Prehabilitation to improve function after autologous stem cell transplantation: A pilot randomized controlled trial (PIRATE).

Background

Autologous stem cell transplantation (autoSCT) improves survival and provides long term disease control for haematological malignancies [ 1 ]. Despite advances in survivorship, people undergoing autoSCT experience adverse treatment effects including fatigue, deconditioning, and psychological distress leading to ongoing functional decline and poor quality of life [ 2 – 4 ]. AutoSCT recipients are also at high risk of developing secondary cancers, and experience high rates of hospital readmission [ 1 , 5 ].

Exercise and nutrition interventions are strongly recommended during cancer treatment, including autoSCT [ 6 ]. These interventions are safe and reduce fatigue, weight-loss and improve function and quality of life in people receiving autoSCT [ 7 – 13 ]. However, the optimal time to provide intervention is unknown, with most trials targeting the peri and post-transplant period [ 7 – 9 ]. Exercise and nutrition interventions delivered pretransplant (prehabilitation) may elicit superior benefits by building functional reserves prior to transplant. Exercise prior to stem cell transplant may result in better outcomes than post-transplant including reduced hospital length of stay of 2 days [ 8 , 9 ]. No trials currently have evaluated combined supervised exercise and nutrition prehabilitation in autoSCT which may provide additional benefit to prevent post-transplant malnutrition [ 14 ]. Therefore, a pilot evaluation of combined exercise and nutrition prehabilitation in autoSCT is needed to determine if a full-scale randomized controlled trial is warranted [ 15 ].

The primary aim of this pragmatic pilot trial was to explore efficacy and provide estimates of effect of multidisciplinary prehabilitation on post-autoSCT physical capacity. Secondary aims were to explore feasibility evaluated through safety and exercise adherence; and efficacy on physical and nutritional status, health-related quality of life, and health service outcomes.

Methods

Study design

A prospective, pragmatic, parallel, single-blind, pilot randomized controlled trial was conducted at a large public tertiary hospital in metropolitan Melbourne, Australia from April 2021 to March 2023. Due to frequent changes in COVID-19 restrictions during this time, recruitment was paused for four-months. Final participants were recruited in August 2022. However medical delays to completing the transplant procedure for the final four participants resulted in extended duration of the trial. The protocol for this study has been published [ 16 ] and was registered prospectively (ACTRN12620000496910). Procedures were approved by the hospital’s ethics committee (E20/003/61055) and are reported consistent with the CONSORT statement for pilot and feasibility trials [ 17 ].

Participants were randomly allocated to either an experimental or usual care control group after baseline assessment according to an online computer-generated randomization program, using permuted blocks without stratification. Allocations were prepared prior to trial commencement by an independent researcher with no role in subject recruitment or administration of interventions. The trial coordinator allocated participants after baseline assessment by contacting the independent researcher by email for allocation. Outcome measures were performed at baseline (T0, week 0), the end of the intervention, before autoSCT (T1, approximately week 8) and 1-month after autoSCT (T2, week 12) by an assessor blinded to group allocation.

Participants

Participants: were aged 18 years and over; had a hematological malignancy and were waitlisted for autoSCT. Participants were excluded if they: were medically unfit to exercise as determined by a clinician based on recommendations (e.g. unstable bony metastases, haemodynamic instability) [ 18 ]; had low physical performance status (Eastern Cooperative Oncology Group (ECOG) score > 2) [ 19 ]; or cognitive impairment precluding ability to provide written, informed consent. Patients were screened consecutively and all patients meeting inclusion were approached for enrolment by the nurse coordinator. T0 measurements were obtained following the consent process.

Intervention

All participants received usual care. Usual care in this trial comprised an assessment with a physiotherapist (60 min), who provided standardized written instructions with guidelines for exercise [ 20 – 22 ] and a referral to a cancer rehabilitation program after autoSCT. Both groups received a comprehensive dietary assessment using the Australian Eating Survey [ 23 ] facilitated by the blinded assessor at T0 and T2. Collection of dietary data from control group participants was in addition to methods reported in the published protocol and enabled comparison of between-group intake [ 24 ]. Participants received their usual medical care, which may have included adjuvant chemotherapy, radiotherapy, inpatient admission, outpatient appointments and general practitioner visits.

Experimental group (prehabilitation)

In addition to usual care, participants allocated to the experimental group received an individualized exercise program. Participants performed twice-weekly, 60-min exercise sessions individually at home, supervised by a cancer physiotherapist for up to 8-weeks pre-transplant (Supplementary File 1 ). To aid adherence, session times were negotiated individually with participants. Exercise sessions comprised moderate-intensity aerobic and resistance exercise [ 6 , 16 ]. Participants completed approximately 25 min each aerobic and resistance exercise, 5-min flexibility/balance training and 5-min warm up and cool down. Initially, participants aimed to exercise at a BORG RPE of 3 (moderate), progressing to a 5–6 (hard) by week 8. For resistance exercise, weights were progressed once a participant achieved 2 to 3 sets of 10–12 repetitions. Resistance exercise included body-weight upper and lower body exercises, free weights, and resistance bands. Aerobic exercise included walking or portable stepper machine. Participants were encouraged to complete an additional once-weekly unsupervised 30-min aerobic exercise session independently and provided with a Fitbit Inspire device to assist compliance with exercise guidelines [ 6 ].

At baseline, all participants were categorized using GLIM Criteria to identify malnutrition risk [ 25 ]. Participants allocated to the experimental group received a further 60-min comprehensive consultation with an Accredited Practising Dietitian who provided written information and tailored medical nutrition therapy via fortnightly phone or video calls pre-transplant (up to 4 review sessions). These sessions focused on supporting oral intake and maintaining nutritional status pre-autoSCT and managing gastrointestinal symptoms post-transplantation [ 26 ].

Outcomes

Patient outcomes were measured at T0, T1 and T2. Hospital length of stay was recorded at T2, emergency department, Symptom and Urgent Review Clinic (SURC) presentations and hospital readmissions were recorded at week 25 from hospital databases.

Primary outcome: physical capacity at T2

Physical capacity was measured as walk distance (m) using the 6-min walk test. The 6-min walk test is a valid and reliable measure of physical function in cancer survivors [ 27 ].

Secondary outcomes

Adverse events were categorised as minor or serious and graded according to Common Terminology Criteria for Adverse Events (CTCAE V5) [ 28 ]. Reasons for non-adherence to exercise or non-completion of the program, including both medical (e.g. fatigue, unwell) and psychosocial reasons and complications related to transplant procedure were recorded.

Physical status measures included: moderate-intensity physical activity and sedentary time measured by a tri-axial accelerometer-based activity monitor (ActivPAL™, PAL Technologies Ltd., Glasgow, UK) [ 29 ], self-reported physical activity self-efficacy [ 30 ], C-reactive protein, time to stem cell engraftment (neutrophils > 0.5 × 10 9 /L for three days without support and platelets > 50 × 10 9 /L for five days without transfusion) [ 31 ] and handgrip strength [ 32 ]. Nutritional status was assessed by Patient-Generated Subjective Global Assessment (PG-SGA) [ 33 ]. The European Organization for Research and Treatment of Cancer QoL Questionnaire-C30 (EORTC-QLQ C30) [ 34 ] and high dose chemotherapy supplement (EORTC-HDC 29) assessed quality of life [ 35 ].

Data analysis

Anticipating a clinically significant change of 41 m on the 6-min walk test [ 27 ], a minimum total sample of n = 12 to produce a one-sided 80% confidence limit that would exclude an effect of 0.5 would be required. A one-sided 90% confidence interval would require a larger sample size of n = 28. Therefore, we recruited 22 participants for this pilot study [ 36 ]. An estimate of effect meeting or exceeding clinical significance would justify proceeding to a larger trial.

The primary outcome was analysed using linear mixed effects models. This method allowed participants to have missing observations at certain time points. Multiple imputation was not used as the assumption of data missing at random was not met [ 37 ]. Linear mixed effects models were also applied for analysis of continuous secondary outcomes. Physical activity data were included where there were at least 3 full (24 h) days of data [ 38 ]. Number of adverse events and intervention adherence was described. Proportion of participants meeting physical activity [ 39 ] and nutritional intake [ 24 ] guidelines was described and compared between groups with a risk ratio. The number of emergency department, SURC presentations and hospital admissions were described due to the low number of expected events. Differences in hospital length of stay and time to engraftment were calculated using Mann–Whitney U tests. All available data were analyzed as per group allocation using intention-to-treat principles, regardless of adherence [ 40 ]. Data were analyzed using IBM SPSS v29.

Impact of COVID-19 pandemic

This trial commenced April 2021 and was completed in March 2023. Modifications were made in response to frequent changes in COVID-19 restrictions during the trial period, as Melbourne was the most locked-down city in the world (263 days) [ 41 ]. Fewer autoSCT were completed and there were periods where non-essential care, including research, was not permitted. The intervention was converted to a home setting [ 16 ], with most exercise sessions conducted in-person, with some completed via videocall. All nutrition interventions were conducted by telehealth (phone or video call). Some physical outcome measurements (6MWT and handgrip strength) were unable to be completed and nutrition outcomes relied on self-report (bodyweight) or video call (PG-SGA).

Results

Thirty-seven patients were approached (Fig. 1 ). Of those, 10 were ineligible. Twenty-two participants consented (recruitment rate 81% of eligible patients) and were allocated. All participants received the intervention as allocated. One participant had their transplant cancelled and another put on hold indefinitely at the end of the intervention period. On average, participants were aged 63 years (range 36 to 71), male ( n = 15, 68%) diagnosed with multiple myeloma ( n = 20, 91%) and were recruited, on average, 13 weeks prior to autoSCT (Table 1 ). Half the participants had stable bony lesions ( n = 11). One usual care group participant was severely malnourished at baseline. Participants were generally well matched at baseline. However, participants in the experimental group were younger, and more time had elapsed since diagnosis. Fig. 1 Flow of participants through trial. Abbreviations: 6mWT 6 min walk test; PG-SGA Patient Generated Subjective Global Assessment; AES Australian Eating Survey; ICU Intensive Care Unit Table 1 Baseline characteristics Randomized Total n = 22 UC n = 11 Exp n = 11 Age (years), median (IQR) 63.0 (53.8 to 67) 65.0 (59 to 70) 57.0 (52 to 64) Gender , n male (%) 15 (68) 7 (64) 8 (73) Ethnicity, n (%) White Australian 18 (82) 9 (82) 9 (82) Asian 2 (9) 1 (9) 1 (9) Aboriginal or Torres Strait Islander 0 (0) 0 (0) 0 (0) Other 2 (9) 1 (9) 1 (9) Current work, y (%) 8 (36) 5 (45) 3 (27) Home alone, y (%) 6 (27) 3 (27) 3 (27) BMI (kg/m 2 ), median (IQR) 30.6 (25.8 to 32.5) 28.8 (25.7 to 31.6) 31.7 (25.9 to 34.6) Comorbidities , y (%) Musculoskeletal 12 (43) 4 (36) 8 (73) Cardiovascular 10 (36) 6 (55) 4 (36) Respiratory 5 (18) 3 (27) 2 (18) Endocrine 4 (14) 0 (0) 4 (36) Other 8 (29) 6 (55) 2 (18) Time since cancer diagnosis (months), median (IQR) 6 (3.8 to 12.8) 5.0 (3.0 to 7.0) 9.0 (5.0 to 18.0) Time from assessment to transplant (weeks), median (IQR) 11.9 (9.0 to 16.04) 14.0 (9.0 to 16.43) 12.0 (8.1 to 15.9) Cancer Type Multiple Myeloma 20 (91) 11 (100) 9 (82) Hodgkins Lymphoma 1 (5) 0 (0) 1 (9) Non-Hodgkins Lymphoma 1 (5) 0 (0) 1 (9) Bony lesions , y (%) 11 (50) 7 (64) 4 (36) Current treatment type VRD 14 (50) 7 (64) 7 (64) VCD 4 (14) 2 (18) 2 (18) R-ICE 1 (4) 0 (0) 1 (9) Pembrolizumab 1 (4) 0 (0) 1 (9) Pomalidomide 1 (4) 1 (9) 0 (0) Daratuzumab 1 (4) 1 (9) 0 (0) ECOG score , n (%) 0 = Fully active 5 (23) 3 (27) 2 (18) 1 = Restricted strenuous activity 17 (77) 8 (73) 9 (82) GLIM Rating No malnutrition, y (%) 21 (75) 10 (91) 11 (100) Severe malnutrition, y (%) 1 (4) 1 (9) 0 (0) Meeting or exceeding ESPEN estimated daily intake requirements, y (%) 11 (50) 7 (64) 4 (36) Meeting PA guidelines (COSA), y (%) 6 (27) 2 (18) 4 (36) BMI Body Mass Index, ECOG Eastern Cooperative Oncology Group, GLIM Global Leadership Initiative on Malnutrition, ESPEN The European Society for Clinical Nutrition and Metabolism, COSA Clinical Oncology Society of Australia

Adherence with study protocol

Time available for prehabilitation varied from 2 to 8 weeks. A total of 99 exercise sessions (Mean 9 SD 4 per participant) and 32 nutrition sessions (Mean 4 SD 1 per participant) were completed. Eight participants (72%) attended ≥ 50% of scheduled exercise sessions. The most common reasons for missing sessions were other appointments (16 missed sessions) or being unwell due to treatment-related side-effects (13 missed sessions). Eight participants (72%) attended all nutrition sessions and three participants missed one session each ( n = 1 work, n = 1 unwell, n = 1 hospital admission) (Fig. 1 ). Experimental participants completed 77 (SD 73) minutes of weekly moderate-intensity exercise during prehabilitation.

Adverse events

No major adverse events resulted from prehabilitation. Two participants declined to wear the physical activity monitor at follow-up due to skin discomfort/irritation at T0. Three participants reported minor adverse events that resolved with rest (delayed muscle soreness n = 2, dizziness n = 1). Participants experienced, on average, 3 complications post-autoSCT. The most common complications were diarrhea ( n = 14) and febrile neutropenia ( n = 11). Five participants experienced disease progression or relapse (Supplementary file 2 ).

Effect on primary outcome

A between-group difference of + 141 m (95% CI 24 to 257 m) favoring the experimental group was observed for the primary outcome (T2 6-min walk distance) (Table 2 ). A between-group difference of + 61 m favoring the experimental group was also observed at T1. The size of the effect (d = 1.4, 95% CI 0.12 to 2.5) exceeded clinical significance [ 42 , 43 ]. Table 2 Mean (SD) of groups, mean (95% CI) difference within groups, and mean (95% CI) difference between groups Outcome Groups Difference within groups Difference between groups (95%CI) Standardised mean difference (95%CI) Baseline (T0) Pre-transplant (T1) 1-month post-transplant (T2) T1 minus T0 T2 minus T0 T1 minus T0 T2 minus T0 T2 Exp ( n = 11) Con ( n = 11) Exp ( n = 11) Con ( n = 11) Exp ( n = 11) Con ( n = 11) Exp Con Exp Con Exp-Con Exp-Con Exp-Con 6-min walk test (m) 442.3 (383.8 to 500.9) 486.2 (432.6 to 539.8) 518.2 (455.5 to 581.0) 501.5 (443.2 to 559.8) 565.5 (477.4 to 653.6) 468.6 (410.6 to 526.6) 67.7 (7.6 to 127.8) 9.6 (−54.3 to 73.0) 136.7 (−110.7 to 384.0) −17.1 (−127.9 to 93.8) 60.6 (−40.2 to 161.5) 140.8 (24.3 to 257.3) 1.4 (0.12 to 2.5) Self-Efficacy (0–3) 2.2 (1.8 to 2.6) 2.3 (1.9 to 2.8) 1.9 (1.5 to 2.3) 2.2 (1.8 to 2.6) 1.6 (1.1 to 2.1) 1.9 (1.5 to 2.3) −0.29 (−0.81 to 0.24) −0.16 (−0.8 to 0.5) −0.66 (−1.6 to 0.27) −0.5 (−0.8 to 0.5) −0.12 (−0.87 to 0.62) −0.14 (−0.92 to 0.65) −0.43 (−1.3 to 0.51) Weight (kg) 89.0 (87.4 to 90.7) 89.6 (87.9 to 91.2) 90.2 (88.5 to 91.8) 89.2 (87.5 to 90.9) 87.1 (85.0 to 89.3) 85.6 (83.9 to 87.3) 1.1 (−0.63 to 2.9) −0.4 (−2.2 to 1.4) −1.8 (−5.9 to 2.4) −4.0 (−7.2 to −0.8) 1.5 (—1.3 to 4.3) 2.1 (- 1.0 to 5.2) 0.58 (−0.48 to 1.58) PG-SGA score (0-) 3.0 (0.86 to 5.1) 2.6 (0.56 to 4.7) 3.0 (0.86 to 5.1) 2.1 (0.01 to 4.2) 8.4 (5.8 to 11.0) 8.1 (5.9 to 10.3) 0.00 (−1.2 to 1.2) −0.55 (−2.3 to 1.2) 5.8 (−0.54 to 12.3) 5.4 (1.4 to 9.3) 0.55 (−3.5 to 4.6) −0.01 (−4.4 to 4.4) 0.09 (−0.88 to 1.05) Handgrip strength (kg) 39.3 (36.9 to 41.8) 41.2 (38.9 to 43.5) 40.7 (37.8 to 43.7) 41.9 (39.4 to 44.4) 35.5 (31.7 to 39.2) 36.2 (33.7 to 38.7) 2.2 (−1.0 to 5.4) 0.9 (−2.5 to 4.2) −3.5 (−16.6 to 9.6) −4.9 (−9.5 to −0.3) 0.73 (−3.9 to 5.4) 1.2 (−4.0 to 6.4) −0.19 (−1.3 to 0.92) C-Reactive Protein (mg/L) 8.3 (−4.8 to 21.4) 1.9 (−13.8 to 16.9) 13.9 (0.8 to 27.0) 1.8 (−13.8 17.5) 17.1 (1.6 to 32.4) 1.9 (−16.4 to 20.2) 5.6 (−16.1 to 27.4) −1.1 (−3.6 to 1.4) 7.7 (−29.6 to 45.0) −2.0 (−4.2 to 0.2) 5.7 (−21.6 to 33.0) 8.7 (- 21.5 to 38.9) 0.68 (−0.44 to 1.7) MVPA (minutes) 15.4 (9.7 to 21.1) 14.8 (9.1 to 20.5) 9.5 (3.1 to 15.9) 18.9 (12.9 to 24.8) 5.4 (−1.3 to 12.0) 11.1 (5.2 to (17.0) −6.4 (−12.0 to −0.3) 4.3 (−6.5 to 15.1) −11 (−23.8 to 1.9) −3.4 (−10.5 to 3.5) −10.0 (−1.1 to 21) - 6.3 (−17.6 to 5.0) −0.60 (−1.50 to 0.36) Sedentary time (hours) 19.0 (18.2 to 19.8) 18.6 (17.9 to 19.4) 19.3 (18.4 to 20.1) 18.5 (17.7 to 19.3) 20.6 (19.7 to 21.5) 20.1 (19.3 to 20.9) 0.27 (−0.36 to 0.91) −0.1 (−1.3 to 1.0) 1.7 (0.3 to 3.1) 1.5 (0.0 to 3.0) 0.430 (−1.0 to 1.9) 0.2 (−1.6 to 1.3) 0.38 (−0.55 to 1.29) EORTC QLQ C30 (0–100) Global 78.7 (70.0 to 87.4) 79.4 (70.7 to 88.1) 77.2 (68.4 to 85.9) 80.2 (71.5 to 88.9) 63.4 (53.2 to 73.6) 60.4 (51.7 to 69.1) −1.5 (−7.6 to 4.5) 0.8 (−11.9 to 13.4) −16.7 (−27.8 to −5.5) −18.9 (−37.2 to −0.7) −2.3 (−19.1 to 14.5) 3.7 (−14.0 to 21.3) 0.21 (−0.72 to 1.11) Physical Function 85.1 (77.1 to 93.1) 88.3 (80.4 to 96.2) 89.3 (81.3 to 97.3) 84.2 (76.2 92.0) 81.7 (72.5 to 90.9) 67.7 (59.8 to 75.6) 4.2 (−6.0 to 14.5) −4.2 (−8.8 to 0.4) −4.2 (−23.2 to 14.9) - 20.6 (−32.0 to −9.2) 8.5 (−5.7 to 22.7) 17.2 (2.3 to 32.1) 1.07 (0.06 to 1.99) Role Function 82.5 (70.5 to 94.5) 86.9 (75.0 to 98.8) 85.6 (73.6 to 97.6) 83.8 (71.9 to 95.8) 76.9 (63.0 to 90.9) 56.6 (44.7 to 68.5) 3.0 (−11.8 to 17.9) −3.0 (−12.8 to −8.8) −4.2 (−32.8 to 24.4) −30.3 (−52.0 to −8.6) 6.1 (−16.5 to 28.6) 24.7 (1.1 to 48.3) 1.03 (0.02 to 1.95) Emotional Function 87.1 (78.2 to 95.9) 86.5 (77.8 to 95.2) 85.5 (76.7 to 94.4 88.9 (80.3 to 97.6) 88.3 (78.2 to 98.4) 85.0 (76.3 to 93.7) −1.5 (−9.4 to −11.8) 3.0 (−7.8 to 12.3) 2.1 (−8.3 to 12.5) −1.5 (−20.2 to 17.2) −3.924 (−19.3 to 11.4) 2.8 (−13.4 to 18.9) 0.23 (−0.69 to 1.14) Cognitive function 83.7 (73.7 to 93.7) 85.6 (75.7 to 95.6) 83.698 (73.7 to 93.7) 88.7 (78.7 to 98.6) 87.3 (75.7 to 99.0) 76.6 (66.6 to 86.5) 0 (−10.0 to 10.0) 3.0 (−8.0 to 14.0) 4.2 (−2.3 to 10.6) −9.1 (−30.5 to 12.4) −3.0 (−22.5 to 16.4) 12.7 (−7.6 to 33.0) 0.65 (−0.31 to 1.6) Social Function 79.2 (68.5 to 90.0) 83.0 (72.3 to 93.7) 80. 8 (70.0 to 91.5) 84.5 (73.8 to 95.226 71.0 (58.5 to 83.6) 61.8 (51.0 to 72.5) 1.5 (−17.5 to 20.6) 1.5 (−7.8 to 10.8) −8.3 (−34.1 to 17.5) −21.2 (−34.5 to −7.9) (0.00 −20.9 to 20.9) 13.0 (−8.8 to 34.8) 0.52 (−0.43 to 1.4) Fatigue 29.3 (19.5 to 39.3) 27.2 (17.4 to 37.1) 32.4 (22.5 to 42.3) 22.2 (12.3 to 32.0) 46.0 (34.4 to 57.5) 46.4 (36.6 to 56.3) 3.0 (−5.9 to 11.9) −5.1 (−12 to 1.9) 16.7 (−11.4 to 44.8) 19.2 (5.8 to 32.6) 8.1 (−11.1 to 27.2) −2.6 (−22.6 to 17.5) −0.03 (−0.94 to 0.88) Pain 20.8 (11.2 to 30.4) 20.3 (10.7 to 29.9) 23.8 (14.2 to 33.4) 15.8 (6.2 to 25. 4) 11.0 (−0.21 to 22.3) 12.8 (3. 2 to 22. 4) 3.03 (−17.5 to −5.9) −4.5 (−13.3 to 4.2) −10.4 (−28.6 to 7.7) −7.6 (−19.2 to 4.0) 7.6 (−11.1 to 26.2) −2.2 (−21.7 to 17.3) −0.11 (−1.0 to 0.81) Dyspnoea 19.0 (7.8 to 30.2) 20.3 (9.1 to 31.5) 6.8 (−4.4 to 18.0) 17.3 (6.1 to 28.4) 10.0 (−3.1 to 23.0) 23.3 (12.2 to 34.5) −12.1 (−23.4 to −0.8) −3.0 (−21.6 to 15.6) −8.3 (−28.0 to 11.4) 3.0 (−18.1 to 24.2) −9.1 (−30.8 to 12.6) −12.0 (−34.7 to 10.7) −0.72 (−1.6 to 0.25) Insomnia 23.1 (7.4 to 38.8) 27.7 (12.0 to 43.3) 26.2 (10.5 to 41.8) 24.7 (9.0 to 40.3) 39.1 (20.4 to 57.6) 21.6 (5.9 to 37.3) 3.0 (−15.6 to 21.6) −3.0 (−24.2 to 18.1) 20.8 (−21.1 to 62.8) −6.1 (−34.1 to 21.9) 6.1 (−24.2 to 36.3) 22.0 (−9.8 to 53.7) 0.67 (−0.29 to 1.6) Appetite 7.3 (−6.5 to 21.1) 4.7 (−9.1 to 18.4) 10.3 (−3.5 to 24.1) 4.7 (−9.1 to 18.4) 27.4 (11.3 to 43.5) 31.9 (18.2 to 45.7) 3.0 (−9.0 to 15) 1.5 (−4.0 to 7.1) 20.8 (−4.7 to 46.4) 27.3 (−2.5 to 57.0) −3.0 (−23.7 to 29.77) −7.2 (−35.1 to 20.8) −0.20 (−1.1 to 0.72) BMT-29 (0–100) Gastrointestinal symptoms 12.6 (7.8 to 17. 3) 12.1 (7.4 to 16.8) 9.5 (4.8 to 14.3) 10.3 ( 5.5 to 14.9) 15.7 (10.2 to 21.2) 18.7 (14.0 to 23.4) −3.0 (−8.1 to 2.0) −1.8 (−6.3 to 2.7) 3.3 (−10.0 to 16.7) 6.7 (0.0 to 13.3) −1.2 (−10.2 to 7.9) −3.5 (−13.0 to 5.9) −0.39 (−1.3 to 0.54) Anxiety 16.8 (8.2 to 25.3) 17.0 (8.5 to 25.4) 17.8 (9.3 to 26.3) 18.8 (10.4 to 27.2) 21.9 (12.2 to 31.7) 22.3 (13.8 to 30.7) 1.0 (−5.2 to 7.2) 2.0 (−5.3 to 9.3) 5.6 (−16.5 to 27.6) 5.3 (−4.6 to 15.2) −0.84 (−12.8 to 14.5) −0.15 (−14.5 to 14.2) −0.02 (−0.93 to 0.89) Family 30.2 (21.0 to 39.4) 25.73 (16.6 to 34.9) 24.9 (15.7 to 34.1) 28.8 (19.7 to 37.9) 32.4 (21.7 to 43.1) 40.3 (31.0 to 49.3) −5.3 (−21.6 to 11.) 3.0 (−15.6 to 21.6) 4.2 (−15.2 to 23.5) 14.4 (3.5 to 25.3) 8.4 (−26.1 to 9.4) −12.2 (−30.8 to 6.4) −0.51 (−1.4 to 0.44) Body Image 15.7 (4.6 to 26.9) 13.4 (2.3 to 24.4) 20.3 (9.1 to 31.5) 8.8 (−2.2 to 19.9) 32.3 (19.4 to 45.3 28.5 (17.4 to 39.6) 4.5 (−4.3 to 13.3) −4.5 (−11.8 to 2.7) 16.7 (−4.4 to 37.7) 15.2 (−5.8 to 36) 9.1 (−11.5 to 29.7) 1.4 (−20.1 to 23.0) 0.21 (−0.71 to 0.44) Ache 20.0 (8.0 to 31.9) 21.7 (9.9 to 33.6) 35.1 (23.1 to 47.0) 24.8 (12.9 to 36.7) 10.0 (−3.9 to 24.0) 15.7 (3.8 to 27.6) 15.2 (−3.2 to 33.5) 3.0 (−15.6 to 21.6) −8.3 (−33.0 to 16.4) −6.1 (−25.6 to 13.5) 12.1 (−10.8 to 35.0) −3.8 (−27.8 to 20.1) −0.29 (−1.2 to 0.64) Life 59.2 (39.9 to 78.5) 38.3 (19.2 to 57.4) 62.2 (42.9 to 81.5) 56.5 (37.4 to 75.5) 62.6 (40.5 to 84.8) 47.4 (28.3 to 66.4) 3.0 (−22.4 to 28.5) 18.2 (−10.8 to 47.1) 8.3 (−40.5 to 57.2) 9.1 (−13.5 to 31.7) −15. 2 (−51.9 to 21.6) −5.6 (−44.2 to 33.0) 0.49 (−0.46 to 0.48) NB Means adjusted for baseline differences in age, time since diagnosis and outcome for between group analyses; Bold indicates significance at p < 0.05

Effect on secondary patient outcomes

Large between-group differences favoring the experimental group were observed for physical (17 points, 95% CI 2 to 32) and role function (25 points, 95% CI 1 to 48) subscales on the EORTC-QLQ C30 at T2. No other secondary outcome achieved significance. However, moderate-to-large effects favoring the experimental group at T2 were observed for higher body weight (+ 2 kg, 95% CI −1 to 5.2), improved cognitive (+ 13 points, 95% CI −8 to 33), social function (+ 13 points, 95% CI −9 to 35), being able to distinguish what is important in life (−6 points, 95% CI −44 to 33 points) and reduced dyspnea (−12 points, 95% CI −35 to 11) and gastrointestinal symptoms (−3.5 points, 95% CI −13 to 5.9).

Participants in the experimental group were not more likely to achieve physical activity [ 39 ] (RR 0.972, 95% CI 0.694 to 1.357) or nutritional intake recommendations [ 24 ] (RR 0.917, 95% CI 0.381 to 2.206) than the usual care group (supplementary file 3 ). Calcium was the most deficient micronutrient ( n = 3, 17%).

Effect on secondary health service outcomes

Time to stem cell engraftment was similar between groups (z = −0.423, p = 0.672) (Table 3 ). Table 3 Health service outcomes Experimental Group n = 9 Control Group n = 11 Hospital Length of Stay Median (IQR), days 15 (14 to 23) 17 (13 to 19) Time to engraftment Median (IQR), days 19 (16 to 20) 18 (16 to 19) ED presentations number of participants (%) 1 (11) 2 (18) Hospital readmissions number of participants (%) 1 (11) 1 (9) SURC presentations number of participants (%) 3 (33) 3 (27) NB N = denotes number of participants. Only one participant in the experimental group contacted the SURC clinic 4 times

There was no between-group difference in hospital length of stay (z = −0.343, p = 0.731). Two participants in the control group and one in the experimental group presented to the emergency department and one patient in each group was readmitted to hospital in the 3 months following transplant (Table 3 ).

Discussion

This randomized controlled trial found multidisciplinary prehabilitation for people awaiting autoSCT was safe, feasible and may result in better walking capacity. Large estimates of effect were observed for self-reported function, higher body weight and less dyspnea and gastrointenstinal symptoms at 1-month post-transplant compared to usual care. There was uncertainty regarding whether prehabilitation had a positive effect on overall quality-of-life or health service outcomes. This is the first pilot trial to evaluate combined exercise and nutrition prehabilitation for autoSCT, with results justifying a larger full-scale trial to confirm effectiveness.

This trial establishes safety of multidisciplinary prehabilitation, aligning with previous evidence supporting exercise prehabilitation [ 9 , 44 ]. This is important given this population may be more vulnerable than other cancer cohorts when participating in physical rehabilitation due to high dose chemotherapy and disease processes causing immunocompromise, bony disease with potential instability and hemodynamic instability [ 45 , 46 ]. The safety of prehabilitation may be attributed to guideline-informed design of assessment and intervention delivered by trained clinicians [ 6 , 18 , 47 ]. These guidelines help provide a framework for decision making about participant suitability and tailoring prehabilitation interventions to optimize safety.

The feasibility of multidisciplinary prehabilitation was indicated by high recruitment, (81% of eligible participants) retention (87%) and attendance to sessions. These rates were much higher than previous studies (e.g. 46%−56% recruitment, 57–60% retention at discharge [ 48 , 49 ]). In our trial, the clinical nurse coordinator was critical for ensuring patients attending the haematology clinic were aware of the study by following ‘ask, assess, refer’ recommendations in their transplant education sessions [ 39 , 50 ].

Acceptability of the trial may have been positively influenced by the home-based setting. Typically, rehabilitation interventions (including prehabilitation), are provided in a health facility [ 51 , 52 ]. However, this patient cohort have many competing medical demands in preparation for their procedure [ 49 , 53 ]. Home-based therapy provides convenience and lower treatment burden [ 54 , 55 ] to overcome these issues although the appropriateness of home-based therapy for patients with unstable bone disease needs to be considered. Participants with unstable bony lesions require high levels of supervision by an exercise professional and may be better suited to being treated within a health facility where the specialist treating team available to communicate with exercise professionals and patients about their capacity to exercise safely [ 47 ]. Telehealth can also overcome many participation barriers and is a feasible and effective alternative to face-to-face care [ 56 ]. The addition of telehealth for nutrition and some exercise sessions because of COVID-19 restrictions allowed participants to continue with rehabilitation during a vulnerable time.

Preliminary evidence of efficacy of multidisciplinary prehabilitation was demonstrated by positive estimates of effect for improved walking capacity increased body weight and self-reported function in experimental participants. This finding supports results from a recent review about exercise before and after SCT [ 9 ], and recent feasibility studies of exercise prehabilitation for people with multiple myeloma [ 48 , 49 ]. AutoSCT results in long term impairments to physical function over 1 year after transplant, suggesting natural recovery of premorbid function doesn’t naturally occur [ 57 ]. Maintenance of physical function after autoSCT is also important given its relationship with premature death and unplanned hospital admission in people with hematological malignancies [ 58 ].

The nutrition intervention may explain other benefits of prehabilitation not detected in previous studies, such as weight gain and lower gastro-intestinal symptoms. Optimising nutritional outcomes is essential in transplant settings given patients are at high risk of malnutrition before, during and after transplant [ 59 ]. Malnutrition and transplant-related weight loss is highly correlated with longer hospital admissions, time to platelet engraftment, infection and 1-year mortality [ 59 ]. Therefore, even small changes in weight gain may be clinically significant. The combination of exercise with nutrition may have compounding effects to build functional reserve and explain positive effects found in this study, contrasting with a similar recent trial [ 53 ] that did not have a dietary component.

Similar to another recent trial [ 48 ], no differences in health service outcomes were observed despite benefits in patient outcomes. This finding contradicts previous literature that prehabilitation may reduce hospital length of stay [ 9 ]. It is possible that the current trial was underpowered to detect an effect in hospital outcomes given the small sample size. However, considering the complexity of transplant recovery and many factors contributing to hospital length-of-stay including medical complications, prehabilitation alone may be unable to overcome these issues. There was a very low rate of hospital readmission in both groups, with reasons for readmission being related to medical treatment. Therefore, once patients are medically stable after initial acute recovery, the risk of modifiable reasons for hospital readmission in the short-term (such as falls) appears to be very low.

Strengths and limitations

This is the first study to demonstrate positive effects of multidisciplinary prehabilitation for people preparing for autoSCT. This study, which had high recruitment rate, was conducted in a pragmatic public hospital setting and included patients who have previously been excluded from prehabilitation research such as those with refractory disease and bony lesions, increasing generalizability of findings.

There were several limitations. Ongoing COVID-19 restrictions throughout the trial resulted in a relatively high amount of missing data, particularly for our primary outcome. However, the impact of these extenuating circumstances was reported in alignment with recommendations [ 60 ] and linear mixed effects-modelling was used to account for missing data. There was wide variability in our outcomes as a result of the small sample size. There may also be an overestimate of the effect of our primary outcome due to Type I error and baseline imbalance in age and time since diagnosis. However, results align with previous research [ 48 , 49 ] and positively correlate with self-reported function of which there was full data available and baseline parity in most outcomes. It should also be acknowledged that tri-modal cancer prehabilitation, including psychology interventions such as stress management, is commonly recommended [ 61 ]. Given the small, pragmatic nature of the trial, additional psychological interventions were unable to be included but warrant further investigation in a future larger trial.

This trial provides preliminary evidence multidisciplinary prehabilitation may improve function and is safe and feasible after autoSCT. Findings support a larger trial to confirm the effectiveness of multidisciplinary prehabilitation. Given the small numbers of autoSCT recipients at most individual tertiary centers, a full-scale trial would need to be multi-site to obtain a sufficient sample size. Successful recruitment in this trial was heavily dependent on a pro-active clinical nurse coordinator and home-based setting suggesting these strategies should be adopted for a future trial.

Supplementary Information

Below is the link to the electronic supplementary material. Supplementary file1 (DOCX 36 KB)

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Acknowledgements

The research team would like to acknowledge Katrina Wragg and the Eastern Health Haematology team for supporting participant recruitment. We would also like to thank Germaine Tan and Emma Venn for their delivery of the intervention.

Author contributions

AD was responsible for designing the trial protocol, recruitment of participants, data collection, analysis and interpretation, writing and editing the first and subsequent drafts of the manuscript. NT, JP and ST contributed to the design of the trial, analysis and interpretation and providing feedback on the manuscript.

Funding

Open Access funding enabled and organized by CAUL and its Member Institutions This trial was supported by a grant from the Eastern Health Foundation.

Data availability

The dataset generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Eastern Health Human Research Ethics Committee E20/003/61055 11th March 2020.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Competing interests

The authors declare no competing interests.

References

1. Majhail NS Rizzo JD Surviving the cure: long term followup of hematopoietic cell transplant recipients Bone Marrow Transplant 2013 48 9 1145 1151 10.1038/bmt.2012.258 23292238 Majhail NS, Rizzo JD (2013) Surviving the cure: long term followup of hematopoietic cell transplant recipients. Bone Marrow Transplant 48(9):1145–1151. 10.1038/bmt.2012.258 23292238 10.1038/bmt.2012.258

2. Steinberg A Asher A Bailey C Fu JB The role of physical rehabilitation in stem cell transplantation patients Support Care Cancer 2015 23 8 2447 2460 10.1007/s00520-015-2744-3 25971213 PMC4703401 Steinberg A, Asher A, Bailey C, Fu JB (2015) The role of physical rehabilitation in stem cell transplantation patients. Support Care Cancer 23(8):2447–2460. 10.1007/s00520-015-2744-3 25971213 10.1007/s00520-015-2744-3 PMC4703401

3. Gielissen MF Schattenberg AV Verhagen CA Rinkes MJ Bremmers ME Bleijenberg G Experience of severe fatigue in long-term survivors of stem cell transplantation Bone Marrow Transplant 2007 39 10 595 603 10.1038/sj.bmt.1705624 17369868 Gielissen MF, Schattenberg AV, Verhagen CA, Rinkes MJ, Bremmers ME, Bleijenberg G (2007) Experience of severe fatigue in long-term survivors of stem cell transplantation. Bone Marrow Transplant 39(10):595–603. 10.1038/sj.bmt.1705624 17369868 10.1038/sj.bmt.1705624

4. Syrjala KL Martin PJ Lee SJ Delivering care to long-term adult survivors of hematopoietic cell transplantation J Clin Oncol 2012 30 30 3746 3751 10.1200/jco.2012.42.3038 23008296 PMC3675679 Syrjala KL, Martin PJ, Lee SJ (2012) Delivering care to long-term adult survivors of hematopoietic cell transplantation. J Clin Oncol 30(30):3746–3751. 10.1200/jco.2012.42.3038 23008296 10.1200/JCO.2012.42.3038 PMC3675679

5. Fu JB Lee J Smith DW Guo Y Bruera E Return to primary service among bone marrow transplant rehabilitation inpatients: an index for predicting outcomes Arch Phys Med Rehabil 2013 94 2 356 361 10.1016/j.apmr.2012.08.219 23022262 PMC3557705 Fu JB, Lee J, Smith DW, Guo Y, Bruera E (2013) Return to primary service among bone marrow transplant rehabilitation inpatients: an index for predicting outcomes. Arch Phys Med Rehabil 94(2):356–361. 10.1016/j.apmr.2012.08.219 23022262 10.1016/j.apmr.2012.08.219 PMC3557705

6. Campbell KL Winters-Stone KM Wiskemann J May AM Schwartz AL Courneya KS Exercise guidelines for cancer survivors: consensus statement from international multidisciplinary roundtable Med Sci Sports Exerc 2019 51 11 2375 2390 10.1249/mss.0000000000002116 31626055 PMC8576825 Campbell KL, Winters-Stone KM, Wiskemann J, May AM, Schwartz AL, Courneya KS et al (2019) Exercise guidelines for cancer survivors: consensus statement from international multidisciplinary roundtable. Med Sci Sports Exerc 51(11):2375–2390. 10.1249/mss.0000000000002116 31626055 10.1249/MSS.0000000000002116 PMC8576825

7. Jarden M Baadsgaard MT Hovgaard DJ Boesen E Adamsen L A randomized trial on the effect of a multimodal intervention on physical capacity, functional performance and quality of life in adult patients undergoing allogeneic SCT Bone Marrow Transplant 2009 43 9 725 737 10.1038/bmt.2009.27 19234513 Jarden M, Baadsgaard MT, Hovgaard DJ, Boesen E, Adamsen L (2009) A randomized trial on the effect of a multimodal intervention on physical capacity, functional performance and quality of life in adult patients undergoing allogeneic SCT. Bone Marrow Transplant 43(9):725–737. 10.1038/bmt.2009.27 19234513 10.1038/bmt.2009.27

8. Liang Y Zhou M Wang F Wu Z Exercise for physical fitness, fatigue and quality of life of patients undergoing hematopoietic stem cell transplantation: a meta-analysis of randomized controlled trials Jpn J Clin Oncol 2018 48 12 1046 1057 10.1093/jjco/hyy144 30277514 Liang Y, Zhou M, Wang F, Wu Z (2018) Exercise for physical fitness, fatigue and quality of life of patients undergoing hematopoietic stem cell transplantation: a meta-analysis of randomized controlled trials. Jpn J Clin Oncol 48(12):1046–1057. 10.1093/jjco/hyy144 30277514 10.1093/jjco/hyy144

9. Abo S, Denehy L, Ritchie D, Lin KY, Edbrooke L, McDonald C et al (2021) People with hematological malignancies treated with bone marrow transplantation have improved function, quality of life, and fatigue following exercise intervention: a systematic review and meta-analysis. Phys Ther 101(8). 10.1093/ptj/pzab130 10.1093/ptj/pzab130 33989413

10. Andersen S Brown T Kennedy G Banks M Implementation of an evidenced based nutrition support pathway for haematopoietic progenitor cell transplant patients Clin Nutr 2015 34 3 536 540 10.1016/j.clnu.2014.06.006 24985122 Andersen S, Brown T, Kennedy G, Banks M (2015) Implementation of an evidenced based nutrition support pathway for haematopoietic progenitor cell transplant patients. Clin Nutr 34(3):536–540. 10.1016/j.clnu.2014.06.006 24985122 10.1016/j.clnu.2014.06.006

11. Atkins L Steer B Ray H Kiss N Implementing and sustaining an evidence-based nutrition service in a haematology unit for autologous stem cell transplant patients Support Care Cancer 2019 27 3 951 958 10.1007/s00520-018-4384-x 30073411 Atkins L, Steer B, Ray H, Kiss N (2019) Implementing and sustaining an evidence-based nutrition service in a haematology unit for autologous stem cell transplant patients. Support Care Cancer 27(3):951–958. 10.1007/s00520-018-4384-x 30073411 10.1007/s00520-018-4384-x

12. Hagiwara S Mori T Tuchiya H Sato S Higa M Watahiki M Multidisciplinary nutritional support for autologous hematopoietic stem cell transplantation: a cost-benefit analysis Nutrition 2011 27 11–12 1112 1117 10.1016/j.nut.2010.11.010 21482071 Hagiwara S, Mori T, Tuchiya H, Sato S, Higa M, Watahiki M et al (2011) Multidisciplinary nutritional support for autologous hematopoietic stem cell transplantation: a cost-benefit analysis. Nutrition 27(11–12):1112–1117. 10.1016/j.nut.2010.11.010 21482071 10.1016/j.nut.2010.11.010

13. Hung YC Bauer JD Horsely P Coll J Bashford J Isenring EA Telephone-delivered nutrition and exercise counselling after auto-SCT: a pilot, randomised controlled trial Bone Marrow Transplant 2014 49 6 786 792 10.1038/bmt.2014.52 24710562 Hung YC, Bauer JD, Horsely P, Coll J, Bashford J, Isenring EA (2014) Telephone-delivered nutrition and exercise counselling after auto-SCT: a pilot, randomised controlled trial. Bone Marrow Transplant 49(6):786–792. 10.1038/bmt.2014.52 24710562 10.1038/bmt.2014.52

14. Dennett AM Sarkies M Shields N Peiris CL Williams C Taylor NF Multidisciplinary, exercise-based oncology rehabilitation programs improve patient outcomes but their effects on healthcare service-level outcomes remain uncertain: a systematic review J Physiother 2021 67 1 12 26 10.1016/j.jphys.2020.12.008 33358544 Dennett AM, Sarkies M, Shields N, Peiris CL, Williams C, Taylor NF (2021) Multidisciplinary, exercise-based oncology rehabilitation programs improve patient outcomes but their effects on healthcare service-level outcomes remain uncertain: a systematic review. J Physiother 67(1):12–26. 10.1016/j.jphys.2020.12.008 33358544 10.1016/j.jphys.2020.12.008

15. Arain M Campbell MJ Cooper CL Lancaster GA What is a pilot or feasibility study? A review of current practice and editorial policy BMC Med Res Methodol 2010 10 1 67 10.1186/1471-2288-10-67 20637084 PMC2912920 Arain M, Campbell MJ, Cooper CL, Lancaster GA (2010) What is a pilot or feasibility study? A review of current practice and editorial policy. BMC Med Res Methodol 10(1):67. 10.1186/1471-2288-10-67 20637084 10.1186/1471-2288-10-67 PMC2912920

16. Dennett AM Porter J Ting SB Taylor NF Prehabilitation to improve outcomes afteR Autologous sTem cEll transplantation (PIRATE): a pilot randomised controlled trial protocol PLoS One 2023 18 4 e0277760 10.1371/journal.pone.0277760 37104482 PMC10138261 Dennett AM, Porter J, Ting SB, Taylor NF (2023) Prehabilitation to improve outcomes afteR Autologous sTem cEll transplantation (PIRATE): a pilot randomised controlled trial protocol. PLoS One 18(4):e0277760. 10.1371/journal.pone.0277760 37104482 10.1371/journal.pone.0277760 PMC10138261

17. Eldridge SM Chan CL Campbell MJ Bond CM Hopewell S Thabane L CONSORT 2010 statement: extension to randomised pilot and feasibility trials BMJ 2016 355 i5239 10.1136/bmj.i5239 27777223 PMC5076380 Eldridge SM, Chan CL, Campbell MJ, Bond CM, Hopewell S, Thabane L et al (2016) CONSORT 2010 statement: extension to randomised pilot and feasibility trials. BMJ 355:i5239. 10.1136/bmj.i5239 27777223 10.1136/bmj.i5239 PMC5076380

18. Mina DS Langelier D Adams SC Alibhai SMH Chasen M Campbell KL Exercise as part of routine cancer care Lancet Oncol 2018 19 9 e433 e436 10.1016/s1470-2045(18)30599-0 30191843 Mina DS, Langelier D, Adams SC, Alibhai SMH, Chasen M, Campbell KL et al (2018) Exercise as part of routine cancer care. Lancet Oncol 19(9):e433–e436. 10.1016/s1470-2045(18)30599-0 30191843 10.1016/S1470-2045(18)30599-0

19. Oken MM Creech RH Tormey DC Horton J Davis TE McFadden ET Toxicity and response criteria of the Eastern Cooperative Oncology Group Am J Clin Oncol 1982 5 6 649 655 10.1097/00000421-198212000-00014 7165009 Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al (1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5(6):649–655 7165009

20. American College of Sports Medicine Exercise is Medicine. Being active when you have cancer. https://www.exerciseismedicine.org/assets/page_documents/EIM_Rx/20for/20Health_Cancer.pdf Accessed 12 Jan 2024

21. American College of Sports Medicine Exercise is Medicine. Sit less, move more. https://www.exerciseismedicine.org/assets/page_documents/EIM_Rx/20for/20Health_Sit/20Less/20Move/20More.pdf Accessed 12 Jan 2024

22. American College of Sports Medicine Exercise is Medicine. Moving through cancer. https://www.exerciseismedicine.org/assets/page_documents/EIM/20moving/20through/20cancer/20form/20web.pdf Accessed 12 Jan 2024

23. Collins CE Boggess MM Watson JF Guest M Duncanson K Pezdirc K Reproducibility and comparative validity of a food frequency questionnaire for Australian adults Clin Nutr 2014 33 5 906 914 10.1016/j.clnu.2013.09.015 24144913 Collins CE, Boggess MM, Watson JF, Guest M, Duncanson K, Pezdirc K et al (2014) Reproducibility and comparative validity of a food frequency questionnaire for Australian adults. Clin Nutr 33(5):906–914. 10.1016/j.clnu.2013.09.015 24144913 10.1016/j.clnu.2013.09.015

24. Arends J Bachmann P Baracos V Barthelemy N Bertz H Bozzetti F ESPEN guidelines on nutrition in cancer patients Clin Nutr 2017 36 1 11 48 10.1016/j.clnu.2016.07.015 27637832 Arends J, Bachmann P, Baracos V, Barthelemy N, Bertz H, Bozzetti F et al (2017) ESPEN guidelines on nutrition in cancer patients. Clin Nutr 36(1):11–48. 10.1016/j.clnu.2016.07.015 27637832 10.1016/j.clnu.2016.07.015

25. Cederholm T Jensen GL Correia M Gonzalez MC Fukushima R Higashiguchi T GLIM criteria for the diagnosis of malnutrition - A consensus report from the global clinical nutrition community Clin Nutr 2019 38 1 1 9 10.1016/j.clnu.2018.08.002 30181091 Cederholm T, Jensen GL, Correia M, Gonzalez MC, Fukushima R, Higashiguchi T et al (2019) GLIM criteria for the diagnosis of malnutrition - A consensus report from the global clinical nutrition community. Clin Nutr 38(1):1–9. 10.1016/j.clnu.2018.08.002 30181091 10.1016/j.clnu.2018.08.002

26. Murray SM, Pindoria S (2017) WITHDRAWN: nutrition support for bone marrow transplant patients. Cochrane Database Syst Rev 3(3):CD002920-CD002920. 10.1002/14651858.CD002920.pub4 10.1002/14651858.CD002920.pub4 PMC6464348 28334434

27. Schmidt K Vogt L Thiel C Jäger E Banzer W Validity of the six-minute walk test in cancer patients Int J Sports Med 2013 34 7 631 636 10.1055/s-0032-1323746 23444095 Schmidt K, Vogt L, Thiel C, Jäger E, Banzer W (2013) Validity of the six-minute walk test in cancer patients. Int J Sports Med 34(7):631–636. 10.1055/s-0032-1323746 23444095 10.1055/s-0032-1323746

28. U.S Department of Health and Human Services National Institutes of Health, National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf Accessed 29 Sept 2021

29. Skipworth RJ Stene GB Dahele M Hendry PO Small AC Blum D Patient-focused endpoints in advanced cancer: criterion-based validation of accelerometer-based activity monitoring Clin Nutr 2011 30 6 812 821 10.1016/j.clnu.2011.05.010 21733604 Skipworth RJ, Stene GB, Dahele M, Hendry PO, Small AC, Blum D et al (2011) Patient-focused endpoints in advanced cancer: criterion-based validation of accelerometer-based activity monitoring. Clin Nutr 30(6):812–821. 10.1016/j.clnu.2011.05.010 21733604 10.1016/j.clnu.2011.05.010

30. Ungar N Wiskemann J Sieverding M Physical activity enjoyment and self-efficacy as predictors of cancer patients' physical activity level Front Psychol 2016 7 898 10.3389/fpsyg.2016.00898 27445882 PMC4914598 Ungar N, Wiskemann J, Sieverding M (2016) Physical activity enjoyment and self-efficacy as predictors of cancer patients’ physical activity level. Front Psychol 7:898. 10.3389/fpsyg.2016.00898 27445882 10.3389/fpsyg.2016.00898 PMC4914598

31. Weaver CH Potz J Redmond J Tauer K Schwartzberg LS Kaywin P Engraftment and outcomes of patients receiving myeloablative therapy followed by autologous peripheral blood stem cells with a low CD34+ cell content Bone Marrow Transplant 1997 19 11 1103 1110 10.1038/sj.bmt.1700808 9193753 Weaver CH, Potz J, Redmond J, Tauer K, Schwartzberg LS, Kaywin P et al (1997) Engraftment and outcomes of patients receiving myeloablative therapy followed by autologous peripheral blood stem cells with a low CD34+ cell content. Bone Marrow Transplant 19(11):1103–1110. 10.1038/sj.bmt.1700808 9193753 10.1038/sj.bmt.1700808

32. Roberts HC Denison HJ Martin HJ Patel HP Syddall H Cooper C A review of the measurement of grip strength in clinical and epidemiological studies: towards a standardised approach Age Ageing 2011 40 4 423 429 10.1093/ageing/afr051 21624928 Roberts HC, Denison HJ, Martin HJ, Patel HP, Syddall H, Cooper C et al (2011) A review of the measurement of grip strength in clinical and epidemiological studies: towards a standardised approach. Age Ageing 40(4):423–429. 10.1093/ageing/afr051 21624928 10.1093/ageing/afr051

33. Jager-Wittenaar H Ottery FD Assessing nutritional status in cancer: role of the Patient-Generated Subjective Global Assessment Curr Opin Clin Nutr Metab Care 2017 20 5 322 329 10.1097/mco.0000000000000389 28562490 Jager-Wittenaar H, Ottery FD (2017) Assessing nutritional status in cancer: role of the Patient-Generated Subjective Global Assessment. Curr Opin Clin Nutr Metab Care 20(5):322–329. 10.1097/mco.0000000000000389 28562490 10.1097/MCO.0000000000000389

34. Osoba D Zee B Pater J Warr D Kaizer L Latreille J Psychometric properties and responsiveness of the EORTC quality of Life Questionnaire (QLQ-C30) in patients with breast, ovarian and lung cancer Qual Life Res 1994 3 5 353 364 10.1007/BF00451727 7841968 Osoba D, Zee B, Pater J, Warr D, Kaizer L, Latreille J (1994) Psychometric properties and responsiveness of the EORTC quality of Life Questionnaire (QLQ-C30) in patients with breast, ovarian and lung cancer. Qual Life Res 3(5):353–364 7841968 10.1007/BF00451727

35. Velikova G Weis J Hjermstad MJ Kopp M Morris P Watson M The EORTC QLQ-HDC29: a supplementary module assessing the quality of life during and after high-dose chemotherapy and stem cell transplantation Eur J Cancer 2007 43 1 87 94 10.1016/j.ejca.2006.09.004 17081744 Velikova G, Weis J, Hjermstad MJ, Kopp M, Morris P, Watson M et al (2007) The EORTC QLQ-HDC29: a supplementary module assessing the quality of life during and after high-dose chemotherapy and stem cell transplantation. Eur J Cancer 43(1):87–94. 10.1016/j.ejca.2006.09.004 17081744 10.1016/j.ejca.2006.09.004

36. Cocks K Torgerson DJ Sample size calculations for pilot randomized trials: a confidence interval approach J Clin Epidemiol 2013 66 2 197 201 10.1016/j.jclinepi.2012.09.002 23195919 Cocks K, Torgerson DJ (2013) Sample size calculations for pilot randomized trials: a confidence interval approach. J Clin Epidemiol 66(2):197–201. 10.1016/j.jclinepi.2012.09.002 23195919 10.1016/j.jclinepi.2012.09.002

37. Sterne JA White IR Carlin JB Spratt M Royston P Kenward MG Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls BMJ 2009 338 b2393 10.1136/bmj.b2393 19564179 PMC2714692 Sterne JA, White IR, Carlin JB, Spratt M, Royston P, Kenward MG et al (2009) Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls. BMJ 338:b2393. 10.1136/bmj.b2393 19564179 10.1136/bmj.b2393 PMC2714692

38. Broderick JM Ryan J O'Donnell DM Hussey J A guide to assessing physical activity using accelerometry in cancer patients Support Care Cancer 2014 22 4 1121 1130 10.1007/s00520-013-2102-2 24389829 Broderick JM, Ryan J, O’Donnell DM, Hussey J (2014) A guide to assessing physical activity using accelerometry in cancer patients. Support Care Cancer 22(4):1121–1130. 10.1007/s00520-013-2102-2 24389829 10.1007/s00520-013-2102-2

39. Cormie P Atkinson M Bucci L Cust A Eakin E Hayes S Clinical Oncology Society of Australia position statement on exercise in cancer care Med J Aust 2018 209 4 184 187 10.5694/mja18.00199 29719196 Cormie P, Atkinson M, Bucci L, Cust A, Eakin E, Hayes S et al (2018) Clinical Oncology Society of Australia position statement on exercise in cancer care. Med J Aust 209(4):184–187 29719196 10.5694/mja18.00199

40. Elkins MR Moseley AM Intention-to-treat analysis J Physiother 2015 61 3 165 167 10.1016/j.jphys.2015.05.013 26096012 Elkins MR, Moseley AM (2015) Intention-to-treat analysis. J Physiother 61(3):165–167. 10.1016/j.jphys.2015.05.013 26096012 10.1016/j.jphys.2015.05.013

41. Macreadie I Reflections from Melbourne, the world’s most locked-down city, through the COVID-19 pandemic and beyond Microbiol Aust 2022 43 1 3 4 10.1071/MA22002 Macreadie I (2022) Reflections from Melbourne, the world’s most locked-down city, through the COVID-19 pandemic and beyond. Microbiol Aust 43(1):3–4. 10.1071/MA22002

42. Granger CL Holland AE Gordon IR Denehy L Minimal important difference of the 6-minute walk distance in lung cancer Chron Respir Dis 2015 12 2 146 154 10.1177/1479972315575715 25749346 Granger CL, Holland AE, Gordon IR, Denehy L (2015) Minimal important difference of the 6-minute walk distance in lung cancer. Chron Respir Dis 12(2):146–154. 10.1177/1479972315575715 25749346 10.1177/1479972315575715

43. Bohannon RW Crouch R Minimal clinically important difference for change in 6-minute walk test distance of adults with pathology: a systematic review J Eval Clin Pract 2017 23 2 377 381 10.1111/jep.12629 27592691 Bohannon RW, Crouch R (2017) Minimal clinically important difference for change in 6-minute walk test distance of adults with pathology: a systematic review. J Eval Clin Pract 23(2):377–381. 10.1111/jep.12629 27592691 10.1111/jep.12629

44. Bolshinsky V Li MH Ismail H Burbury K Riedel B Heriot A Multimodal prehabilitation programs as a bundle of care in gastrointestinal cancer surgery: a systematic review Dis Colon Rectum 2018 61 1 124 138 10.1097/dcr.0000000000000987 29219922 Bolshinsky V, Li MH, Ismail H, Burbury K, Riedel B, Heriot A (2018) Multimodal prehabilitation programs as a bundle of care in gastrointestinal cancer surgery: a systematic review. Dis Colon Rectum 61(1):124–138. 10.1097/dcr.0000000000000987 29219922 10.1097/DCR.0000000000000987

45. San Miguel JF Schlag R Khuageva NK Dimopoulos MA Shpilberg O Kropff M Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma NEJM 2008 359 9 906 917 10.1056/NEJMoa0801479 18753647 San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M et al (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. NEJM 359(9):906–917. 10.1056/NEJMoa0801479 18753647 10.1056/NEJMoa0801479

46. Díaz-Tejedor A, Lorenzo-Mohamed M, Puig N, García-Sanz R, Mateos MV, Garayoa M et al (2021) Immune system alterations in multiple myeloma: molecular mechanisms and therapeutic strategies to reverse immunosuppression. Cancers 13(6). 10.3390/cancers13061353 10.3390/cancers13061353 PMC8002455 33802806

47. Campbell KL, Cormie P, Weller S, Alibhai SMH, Bolam KA, Campbell A et al (2022) Exercise recommendation for people with bone metastases: expert consensus for health care providers and exercise professionals. JCO Oncol Pract OP.21.00454. 10.1200/OP.21.00454 10.1200/OP.21.00454 PMC9810134 34990293

48. McCourt O Fisher A Ramdharry G Land J Roberts AL Rabin N Exercise prehabilitation for people with myeloma undergoing autologous stem cell transplantation: results from PERCEPT pilot randomised controlled trial Acta Oncol 2023 62 7 696 705 10.1080/0284186X.2023.2178326 36794394 McCourt O, Fisher A, Ramdharry G, Land J, Roberts AL, Rabin N et al (2023) Exercise prehabilitation for people with myeloma undergoing autologous stem cell transplantation: results from PERCEPT pilot randomised controlled trial. Acta Oncol 62(7):696–705. 10.1080/0284186X.2023.2178326 36794394 10.1080/0284186X.2023.2178326

49. Mawson S, Keen C, Skilbeck J, Ross H, Smith L, Dixey J et al (2021) Feasibility and benefits of a structured prehabilitation programme prior to autologous stem cell transplantation (ASCT) in patients with myeloma; a prospective feasibility study. Physiotherapy 113:88–99. 10.1016/j.physio.2021.08.001 10.1016/j.physio.2021.08.001 PMC8612275 34563917

50. Schmitz KH Campbell AM Stuiver MM Pinto BM Schwartz AL Morris GS Exercise is medicine in oncology: engaging clinicians to help patients move through cancer CA Cancer J Clin 2019 69 6 468 484 10.3322/caac.21579 31617590 PMC7896280 Schmitz KH, Campbell AM, Stuiver MM, Pinto BM, Schwartz AL, Morris GS et al (2019) Exercise is medicine in oncology: engaging clinicians to help patients move through cancer. CA Cancer J Clin 69(6):468–484. 10.3322/caac.21579 31617590 10.3322/caac.21579 PMC7896280

51. Dennett AM Peiris CL Shields N Morgan D Taylor NF Exercise therapy in oncology rehabilitation in Australia: a mixed-methods study Asia Pac J Clin Oncol 2017 13 5 e515 e527 10.1111/ajco.12642 28004526 Dennett AM, Peiris CL, Shields N, Morgan D, Taylor NF (2017) Exercise therapy in oncology rehabilitation in Australia: a mixed-methods study. Asia Pac J Clin Oncol 13(5):e515–e527. 10.1111/ajco.12642 28004526 10.1111/ajco.12642

52. Lopez C McGarragle K Pritlove C Jones JM Alibhai SMH Lenton E Variability and limitations in home-based exercise program descriptions in oncology: a scoping review Support Care Cancer 2020 28 9 4005 4017 10.1007/s00520-020-05453-6 32296982 Lopez C, McGarragle K, Pritlove C, Jones JM, Alibhai SMH, Lenton E et al (2020) Variability and limitations in home-based exercise program descriptions in oncology: a scoping review. Support Care Cancer 28(9):4005–4017. 10.1007/s00520-020-05453-6 32296982 10.1007/s00520-020-05453-6

53. McCourt O, Fisher A, Land J, Ramdharry G, Yong K (2024) The views and experiences of people with myeloma referred for autologous stem cell transplantation, who declined to participate in a physiotherapist-led exercise trial: a qualitative study. Physiother Theory Pract 40(10):2331–2343. 10.1080/09593985.2023.2244068 10.1080/09593985.2023.2244068 PMC11458126 37555437

54. Dennett AM Harding KE Reed MS The challenge of timing: a qualitative study on clinician and patient perspectives about implementing exercise-based rehabilitation in an acute cancer treatment setting Support Care Cancer 2020 10.1007/s00520-020-05436-7 32291598 Dennett AM, Harding KE, Reed MS (2020) The challenge of timing: a qualitative study on clinician and patient perspectives about implementing exercise-based rehabilitation in an acute cancer treatment setting. Support Care Cancer. 10.1007/s00520-020-05436-7 32291598 10.1007/s00520-020-05436-7

55. Hardcastle SJ Cohen PA Effective physical activity promotion to survivors of cancer is likely to be home based and to require oncologist participation J Clin Oncol 2017 35 32 3635 3637 10.1200/jco.2017.74.6032 28915086 Hardcastle SJ, Cohen PA (2017) Effective physical activity promotion to survivors of cancer is likely to be home based and to require oncologist participation. J Clin Oncol 35(32):3635–3637. 10.1200/jco.2017.74.6032 28915086 10.1200/JCO.2017.74.6032

56. Lambert G Drummond K Ferreira V Carli F Teleprehabilitation during COVID-19 pandemic: the essentials of “what” and “how” Support Care Cancer 2021 29 2 551 554 10.1007/s00520-020-05768-4 32918606 PMC7486157 Lambert G, Drummond K, Ferreira V, Carli F (2021) Teleprehabilitation during COVID-19 pandemic: the essentials of “what” and “how.” Support Care Cancer 29(2):551–554. 10.1007/s00520-020-05768-4 32918606 10.1007/s00520-020-05768-4 PMC7486157

57. Tuchman SA Lane A Hornsby WE Bishop C Thomas S Herndon JE Quantitative measures of physical functioning after autologous hematopoietic stem cell transplantation in multiple myeloma: a feasibility study Clin Lymphoma Myeloma Leuk 2015 15 2 103 109 10.1016/j.clml.2014.09.002 25445473 Tuchman SA, Lane A, Hornsby WE, Bishop C, Thomas S, Herndon JE et al (2015) Quantitative measures of physical functioning after autologous hematopoietic stem cell transplantation in multiple myeloma: a feasibility study. Clin Lymphoma Myeloma Leuk 15(2):103–109. 10.1016/j.clml.2014.09.002 25445473 10.1016/j.clml.2014.09.002

58. Liu MA DuMontier C Murillo A Hshieh TT Bean JF Soiffer RJ Gait speed, grip strength, and clinical outcomes in older patients with hematologic malignancies Blood 2019 134 4 374 382 10.1182/blood.2019000758 31167800 PMC6659254 Liu MA, DuMontier C, Murillo A, Hshieh TT, Bean JF, Soiffer RJ et al (2019) Gait speed, grip strength, and clinical outcomes in older patients with hematologic malignancies. Blood 134(4):374–382. 10.1182/blood.2019000758 31167800 10.1182/blood.2019000758 PMC6659254

59. Lazarow H Nicolo M Compher C Kucharczuk CR Stadtmauer EA Landsburg DJ Nutrition-related outcomes for autologous stem cell transplantation patients Clin Lymphoma Myeloma Leuk 2019 19 7 e393 e398 10.1016/j.clml.2019.04.002 31053549 Lazarow H, Nicolo M, Compher C, Kucharczuk CR, Stadtmauer EA, Landsburg DJ (2019) Nutrition-related outcomes for autologous stem cell transplantation patients. Clin Lymphoma Myeloma Leuk 19(7):e393–e398. 10.1016/j.clml.2019.04.002 31053549 10.1016/j.clml.2019.04.002

60. Orkin AM Gill PJ Ghersi D Campbell L Sugarman J Emsley R Guidelines for reporting trial protocols and completed trials modified due to the COVID-19 pandemic and other extenuating circumstances: the CONSERVE 2021 statement JAMA 2021 326 3 257 265 10.1001/jama.2021.9941 34152382 Orkin AM, Gill PJ, Ghersi D, Campbell L, Sugarman J, Emsley R et al (2021) Guidelines for reporting trial protocols and completed trials modified due to the COVID-19 pandemic and other extenuating circumstances: the CONSERVE 2021 statement. JAMA 326(3):257–265. 10.1001/jama.2021.9941 34152382 10.1001/jama.2021.9941

61. Macmillan Cancer Support (2019) Prehabilitation for people with cancer: principles and guidance for prehabilitation. https://cdn.macmillan.org.uk/dfsmedia/1a6f23537f7f4519bb0cf14c45b2a629/1532-source/prehabilitation-for-people-with-cancer-tcm9-353994#:~:text=Personalised%20prehabilitation%20care%20plans%20(PPCP,need%2C%20and%20an%20individualised%20intervention Accessed 30 May 2024