Study design
This is a prospective, parallel, single-blind, pragmatic, pilot randomised controlled trial to assess preliminary efficacy of multidisciplinary prehabilitation on post-autologous stem cell transplant physical capacity (See Fig. 1 for study flow chart). An 8-week intervention will be completed pre-transplant with participants followed up at week 13, approximately 4 weeks after transplant and health service measures collected at week 25, approximately 12 weeks after transplant (Additional File 1).
Randomisation procedures
Eligible participants who have completed baseline measurements will be randomly allocated to the prehabilitation group or usual care control group according to an online computer-generated randomisation program, www.randomization.com, using permuted blocks. Assignments will be placed in sequentially numbered, opaque, sealed envelopes prepared prior to trial commencement by an independent researcher with no role in subject recruitment or administration of trial interventions.
Setting
The trial will be conducted in a public, tertiary cancer treatment unit that conducts approximately 30 autologous stem cell transplants annually.
Patient selection and consent
All patients referred to the haematology cancer unit for autologous stem cell transplant will be approached to participate in the trial. Potential candidates will be advised about the trial by clinic staff verbally and/or through flyers. If a patient gives permission to being contacted about the research project, they will be contacted by a member of the research team who will provide them with details of the study and arrange an outpatient appointment to provide an opportunity for questions to be clarified and to provide written informed consent.
Inclusion and exclusion criteria
Participants will be eligible if they are aged 18 years and over; have a haematological malignancy and are waitlisted for autologous stem cell transplant; and are able to give written informed consent.
Participants will be excluded if they: are medically unfit to participate in exercise as determined by a physiotherapist and/ or medical practitioner based on published recommendations [23]; have low physical performance status (Australian-modified Karnofsky Performance status (AKPS) of < 60 or Eastern Cooperative Oncology Group (ECOG) score > 2); or have cognitive impairment precluding ability to provide written, informed consent as assessed by their treating clinician.
Intervention
All participants, whether allocated to experimental or control groups will receive usual care. Usual care will include an initial assessment with a research physiotherapist who, at this session will also provide standardised written instructions with guidelines for exercise after cancer [24–26] and a referral to a sub-acute oncology rehabilitation program after stem cell transplant. They will continue to receive their usual medical care, which may include adjuvant chemotherapy, radiotherapy, inpatient admission post-transplant, specialist, nursing and allied health outpatient appointments and visits to their general practitioner
Prehabilitation intervention
Following physiotherapy assessment and randomisation, participants allocated to the experimental group will be introduced to the gym space and have individualised exercise program designed for them based on assessment findings and goals. They will participate in twice-weekly, 60-minute exercise classes for up to 8 weeks pre-transplant following a 1-week period of physical activity monitoring (Table 1). Exercise will be supervised by a physiotherapist with cancer rehabilitation experience within the hospital gymnasium. The exercise intervention, tailored to individual patient needs, will be in a circuit format one on one or in small groups of up to 4 people. It will comprise aerobic and resistance exercise, completed at a moderate intensity (4–6 BORG rating of perceived exertion (RPE) and/or 60–80% Heart rate (HR) maximum for aerobic exercises, 60–80% 1-repetition maximum (for pin-loaded machines or 10–12 repetition maximum (RM) for resistance exercise) in accordance with guidelines [8]. Participants will complete a 5-minute warm up, aim to complete 25 minutes aerobic exercise, 20 minutes of resistance exercise, 5-minutes of flexibility or balance training (as indicated) and 5-minute cool down. Exercise intensity during aerobic exercise will be monitored by the physiotherapist using the modified BORG scale and using a portable heart rate monitor. During weeks 1 and 2, participants will aim to exercise at a BORG RPE of 3 (moderate), and by week 8 participants will aim to exercise at a 5–6 (hard) on the scale. For resistance exercise, weights will be progressed once a participant is achieving 2 to 3 sets of 10–12 repetitions. Resistance exercise may include upper and lower body resistance exercise such as squats, step ups, free weights, wall push-ups, free weights, resistance exercise bands, pin-loaded machines (lateral pull down, leg press, chest press). Aerobic exercise may include treadmill, stationary cycle, or an arm ergometer. Various upper and lower body stretches and balance exercise will be incorporated into the program as required. Participants in the prehabilitation group will be encouraged to complete an additional once-weekly 30-minute aerobic exercise training session at home to comply with exercise guidelines for people with cancer [8]. Patients will be also be instructed to remain as active as possible and avoid prolonged periods of sitting and lying in the period following stem cell transplant.
A dietitian will provide written information and fortnightly phone calls over the 8-week period (up to 4 sessions) to patients offering tailored medical nutrition therapy based on initial dietetic consultation. The focus will be on supporting oral intake and maintaining nutritional status during the prehabilitation period. Guidelines for managing potential gastrointestinal symptoms during the post-transplantation period will also be provided [13].
The fidelity of the intervention will be monitored by recording the content of exercise and nutrition sessions in logbooks, recording the number and duration of completed sessions with the physiotherapist and dietitian and monthly meetings with clinical staff.
Control group
Participants randomised to the control group will receive their usual medical care and receive standardised written instructions with guidelines for exercise after cancer from the physiotherapist [24–26].
| Experimental Group | Control Group |
Brief Name | Prehabilitation | Usual Care |
Why | Prehabilitation may build functional reserves to better cope with transplant | Pragmatic trial design |
What: Materials | • Participants will receive access to the hospital gymnasium: - Free weights - Resistance exercise bands - Pin-loaded machines (lateral pull down, leg press, chest press) • Participants will receive 1) standardised written handout exercise 2) standardised written handout nutrition 3) referral to Oncology Rehabilitation Program post-transplant • Participants will receive usual hospital care | • Participants will receive 1) standardised written handout exercise 2) referral to Oncology Rehabilitation Program post-transplant • Usual care also includes usual medical care which may include adjuvant chemotherapy, radiotherapy, inpatient admission post-transplant, specialist, nursing and allied health outpatient appointments, visits to their general practitioner and general advice from their medical team to remain active and eat a healthy diet. |
What Procedures | |
Provider | Physiotherapist and dietitian with oncology experience provided by the hospital | Usual hospital staff |
How | Face to face sessions | No intervention |
Where | Hospital gymnasium | No intervention |
When/How much Intensity Frequency Session time Overall duration | Exercise | Nutrition | • Standardised written advice about exercise and cancer guidelines |
Moderate (BORG 4–6) 60–80% HR maximum 60–80% 1-RM | |
2x weekly in centre 1X weekly at home | Fortnightly |
60 minutes | 30 minutes |
8 weeks |
Tailoring | • Individualised exercise program and nutrition advice based on initial consultation and goals | • None |
Trial fidelity | • Staff with a background in oncology physiotherapy and dietetics who had prior formal training were employed by the hospital to provide the intervention • Exercise log-books will be completed and reviewed by research staff. Estimated 1-RM testing will be reassessed at week 4 to ensure sufficient strength training stimulus. • Nutrition log-books will be completed and reviewed by research staff. • Records of the number and duration of completed sessions. • Monthly meetings with clinical research staff | • Participants will be asked if they participated in any physical activity or nutrition intervention during the usual care period. |
Study outcomes
Participants will complete an assessment of physical capacity, physical activity, inflammation, time to engraftment, health-related quality of life, self-efficacy, nutritional status and muscle strength at baseline and after the intervention phase at week 8 (pre-transplant) and week 13 (post-transplant infusion). Hospital length of stay will be recorded at week 13, and emergency department, Symptom and Urgent Review Clinic (SURC) presentations and hospital readmissions will be recorded at week 25 from hospital data bases. A trained allied health clinician blind to group allocation will complete baseline and follow-up assessments to ensure blinding of outcome measures. Peripheral blood count analysis and blood product use will be completed by an independent assessor, blinded to group allocation. Primary and secondary outcomes are outlined in Table 2.
Adverse events related to the intervention as defined by the World Health Organization [27] will be documented to report safety of the intervention. The event may or may not be related to the intervention, but it occurs while the person is participating in the intervention phase (during prehabilitation) of the trial. Adverse events will be categorised as minor adverse events or serious adverse events. A minor adverse event is defined as an incident that occurs
while participating in the intervention that results in no injury or minor injury (e.g. fatigue, exacerbation of pre-existing musculoskeletal pain) that requires none or minor medical intervention. A serious adverse event is defined as an incident that occurs while the person is participating in the intervention that results in death, serious injury or re-hospitalisation.
Table 2
Primary and secondary outcomes
Primary outcome | Measure/source | Definition |
Physical Capacity | 6-Minute Walk Test | Change in walk distance (m) pre-post intervention. Primary endpoint is 4 weeks post-transplant infusion |
Secondary outcomes | | |
Physical Activity | ActivPal™ | Change in time spent walking, standing, sitting, sit-to-stand transitions, and step count pre and post intervention. Participants will wear the activity monitor continuously or 8 consecutive days. Only complete 24-hour recording days will be included for analysis. However, as monitors may need to be removed for the purpose of swimming or bathing, evidence of non-wear matching with an activity logbook will still be included. |
Health-Related Quality of Life | EORTC-QLQ C30 and EORTC QLQ-HDC29 | Change of score on validated quality of life questionnaires QLQ-C30 and HDC29 pre and post intervention. |
Self-efficacy for physical activity | Questionnaire developed using HAPA (Additional file 2) | Change of score on self-efficacy questionnaire for physical activity pre and post intervention. |
Nutritional status | PG-SGA | Change of score on validated PG-SGA pre and post intervention. |
Handgrip strength | Jamar handgrip dynamometer | Change in handgrip strength (kg) pre and post intervention assessed using the best measure of 6 trials (3 in each hand). |
Inflammation | C-Reactive Protein | Change in CRP levels pre and post intervention. Patients will be instructed not to undertake moderate to vigorous intensity exercise for 24 hours prior to collection. |
Stem cell engraftment | Routine blood samples | Number of days from transplant to engraftment. Engraftment is defined as neutrophils > 0.5 × 109/L for three days without support and platelets > 50 × 109/L for five days without transfusion. |
Hospital length of stay | Hospital database | Days that the patient is in the hospital from day of stem cell infusion to day of discharge. |
ED/SURC presentations | Hospital database and electronic medical record | Number of emergency department presentations and Symptom and Urgent Review Clinic (SURC) presentations over three months after discharge from the autologous stem cell transplant admission. |
Hospital re-admissions | Hospital database | Number of hospital readmissions over 3 months after discharge from the autologous stem cell transplant admission and associated inpatient days with each readmission |
EORTC QLQ: European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire; PG-SGA Patient-Generated Subjective Global Assessment; HAPA: Health Action Process Approach |
Reasons for non-participation in an exercise session or non-completion of the program will be recorded (e.g. pain, fatigue, unwell). Complications related to the stem cell transplant procedure will also reported for each group (e.g. infection, bleeding, mucositis, parental nutrition requirements, intensive care support).
Other routinely collected data will be used to describe the sample including age, gender, cancer type, cancer stage, treatment regimens, co-morbidities, functional performance status (AKPS and ECOG), body mass index.
Sample size estimation
To gain a preliminary understanding of the effect of the intervention on clinical outcomes, a sample size sufficient to detect a clinically significant between-group difference in physical capacity of 53 m, assuming a large effect size of 1.3 at a power of 0.8 and an alpha level of 0.05, will be sought. It was calculated a sample of 22 patients waitlisted for autologous stem cell transplant at the health service would be adequate. No minimal clinically significant difference has been calculated in patients receiving autologous stem cell transplant therefore it was estimated to be 41 m based on half a standard deviation [28] of scores of a mixed cohort of cancer survivors [29]. Approximately 30 people are treated with autologous stem cell transplant at the health service annually. Our sample size represents a recruitment rate of 75% which is similar to a recently completed cancer rehabilitation trial at the health service [30].
Statistical analysis
The primary outcome (physical capacity at 4-weeks post-transplant) will be analysed using linear mixed effects models. Modelling will account for variation in baseline values. This method accounts for within-participant dependence of observations over time, and for missing data, allowing some participants to have missing observations at certain time points. If more than 5% of data are missing, a multiple imputation process will be used, providing the assumption data are missing at random is met. A similar approach will be used for analysis of continuous secondary outcomes collected longitudinally. The time spent in moderate to vigorous physical activity will be estimated using a cut-off of 100 steps/minute for moderate intensity physical activity [31]. The proportion of participants meeting physical activity guidelines will be described and compared between groups with a risk ratio. The number of emergency department, SURC presentations and hospital admissions will be reported as an incidence rate ratio using a negative binomial regression model. To avoid bias and to maximize the randomisation process, all available data will be analysed according to allocation (intention to treat analysis), regardless of compliance.