were lost because they did not return their baseline questionnaires, and thus the baseline DASH scores required for treatment group comparison over time could not be calculated. These losses mostly occurred during the internal pilot study, when procedures were being refined. We extended recruitment by 1 month to achieve the required sample size of 350. We analysed data according to the ITT principle of allocated treatment, irrespective of subsequent non-compliance, and without imputation. Imputation for data missingness did not change the strength or direction of our estimates. Unlike other surgical trials, we did not undertake a modified ITT142 (excluding the 10 randomisations in error and those withdrawn at point of randomisation) or a per-protocol analysis, although the compliance-based approach does provide a realistic estimate of those who complied with treatment.

Response rates to follow-up postal questionnaires were lower than predicted, increasing the risk of attrition bias. We predicted a 25% loss to follow-up at 1 year, based on other clinical trials investigating exercise interventions. 67 However, we observed a slightly higher loss to follow-up, with 70% (274/392) of our randomised sample returning final 12-month questionnaires (although this equated to 78% of those returning baseline data). Despite losses, the trial was sufficiently powered, as the required sample size was calculated to be 256 participants at 12 months. Rates of withdrawal were comparable by treatment group, and reasons for withdrawing were mostly cited as treatment burden, including being informed of a cancer recurrence, or that women did not want to complete questionnaires during adjuvant treatment.

Risk screening criteria

Only women at high risk of developing shoulder problems after breast cancer treatment were eligible to take part in the study. We developed our own criteria, based on the published literature, to determine future risk of developing shoulder problems. Screening criteria were applied preoperatively, based on planned cancer treatment pathways. Over half of participants (59%) were booked for ANC surgery when recruited, although actual cancer treatments delivered after randomisation differed from preoperative treatment plans. A total of 327 out of 392 (83%) of women underwent ANC, thus we are confident that we recruited those who were, indeed, at higher risk of developing shoulder problems. One-third of women had both ANC and radiotherapy to the axilla/supraclavicular area, regardless of other entry criteria. A high proportion (75%) of women were screened as being overweight or obese, having a BMI of ≥ 25 kg/m². Preoperative height and weight were recorded at preoperative clinics and used by clinical teams for risk screening. We also captured patient-reported height and weight from baseline questionnaires. Patient-reported BMI was marginally lower than clinically recorded data (72% overweight/obese). Cancer treatment covered a wide spectrum and different combinations of modalities, including repeated surgeries, adjuvant chemotherapy, radiotherapy and hormonal therapy. Although treatment modality and sociodemographic variables were well balanced across treatment groups at baseline, we noted differences between planned and actual cancer treatments delivered over the 12-month follow-up. For example, a higher proportion of women in the exercise group underwent mastectomy (44%) than those randomised to usual care (38%), and thus those in the exercise group were more likely to have more extensive breast surgery and less likely to have breast-conserving procedures with adjuvant therapy. We adjusted for cancer treatment in all analyses. We also noted differences in proportions of participants reporting a history of shoulder problems, although this was not reflected in baseline DASH scores. We did not stratify allocation by risk criteria; therefore, some random variation is expected. Nevertheless, we undertook sensitivity analyses to explore this further, but adjustment for self-reported shoulder problems did not change effect estimates.

Almost one-quarter of women (22%) underwent repeat surgery; this reoperation rate is similar to that reported across 156 NHS trusts for women having breast conserving procedures over a 3-year period (20%; 95% CI 19.6% to 20.3%), with higher repeat surgery rates (30%) noted after invasive cancer surgery. 138 Within PROSPER, reoperations were mostly revisions of tumour resection margins undertaken as an additional day-case procedure. Five women opted for a delayed breast reconstruction. No adjustment was undertaken for revisional surgeries, as these were equally distributed by treatment group and all statistical analyses were adjusted based on the most invasive breast and axillary procedure over follow-up. For intervention participants already following the exercise programme, physiotherapists advised them to restart exercises from the 7th postoperative day after revisional surgery.

Participant characteristics

Our recruited sample had a mean age of 58 years and were, thus, representative of newly diagnosed breast cancer patients. 1 Over one-quarter (28%) of women were < 50 years. Among our sample returning baseline questionnaires, participants were predominantly white (92%), although we had fair representation from the black and ethnic minority population (8%) relative to national English statistics (UK Census data: 86% white). 143 As described, most women were overweight/obese and were relatively inactive in the week prior to recruitment. Three-quarters (76%) reported not taking part in any physical activities or sport, such as dancing, swimming, jogging, cycling or tennis. We are confident, therefore, that we did not recruit a sample of highly active women who exercised regularly. This may be important when considering generalisability and wider implementation of the intervention, as well as the longer-term potential health benefits from promoting physical activity. Other studies have shown that physical activity declines after a breast cancer diagnosis and during treatment. 144 Women receiving adjuvant treatment are least likely to remain physically active; one large cohort study found that physical activity halved in those receiving both radiotherapy and chemotherapy. 145

Despite being relatively inactive in the week before recruitment, our participant sample were confident that they would return to usual activities and/or regular physical activity in the future, after cancer treatment. Confidence scores were higher in the exercise group than in the usual-care group across all postoperative time points. Some argue that the time of diagnosis is the window of opportunity to identify and motivate sedentary patients with breast (and colon) cancer, to target motivational support and sustain lifestyle changes. 146 Having confidence in ability to return to future activity is therefore an important consideration for encouraging behaviour change.

We found differences in rates of outdoor walking between groups over time, with higher rates of activity in the exercise group than in the usual-care group at 6 weeks and 6 months, but rates were broadly similar at 1 year. Light and moderate physical activity, as encouraged within the PROSPER exercise programme, has been associated with improved QoL. 147 Interestingly, at the 1-year follow-up, the majority of women reported that the arm and shoulder exercises had helped their recovery, suggesting that participants in both treatment groups attributed at least some of their recovery to exercise. We can assume that those in the exercise programme undertook their prescribed exercises, but we cannot know what exercises those in the usual-care group were following. Although women in the usual-care group perceived their exercises as being helpful to their recovery, these did not have the same impact on their upper limb disability (as measured by the DASH scale) as the structured, supported programme.

Health-related quality of life

Our sample had lower QoL scores on recruitment than population normative scores for UK females aged 45–64 years [SF-12 PCS 49.1 (SD 10.6); MCS 51.4 (SD 9.8)]. 148 We observed lower scores in our sample for mental health at recruitment than at 6 and 12 months and also when compared with population normative scores for women < 45 years and > 64 years. 148 These lower scores at baseline may reflect diagnosis-related distress and pending cancer surgery. 149 QoL scores were lower at the 6-month follow-up than at 1 year, reflecting the impact of ongoing adjuvant treatment. Among postal responders, item missingness was low for SF-12 data at baseline (4%), 6 months (5%) and 12 months (6%). We followed validated scoring guidelines for all standardised measures. Comparison of complete-case and imputed data for EQ-5D-5L scores used in the cost-effectiveness analysis did not change estimates. At 12 months, the exercise group had significantly better physical QoL than women receiving usual care.

Exercise intervention: uptake and adherence

Usual NHS postoperative care for non-reconstructive breast surgery is written information about exercise, and referrals are made to physiotherapy only when a problem has been identified. We designed an exercise programme cognisant of busy physiotherapy clinics and what could reasonably be offered within the NHS. The exercise programme was planned to start after the first postoperative week and continue throughout cancer treatment. Uptake of the intervention was excellent, with 181 out of 196 (92%) of those randomised attending at least one appointment with their physiotherapist (95% of referred). Despite the known barriers to exercise during cancer treatment, adherence to the programme was good. Twenty per cent of participants either withdrew or were discharged after two appointments, and the remainder completed three or more physiotherapy sessions (143/191; 75%). The adherence rate was higher than those reported in other trials testing exercise intervention with patients with breast cancer. 150,151 We recommended that women continue with shoulder-specific exercises and physical activity for up to 12 months, despite the fact that symptom burden, such as fatigue and other side effects caused by chemotherapy, may overwhelm the motivation to exercise. 146

All participants were advised to restrict arm movements for the first postoperative week to avoid the risk of increasing wound drainage. 12 There is debate around the optimal timing to start exercise in relation to cancer surgery. 152 Our findings show that unrestricted ROM shoulder exercises started at 7–10 days postoperatively did not increase the risk of self-reported wound-related AEs at 6 weeks. Physiotherapists notified the study team of six adverse events (6/191; 3%), although four of the six women who experienced postoperative events continued with the exercise programme. We did not objectively measure postoperative wound drainage (volume or duration), as this would have required additional hospital clinic visits. For women requiring additional surgery after starting the exercise programme, physiotherapists advised that they restart the programme from the 7th postoperative day. The intervention was designed such that face-to-face appointments were strategically planned to allow controlled, supervised progression of exercise difficulty while dovetailing with routine oncological follow-up. We used the frequency, intensity, time and type (FITT) principle to prescribe and tailor the exercise programme. The programme was adaptable and flexible, and thus could be adjusted in accordance with individual needs, preferences and cancer treatments.

Comparison of findings with other studies

We found evidence of improved upper limb function, lower intensity acute pain, reduced chronic pain, fewer arm symptoms and improved QoL in the exercise group over 1 year. We found statistically significant differences between groups for the DASH score at 6 and 12 months; the mean difference at 12 months was greater than the estimate specified a priori as the MCID. We defined MCID as a 7-point difference and our primary and sensitivity analyses confirmed this difference. Other studies38 suggest that slightly larger differences are clinically meaningful but in relation to those with other chronic conditions receiving different interventions with shorter follow-up time periods. We specified 7 points to account for the pragmatic nature of the trial and the longer duration of follow-up of over 1 year. This was also to account for the prolonged and complex cancer treatment pathways after primary surgery. We are confident of some benefit from our programme, with CIs suggesting evidence of benefit in total DASH score, and also for impairment, activity limitations and participant restriction subscores, although CIs were wider for subscores.

The primary source of evidence for exercise after breast cancer treatment remains the Cochrane review,12 which is now out of date given that at least 10 RCTs have since been registered or completed, as per our literature review update. Our findings are similar to findings from some small trials comparing exercise programmes to either non-active or information-only control groups. 14 For example, the small Dutch trial41 that we used for our sample size calculation compared a shoulder exercise programme with information leaflets on outcomes at 3 and 6 months in 30 women. The authors reported improved ROM and strength and lower pain scores in the exercise group, with a similar difference in DASH scores (unadjusted MD –9.0; p = 0.03; n = 30 participants) at 6 months after exercise41 to that observed in PROSPER (adjusted MD –8.74; p = 0.001; n = 235 CACE analysis).

Other trials have recruited patients to exercise postoperatively, either during or months after completion of adjuvant therapy. 12 ROM exercises are important to maintain shoulder mobility and to avoid common problems related to axillary surgery, such as axillary web syndrome. We found evidence of progression in ROM exercise difficulty, but this was not captured in the work capacity outcome. Participants increased the difficulty of exercises over subsequent appointments but maintained the same number of repetitions and sets. We observed improvements in strength over time using our composite measure of work capacity (incorporating band resistance) among intervention compliers. Strength exercises are important to maintain muscle strength and mass during cancer treatments; chemotherapy can reduce upper limb strength by as much as 16%. 80 A recent systematic review,153 based on several small trials with short-term follow-up, concluded that there was low-level evidence regarding the effectiveness of range of motion and muscle strength exercises to improve arm function. Our findings suggest that an early, structured, progressive exercise programme is beneficial for improving upper arm function in those who are at highest risk of shoulder problems and these findings are clinically relevant.

Intervention fidelity

Intervention fidelity is an important consideration for complex intervention trials. Multicentre trials delivering complex interventions are more vulnerable than studies testing simple interventions, being at greater risk of not being implemented as intended. 154 We developed clear treatment pathways and protocols throughout the first year, thus developing and testing the exercise intervention, incorporating multidisciplinary expert and patient input to co-design a programme suitable for delivery within the NHS. Some intervention elements were novel for physiotherapy staff, for example behavioural change strategies and co-decision of exercise prescription to encourage adherence. Although participating physiotherapists were experts in the management of musculoskeletal conditions, none was formally embedded within oncology services. Each physiotherapist completed training and achieved the required competence before training certificates were signed. Quality of training delivered was assessed and adapted during the internal pilot study. We provided clear supportive materials (e.g. laminated prompt sheets for motivational interviewing, ROM, strength assessment etc.). We did not undertake video recordings of participant consultations, as this may have affected adherence, particularly given the sensitive nature of consultations. Qualitative interviews revealed that some women became emotional during appointments, particularly in the earlier postoperative assessments, when adjusting to their new body image. We are confident, through our quality assurance procedures, that physiotherapists adhered to and prescribed the recommended programme. We are also confident that our intervention is ‘futureproof’, given that women underwent contemporaneous cancer treatment for those requiring invasive axillary treatment.

Qualitative findings

We included the qualitative study to explore insights and perspectives from patients and health-care providers taking part in the trial. Women described feeling motivated to comply with the exercise programme because they felt that it contributed to their overall well-being and recovery. Women also reported that it was something that they could achieve themselves during cancer treatment, thus having control over their own body rather than passively receiving cancer treatments. Physiotherapists described the exercise programme as rewarding; they enjoyed providing support and encouragement to women and reassuring them that it was safe to move their arm after surgery. Other positives described by physiotherapists included the longer appointment sessions and emphasis on patient choice and joint decision-making. Several issues for future implementation within the NHS setting were identified: the need for a private space for appointments, access to emotional support for physiotherapists and integration of physiotherapy expertise within the multidisciplinary oncology team.

Strengths of the study

The strengths of the study included the methodological rigour, excellent uptake of exercise and good adherence to interventions over time. Clinical data confirmed that most of our recruited sample had axillary surgery or radiotherapy treatment; only 14% were recruited for other risk factors (obesity or shoulder problems only). Although we cannot fully eliminate the risk of selection bias, we believe that the risk of bias was low, as randomisation was stratified by site and we avoided the use of permuted blocks. A major strength was the effort invested in the production of a well-designed programme with high-quality intervention materials packaged as a deliverable, stand-alone treatment programme. The intervention was delivered by NHS staff with the aim of testing the programme in an everyday clinical setting. We carefully tracked treatment referrals and monitored compliance. We incorporated an embedded processes valuation with qualitative interviews to better understand the challenges and acceptability of our interventions from the perspectives of both patients and physiotherapists. For the health economic analyses, data were triangulated from multiple sources: self-report and clinical records and routine national statistics via HES data. We undertook sensitivity analyses and also explored the impact of imputation for missingness, but these analyses did not change our findings.

Limitations

The main limitation of the trial was the loss to follow-up over study duration, being 5% higher than predicted. Although disappointing, losses to follow-up were equally distributed by treatment allocation; therefore, we are confident that systematic error (attrition bias) from disproportionate losses did not occur. Drop-out mostly occurred between 6 weeks and 6 months during ongoing cancer treatments, with minimal loss thereafter (2%). We compared the characteristics of the randomised sample with those of participants remaining in the trial at 12 months and found no differences in marital status, comorbidity, body weight or cancer treatments. However, younger women were more likely to withdraw, possibly because of family or work commitments. We could postulate that younger women are possibly more physically active in general or less in need of a supportive exercise intervention throughout cancer treatment. However, evidence from many studies suggests that younger women are more likely to experience more problems with functional limitations,155 delayed return to work, declines in physical activity156 and chronic post-surgical pain. 13,15 Nevertheless, strategies to encourage adherence to exercise during periods of intensive treatment, chemotherapy in particular, should be explored. Despite losses, the trial study was adequately powered to be definitive and we completed all prespecified statistical analyses. We made one amendment to the statistical analysis plan after protocol publication to adjust for baseline values. We observed consistency in findings across a range of patient-reported outcomes, all of which support rejection of the null hypothesis. Another limitation was that we used self-report indicators for the secondary outcome of lymphoedema, rather than objective perometry, although our primary focus was to assess patient-reported upper limb function as per the commissioned brief.

Cost-effectiveness findings

Exercise was found to be more cost-effective than usual care, with the exercise intervention having a 78% chance of being the more cost-effective option at the NICE-recommended cost-effectiveness threshold of £20,000 per QALY, and an 84% chance at £30,000 per QALY. These results were robust to a range of sensitivity analyses. The intervention itself was relatively cheap to implement, at an additional £129 per person, and was associated with lower health-care costs and improved HRQoL. As QoL utility scores were diverging at the 12-month follow-up, we conclude that these estimates are conservative as benefits may accrue beyond the end of the trial.

Patient and public involvement

We included lay members in our external committees and at all stages throughout the trial. We included PPI in the design stage and during early intervention development. A patient dissemination event was planned at the University of Warwick to feed back study findings to trial participants. This was postponed because of coronavirus but will be rearranged in due course.

Trial Management Group

Professor Julie Bruce (chief investigator).

Professor Alastair Thompson (co-applicant, lead surgeon).

Professor Stavros Petrou (co-applicant, lead health economist).

Professor Ranjit Lall (co-applicant, lead statistician).

Professor Sallie Lamb (co-applicant).

Dr Esther Williamson (co-applicant).

Mrs Emma Padfield (trial manager/senior project manager).

Mrs Lauren Betteley (trial manager).

Mr Pankaj Mistry (trial statistician).

Dr Alastair Canaway (health economist).

Dr Sophie Rees (research fellow).

Dr Helen Richmond (research fellow/physiotherapist).

Dr Bruno Mazuquin (research fellow/physiotherapist).

Ms Clare Lait (research fellow/physiotherapist).

Mrs Loraine Chowdhury (trial administrator).

Mr Craig Turner (trial administrator).

Mr Phil Moss (data entry clerk).

Mrs Marie van Laar (patient representative).

Miss Raghavan Vidya (breast surgeon), Royal Wolverhampton NHS Trust.

Ms Jane Prewit (University of Warwick sponsor).

Ms Ceri Jones (University Hospitals Coventry and Warwickshire co-sponsor).

Miss Abigail Tomlins (oncoplastic breast surgeon).

Trial Steering Committee

Professor Adele Francis (deceased).

Professor Stephen Duffy (independent).

Dr Anna Kirby (independent).

Dr Karen Robb (independent).

Professor Julie Bruce (chief investigator).

Professor Ranjit Lall (statistician).

Professor Sallie Lamb (observer).

Mrs Emma Padfield (trial manager/senior project manager).

Data Monitoring and Ethics Committee

Professor Malcolm Reed (independent chairperson).

Dr Rhian Gabe (independent).

Dr Matthew Maddocks (independent).

Statisticians

Professor Ranjit Lall (lead).

Mr Pankaj Mistry (research assistant).

Dr Anower Hossain (research associate).

Ms Katie Booth (research associate).

Health economists

Dr Alastair Canaway (research fellow).

Professor Stavros Petrou (lead).

Dr Kamran Khan (research assistant).

Core trial team

Surgical oncologists

Professor Alastair Thompson, Baylor College of Medicine (USA).

Miss Raghavan Vidya, Royal Wolverhampton NHS Trust.

Mrs Katherina McEvoy, University Coventry and Warwickshire NHS Trust.

Miss Abigail Tomlins, University Coventry and Warwickshire NHS Trust.

Principal investigators by NHS site

Birmingham City Hospital, Sandwell and West Birmingham Hospitals NHS Trust (Miss Fiona Hoar).

Chesterfield Royal Hospital NHS Foundation Trust (Miss Iman Azmy).

Dorset County Hospital NHS Foundation Trust (Dr Caroline Osborne).

George Eliot Hospital NHS Trust (Mr Kishore Makam).

Hereford County Hospital, Wye Valley NHS Trust (Miss Jill Donnelly).

Hillingdon Hospitals NHS Foundation Trust (Mr Ekambaran Babu).

John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust (Ms Pankaj Roy).

Macclesfield District General Hospital, East Cheshire NHS Trust (Mrs Nicola Van der Ploeg).

Milton Keynes University Hospital NHS Foundation Trust (Ms Rachel Soulsby).

Musgrove Park Hospital, Taunton & Somerset NHS Foundation Trust (Miss Amanda Thorne).

New Cross Hospital, Royal Wolverhampton NHS Trust (Mr Tapan Sircar).

Portsmouth Hospitals (Mrs Maria Noblet) and Solent NHS Trust (Ms Emma McLoughlin).

Royal Blackburn Hospital, East Lancashire Hospitals NHS Trust (Miss Jane McNicholas).

Royal Cornwall Hospitals NHS Trust (Ms Sadie Mitchell).

Royal Stoke University Hospitals, North Midlands NHS Trust (Mr Soni Soumian).

University Hospital Coventry & Warwickshire NHS Trust (Miss Abigail Tomlins).

Walsall Manor Hospital, Walsall Healthcare NHS Trust (Mrs Lynda Wagstaff).

Physiotherapists by hospital site

Birmingham City Hospital: Carolyn Casey, Yogita Stokes, Sarah Calloway, Emma Fletcher and Hannah Brown.

Chesterfield Royal Hospital: Carolyn Lindsay and Sarah Wright.

Dorset County Hospital: Clare Ruston and Rebecca Bower.

George Eliot Hospital: Nicola Layte and Julie Barratt.

Hereford County Hospital: Kim Jones and Hannah Thomas.

Hillingdon Hospital: Lisa Graves and Donna Pilgrim.

John Radcliffe Hospital: Lucy Ridgeway, Naomi Ekers and Anna McMullen.

Macclesfield Hospital: Anoosheh Redfern and Annabel Allen.

Milton Keynes Hospital: Chrissie Edley, Rosie Conway and Jo Pitts.

Musgrove Park Hospital: Alex Chisholm, Sarah Woodhill, Nicky Clarke and Sarah West.

New Cross Hospital: Anna Simpson, Michelle Evans, Tina Hadley-Burrows and Sharon Rudge.

Portsmouth and Solent Hospitals: Emma McLoughlin, Alexandra Stephenson and Jo Burke.

Royal Blackburn Teaching Hospital: Emily McNeill and Sarah Greenwood.

Royal Cornwall Hospital: Deanne De Beer, Sally Kennedy and Donna Dungey,

Royal Stoke Hospital: Clare Johnson, Amanda Heath, Gabi Evans, Lisa Beadle and Rachel Scarisbrick.

University Hospital Coventry & Warwickshire: Catherine Hegarty, Elizabeth Abbey (deceased) and Jenny Holt.

Walsall Hospital: Stephanie Rook, Sophie Horne and John O’Regan.

Intervention development

We are very grateful to the experts who contributed to the Exercise Intervention Development Day hosted at WCTU in March 2015: Elizabeth Fort (nee Abbey), Catherine Hegarty, Lyn Ankcorn, Jocelyn Choyce, Alison Jelly, Wendy Leonard, Nicola Lidstone, Kelvin Marshall, Kat Tunnicliffe, Sally Winterbourne, Jo Dixey, Leah Dalby, Karen Wilkinson, Clare Lait, Meredith Newman, Jane Moser, Cynthia Srikesavan, Esther Williamson, Helen Richmond and Lauren Betteley. We thank Janet Lowe and Susie Henning for reviewing draft versions the physiotherapy manual.

We extend grateful thanks to study participants and to the physiotherapists delivering the PROSPER intervention.

Thanks are due to Mrs Emma Padfield and Mrs Loraine Chowdhury for providing administrative support throughout. We also thank members of the Coventry Breast Cancer Support Group and our patient representatives: Dr Catherine Harkin (deceased), Mrs Marie van Laar and Lyn Ankcorn.

Contributions of authors

Professor Julie Bruce (https://orcid.org/0000-0002-8462-7999) (Chief Investigator) co-developed interventions, was a member of the Trial Management Group (TMG) and the TSC, and was responsible for writing and reviewing the report.

Dr Bruno Mazuquin (https://orcid.org/0000-0003-1566-9551) (Research Physiotherapist) was a member of the TMG and was co-responsible for the delivery of the exercise intervention and writing and reviewing the report.

Mr Pankaj Mistry (https://orcid.org/0000-0003-0351-3090) (Research Fellow, Trial Statistician) was a member of the TMG and was responsible for the statistical analysis of the trial and writing and reviewing the report.

Dr Sophie Rees (https://orcid.org/0000-0003-4399-2049) (Research Fellow, Qualitative) was a member of the TMG and was responsible for the qualitative substudy and writing and reviewing the report.

Dr Alastair Canaway (https://orcid.org/0000-0002-4270-6808) (Research Fellow, Health Economics) was a member of the TMG and was responsible for the health economic analysis and writing and reviewing the report.

Dr Anower Hossain (https://orcid.org/0000-0002-1708-9940) (Research Associate, Statistics) was responsible for the statistical analysis and writing and reviewing the report.

Dr Esther Williamson (https://orcid.org/0000-0003-0638-0406) (Research Fellow) was a member of the TMG, co-developed the intervention, and contributed to writing and reviewing the report.

Mrs Emma J Padfield (https://orcid.org/0000-0003-4832-9609) (Trial Manager/Senior Project Manager) was a member of the TMG and was responsible for trial management and writing and reviewing the report.

Professor Ranjit Lall (https://orcid.org/0000-0003-1737-2866) (Professor of Clinical Trials, Lead Statistician) was a member of the TMG and was responsible for study design, oversight of statistical analysis, and writing and reviewing the report.

Dr Helen Richmond (https://orcid.org/0000-0002-5561-016X) (Research Fellow/Physiotherapist) was a member of the TMG, co-developed the intervention and the training and delivery of the exercise intervention, and was responsible for writing and reviewing the report.

Mrs Loraine Chowdhury (https://orcid.org/0000-0002-0339-2332) (Data Entry Clerk) was a member of the TMG and contributed to trial administration and reviewing of report.

Mrs Clare Lait (https://orcid.org/0000-0002-2998-3528) (Physiotherapist) was a member of the TMG, co-developed intervention, and contributed to the training and delivery of the exercise intervention and writing and reviewing the report.

Professor Stavros Petrou (https://orcid.org/0000-0003-3121-6050) (Lead Health Economist) was a member of the TMG and was responsible for oversight of the health economics analysis and writing and reviewing the report.

Ms Katie Booth (https://orcid.org/0000-0001-8530-2566) (Research Associate) provided statistical support and contributed to writing and reviewing the report.

Professor Sarah E Lamb (https://orcid.org/0000-0003-4349-7195) (Professor of Trauma Rehabilitation) was a member of the TMG and contributed to intervention development and writing and reviewing the report.

Miss Raghavan Vidya (https://orcid.org/0000-0002-6129-2444) (Breast Surgeon, Principal Investigator) was a member of the TMG and contributed to writing and reviewing the report.

Professor Alastair M Thompson (https://orcid.org/0000-0003-0604-7267) (Lead Surgical Oncology Advisor) contributed to writing and reviewing the report.

All co-applicants contributed to PROSPER study design and protocol development.

Publications

Bruce J, Williamson E, Lait C, Richmond H, Betteley L, Lall R, et al. 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). BMJ Open 2018;8:e019078.

Richmond H, Lait C, Srikesavan C, Williamson E, Moser J, Newman M, et al. Development of an exercise intervention for the prevention of musculoskeletal shoulder problems after breast cancer treatment: the prevention of shoulder problems trial (UK PROSPER). BMC Health Serv Res 2018;18:463.

Khan KA, Mazuquin B, Canaway A, Petrou S, Bruce J. Systematic review of economic evaluations of exercise and physiotherapy for patients treated for breast cancer. Breast Cancer Res Treat 2019;176:37–52.

Bruce J, Mazuquin B, Canaway A, Hossain A, Williamson E, Mistry P, et al. Exercise versus usual care after non-reconstructive breast cancer surgery (UK PROSPER): multicentre randomised controlled trial and economic evaluation. BMJ 2021;375:e066542.

Mazuquin B, Sunemi MMO, E Silva MPP, Sarian LOZ, Williamson E, Bruce J. Current physical therapy care of patients undergoing breast reconstruction for breast cancer: a survey of practice in the United Kingdom and Brazil. Braz J Phys Ther 2021;25:175–185.

Rees S, Mazuquin B, Richmond H, Williamson E, Bruce J, UK Prosper Study Group. Role of physiotherapy in supporting recovery from breast cancer treatment: a qualitative study embedded within the UK PROSPER trial. BMJ Open 2021;11:e040116.

Data-sharing statement

All requests for data should be sent to the corresponding author. Access to anonymised data may be granted following review.

Patient data

This work uses data provided by patients and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people’s patient records, to understand more about disease, develop new treatments, monitor safety, and plan NHS services. Patient data should be kept safe and secure, to protect everyone’s privacy, and it’s important that there are safeguards to make sure that it is stored and used responsibly. Everyone should be able to find out about how patient data are used. #datasaveslives You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/data-citation.

Disclaimers

This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care.