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ARTICLE
Clinical Study
Fatigue, quality of life and physical fitness following an
exercise intervention in multiple myeloma survivors
(MASCOT): an exploratory randomised Phase 2 trial
utilising a modified Zelen design
Dimitrios A. Koutoukidis
1,2,3
, Joanne Land
1
, Allan Hackshaw
4
, Malgorzata Heinrich
1
, Orla McCourt
1,5
, Rebecca J. Beeken
1,6
,
Stephanie Philpott
1
, Dunnya DeSilva
5
, Ali Rismani
7
, Neil Rabin
7
, Rakesh Popat
7
, Charalampia Kyriakou
7
, Xenofon Papanikolaou
8
,
Atul Mehta
7
, Bruce Paton
9
, Abigail Fisher
1
and Kwee L. Yong
5
BACKGROUND: Exercise may improve fatigue in multiple myeloma survivors, but trial evidence is limited, and exercise may be
perceived as risky in this older patient group with osteolytic bone destruction.
METHODS: In this Phase 2 Zelen trial, multiple myeloma survivors who had completed treatment at least 6 weeks ago, or were on
maintenance only, were enrolled in a cohort study and randomly assigned to usual care or a 6-month exercise programme of
tailored aerobic and resistance training. Outcome assessors and usual care participants were masked. The primary outcome was the
FACIT-F fatigue score with higher scores denoting less fatigue.
RESULTS: During 2014–2016, 131 participants were randomised 3:1 to intervention (n=89) or usual care (n=42) to allow for
patients declining allocation to the exercise arm. There was no difference between groups in fatigue at 3 months (between-group
mean difference: 1.6 [95% CI: −1.1–4.3]) or 6 months (0.3 [95% CI: −2.6–3.1]). Muscle strength improved at 3 months (8.4 kg [95% CI:
0.5–16.3]) and 6 months (10.8 kg [95% CI: 1.2–20.5]). Using per-protocol analysis, cardiovascular fitness improved at 3 months (+1.2
ml/kg/min [95% CI: 0.3–3.7]). In participants with clinical fatigue (n=17), there was a trend towards less fatigue with exercise over
6 months (6.3 [95% CI: −0.6–13.3]). There were no serious adverse events.
CONCLUSIONS: Exercise appeared safe and improved muscle strength and cardiovascular fitness, but benefits in fatigue appeared
limited to participants with clinical fatigue at baseline. Future studies should focus on patients with clinical fatigue.
CLINICAL TRIAL REGISTRATION: The study was registered with ISRCTN (38480455) and is completed.
British Journal of Cancer https://doi.org/10.1038/s41416-020-0866-y
BACKGROUND
The survival of patients with multiple myeloma (MM) continues to
improve with the use of increasingly effective multidrug regimens.
However, the disease remains incurable, and patients continue to
experience a high symptom burden, particularly fatigue, through-
out the disease trajectory and even during treatment-free
periods.
1
Up to 90% of patients suffer from osteolytic bone
disease, causing pain, fractures, vertebral collapse and spinal cord
compression.
2
Even when the disease has responded to che-
motherapy, and patients enjoy a treatment-free interval, the
sequelae of bone destruction (reduced physical functioning, loss
of muscle mass and chronic pain) affect their quality of life (QoL).
2
Fatigue is associated with greater impairment of daily activities
and lower quality of life, as well as shorter progression-free and
overall survival.
3,4
Therefore, managing these symptoms may help
this growing population improve their QoL.
One way of managing cancer-related fatigue is through exercise
interventions, and a considerable evidence base exists to support
guidelines recommending exercise for survivors with fatigue.
5
However, most of the evidence comes from patients with solid
tumours, primarily breast cancer. A recent Cochrane review of 18
randomised clinical trials (RCTs) in survivors of haematological
www.nature.com/bjc
Received: 31 July 2019 Revised: 6 February 2020 Accepted: 26 February 2020
1
Department of Behavioural Science and Health, University College London, London, UK;
2
Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK;
3
NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK;
4
Cancer Research UK & UCL Cancer Trials Centre, University College London,
London, UK;
5
Cancer Institute, University College London, London, UK;
6
Leeds Institute of Health Sciences, University of Leeds, Leeds, UK;
7
Department of Haematology,
University College London Hospitals NHS Foundation Trust, London, UK;
8
Department of Haematology, Lister Hospital, Stevenage, UK and
9
Institute of Sport, Exercise and Health,
London, UK
Correspondence: Kwee L. Yong (kwee.yong@ucl.ac.uk)
These authors contributed equally: Dimitrios A. Koutoukidis, Joanne Land
These authors jointly supervised this work: Abigail Fisher, Kwee L. Yong
©The Author(s) 2020 Published by Springer Nature on behalf of Cancer Research UK
cancers found that most studies were poorly reported, generally
of low quality, affected by bias due to contamination as blinding is
not possible, and had insufficient follow-up.
6
Exercise interventions specifically in MM survivors are sparse.
Data suggest that physical activity is positively associated with
QoL, but only about a fifth of MM survivors are meeting the
exercise guidelines.
7
Although MM patients express a desire for
exercise support, they also fear injury and pain,
8
which is
understandable given the risk of fracture. Only two RCTs have
focused exclusively on MM patients, and both evaluated home-
based exercise programmes while undergoing first-line anticancer
therapy.
9,10
One RCT in 24 patients reported improved muscle
strength and sleep.
9
The other trial in 187 patients found no
benefits for fatigue, sleep and aerobic capacity,
10
potentially due
to the usual care participants receiving exercise instructions from
their clinician. A major problem with traditional behavioural
change trials is that those allocated to the usual care group may
take up the experimental intervention or be dissatisfied with the
usual care allocation and drop out.
11
This ‘contamination’effect
might substantially dilute any treatment effect.
11
We previously carried out a single-arm pilot study of a tailored
exercise intervention in 37 MM survivors. The intervention was
acceptable and feasible, and showed improvements in fatigue,
QoL and muscle strength over 6 months.
12
To confirm the
beneficial effects of exercise training, we designed a randomised
trial utilising a Zelen design that aimed to avoid contamination
bias.
13
The Zelen design has to our knowledge rarely been used in
cancer exercise trials. Unlike previous RCTs in MM, our trial focused
on patients after they finished first-line therapies, because this is
usually the longest treatment-free interval. The primary aim was to
explore the benefits of an individually tailored exercise pro-
gramme on levels of fatigue. Secondary outcomes included QoL,
fitness and strength.
METHODS
Study design
This was a randomised parallel trial of an exercise intervention.
The study was conducted at a tertiary hospital in central London
(UK), and had full ethical approval by the National Research Ethics
Service Committee London—Queens Square. The study protocol
is available in Supplementary Information 1. The completed
CONSORT and TIDieR checklists are available in Supplementary
Information 2 and 3, respectively.
Participants
MM survivors were recruited by clinicians at their routine myeloma
appointments. They were eligible if they had stable disease for at
least 6 weeks, completed their initial treatment or were on
maintenance therapy, had ECOG performance status 0–2 and
were able to undergo a regular exercise programme (exclusion
criteria in Supplementary Table 1). Eligibility assessment was
performed by a doctor, and included tests for disease status, X-
rays, magnetic resonance imaging or electrocardiogram as
clinically indicated. Scans and plain X-rays were reviewed in the
multidisciplinary meeting and assessed for fracture risk using
Mirels score.
14
Patients interested to participate were referred to a
researcher for more information. All participants provided written
informed consent to participate.
Randomisation and masking
The adapted Zelen study design with double consent aimed to
avoid the potential contamination bias.
13
Patients were invited to
participate in an observational cohort study to understand the
relationship between lifestyle, physical and mental health and
biomarkers, without specific emphasis on exercise, as per the
published protocol.
15
The initial participant information sheet (PIS)
outlined the types and timings of assessments to be performed,
including all outcome measures. Following consent and the
baseline assessment, participants were randomised with a 3:1 ratio
to either the exercise or usual care, and all received care as usual.
Randomisation was performed by R.J.B. or S.P. using minimisation
(MinimPy software) stratified by gender and fatigue score (≤37
and >37).
After randomisation, R.J.B. or S.P., neither of whom had patient
contact, immediately informed the physiotherapists (J.L. and O.M.)
of the allocation by phone. The physiotherapists contacted only
the participants who had been allocated to the exercise arm to
invite them to participate in an interventional study of exercise,
and to provide a second consent. The allocation was concealed
from all other researchers. The second PIS contained only details
specific to the exercise-training programme. Participants who
agreed to the exercise intervention provided a second consent,
whilst those who declined continued with the follow-up assess-
ments as per the observational study. The usual care group were
unaware that they had been randomised on any details about the
intervention. Most assessments were performed by researchers
(B.P., D.A.K. or M.H.) blinded to allocation, but occasionally
performed by the unblinded physiotherapist (J.L.) given resource
constraints.
Procedures
Participants received a 6-month aerobic and resistance exercise-
training programme individualised to their abilities, and based on
published guidelines for cancer survivors.
16
This aimed to ensure
suitability, safety and adherence to the programme. For the first
3 months, the intervention involved one session per week at the
hospital gym in central London, and participants were expected to
exercise a further two times per week at home. They were
provided with exercise diaries for completion. The physiotherapist
reviewed the diaries at the following session, provided feedback
on behaviour, facilitated goal setting and action planning and
tailored the exercises accordingly. In the second 3 months
(months 4–6), participants were expected to exercise at home
three times per week and exercised at the hospital gym once
per month.
Aerobic training consisted of treadmill walking, cycle erg-
ometer, cross-trainer or stepper (whichever they preferred) at a
target intensity of 50–75% of predicted maximum heart rate,
calculated during baseline cardiorespiratory fitness testing. Target
duration of aerobic training was increased progressively up to 30
min, in minimum 10-min bouts. Gradual progression was achieved
by increasing exercise duration by 5 min and intensity by 5%
maximum heart rate every 4 weeks. Resistance exercises covered
the trunk, and upper and lower body, using weightlifting
equipment, body weight or resistance bands. Resistance exercises
were prescribed, individually tailored and gradually progressed by
the study physiotherapist using 10-repetition maximum assess-
ment, according to published principles.
17
All sessions were
delivered by a physiotherapist trained in behavioural support
using Habit Theory,
18
so that participants could create exercise
habits outside the sessions (details in Supplementary
Information 1).
The usual care group were asked to maintain their usual lifestyle.
All outcomes were assessed at baseline, 3, 6 and 12 months.
Outcome measures
The primary outcome was fatigue improvement at 3 months
because it is considered a central symptom in multiple myeloma
survivors, and our pilot study showed that exercise may improve
fatigue.
12
Fatigue is also a major issue for patients with solid
cancers, and perhaps the most common endpoint (or co-
endpoint) of trials of behavioural change or other non-drug
interventions aimed at improving QoL/symptoms. It was mea-
sured by the Functional Assessment of Chronic Illness
Therapy–Fatigue (FACIT-F) scale that has demonstrated reliability
Fatigue, quality of life and physical fitness following an exercise.. .
DA. Koutoukidis et al.
2
1234567890();,:
and sensitivity to change in cancer patients.
19
Higher scores
denote lower fatigue levels. Secondary QoL outcomes were the
functional and emotional subscales of the Functional Assessment
of Cancer Therapy—General instrument (FACT-G),
20
and emo-
tional distress using the Hospital Anxiety and Depression Scale.
21
Cardiorespiratory fitness was assessed using an ergometer bike,
and VO
2peak
was estimated using the Metasoft Expair software
according to US recommendations.
22
Lower-limb muscle strength
was assessed with each leg, ten-repetition maximum load and leg
extension test, and averaged over both legs.
12
Hand grip strength
was measured with a handheld dynamometer. Three measure-
ments were taken from each arm and averaged for analysis.
Participants wore a triaxial accelerometer (ActiGraph-wGT3X-BT,
Florida, USA) for 7 consecutive days above the non-dominant hip,
and physical activity data were integrated into 60-s epochs and
converted into total daily activity adjusted for wear time as mean
accelerometer counts per minute.
As exercise can improve body composition, body weight (kg),
percentage of body fat (%) and muscle mass (kg) were assessed
using bioelectrical impedance (TANITA MC-980), which has been
shown to have acceptable reliability and accuracy.
23
Height was
measured with a stadiometer with shoes removed, and the body
mass index (BMI) was calculated.
Patients had regular haematology and biochemistry blood tests
as per routine clinical care, and to confirm that their disease
remained stable during the study. Patients with evidence of
disease progression, whether biochemical or clinical, were with-
drawn from the trial, because of the potential confounding effects
of disease and treatment-related effects on outcome measures,
and on adherence to the exercise regimen. Adverse events were
monitored at each visit. The physiotherapist spoke to intervention
participants prior to commencement of each exercise session to
identify any potential adverse events.
Statistical analysis
We aimed to detect an improvement in fatigue score of four units
(FACIT-F) at 3 months, considered a clinically significant effect,
24
equivalent to a standardised difference of 0.69. This was based on
the observed 4.3-unit increase in the 6-month fatigue score and
standard deviation 5.8 from our pilot study.
12
With 80% power
and two-sided 5% statistical significance, 34 patients per arm were
required. To allow for patients declining allocation to the exercise
arm, a randomisation ratio of 3:1 was used, aiming to randomise
~140 patients.
Analyses were performed for each variable using linear
regression, with the baseline value and treatment group as
covariates. The primary analysis was modified with intention to
treat using available cases. It compared those who accepted the
intervention with the usual care group. Thus, participants who
declined the exercise programme were excluded. This method of
analysis aimed to ensure that a high decline rate would not dilute
the effect size, and that the data could form the basis for future
larger trials.
Per-protocol analyses compared the usual care group with
those who had high adherence to the group exercise sessions. The
latter were defined as the participants attending at least 6 of the
12 (50%) sessions in the first 3 months, because training for less
than 2 days per week appears insufficient for maximising muscle
development.
25
We examined the correlation between fatigue and other
variables at baseline. A repeated measures/mixed-effect analysis
was also performed for all time points up to 6 months. We
undertook a planned per-protocol analysis of the subgroup with
clinical fatigue at baseline (i.e. with a fatigue score below 34 as
defined appropriate for cancer patients).
26
No allowance was
made for multiple testing, because we wanted to see which
outcomes were improved to be considered for a subsequent
larger trial. Imputation was not applied, because few patients had
missing data at 3 or 6 months, and there were no striking
differences between these patients and those who had non-
missing data. SPSS (v25) was used for all analyses. The trial was
prospectively registered at ISRCTN (ID:38480455).
We conducted semi-structured interviews in the exercise group
to elicit their attitudes and experiences (n=20). These results will
be reported in detail in a separate paper, but a summary is
provided here. Data were transcribed, and two researchers coded
them in NVivo (v10) to identify data-driven themes using the six-
stage thematic analysis at an explicit level with a realist approach.
27
RESULTS
Between June 2014 and November 2016, 313 patients were
identified, of whom 131 were randomised. Fifty-one of 89 patients
(57%) allocated to the exercise programme accepted the
intervention. Baseline characteristics were similar between the
randomised subgroups of patients (Table 1). Most participants had
bone disease (69%), around one-third reported pain and 22%
were on maintenance treatment (thalidomide or lenalidomide)
(Supplementary Table 2).
Retention and adherence
Retention rates at 3 months were high: 88% for those accepting
the intervention, 76% for those declining the intervention and
95% for the usual care group. At 6 months, these rates were 76%,
66 and 83%, respectively (CONSORT diagram in Fig. 1). The
participants in the exercise group (n=51) attended a median of 9
out of 12 exercise classes (75%; range: 1–12), and 41 (80%)
participants attended at least 50% of the 12 classes in the first
3 months. The reasons for non-attendance are shown in Fig. 1.
Between months 4 and 6, 20 participants (64.5%) completed all
three-monthly classes.
Correlation analysis at baseline
Correlation analysis showed that fatigue at baseline was not
correlated with age (r=−0.09, p=0.41) or time since treatment
(r=0.15, p=0.14), but with measures of physical fitness. Thus,
participants reporting more fatigue had higher body fat percen-
tage (r=0.29, p=0.005), and lower VO
2peak
(r=−0.33, p< 0.001),
and leg strength (r=−0.25, p=0.017).
Primary (modified intention-to-treat) analysis
There was little effect of the exercise programme on fatigue at
either 3 (between-group difference 1.6 units) or 6 months
(difference 0.3 units) (Tables 2and 3). From the repeated
measures analysis, the mean difference between the groups was
0.8 (95% CI: −3.0 to 4.7) for time points up to 6 months. There was
no evidence of between-group differences in changes in physical
or emotional functioning, anxiety or depression at 3 or 6 months
(Tables 2and 3).
Leg muscle strength was significantly improved following the
exercise intervention. The between-group improvement was 8.4
kg (95% CI: 0.5–16.3) in favour of exercise at 3 months, and 10.8 kg
(95% CI: 1.2–20.5) at 6 months (Tables 2and 3). From the repeated
measures model, there was strong evidence that the difference in
leg strength between groups depended on the time point (p<
0.002 for the interaction, Supplementary Fig. 1).
Only 14.6% of those in the intervention group and 15.8% in the
usual care group were meeting the 150-min/week moderate-to-
vigorous physical activity guidelines at baseline. Baseline obesity
(BMI ≥30 kg/m
2
) was seen in 27 and 38% of participants in the
exercise and usual care group, respectively. No effect of the
intervention on physical activity was observed. There seemed to
be a small improvement in percentage of body fat (−0.9%) at
3 months (p=0.07), which was not seen at 6 months (p=0.47) in
the exercise group. VO
2peak
also showed a trend to improvement
at 3 months (p=0.08), but this was not seen at 6 months (p=
Fatigue, quality of life and physical fitness following an exercise. . .
DA. Koutoukidis et al.
3
0.27) (Tables 2and 3). There were no between-group differences
for grip strength at 3 or 6 months (Tables 2and 3).
Supplementary Tables 3–5 compare the characteristics of
patients who went through the exercise programme, and those
who declined it after being randomised. With the exception of leg
strength at 3 and 12 months, there were no striking differences
between the groups.
Secondary (per-protocol) analysis
Figure 2and Supplementary Tables 6–7 show the per-protocol
analysis (patients in the exercise group who attended at least 50%
of the sessions) for several endpoints. The results were broadly
similar to the primary analysis, except for a significant positive
effect on VO
2peak
(+1.2 ml/kg/min, p=0.02) and on percentage of
body fat (−0.9%, p=0.05, Supplementary Table 6). The benefits
on leg strength were also seen in this analysis: differences of
7.9 kg (p=0.05) and 11.3 kg (p=0.03) at 3 and 6 months,
respectively.
Long-term effects
Looking at the longer-term effects, Supplementary Table 5
presents descriptive data at 12 months. The means of the
outcome measures in each trial group were consistent with those
at 3 and 6 months. The increase in leg muscle strength in the
modified ITT exercise group was maintained at 12 months,
suggesting some longer-term benefit of the intervention (Fig. 2b;
Supplementary Table 5). There was no long-term impact on
fatigue or other measures.
Exploratory analysis
At baseline, 10 (19%) and 10 (24%) participants in the exercise and
usual care groups respectively, had clinical fatigue. Therefore, we
undertook a post hoc exploratory subgroup analysis of those with
clinical fatigue who had completed ≥50 of classes (exercise: n=7,
usual care: n=10), because there could be more scope to see
benefits in this particular group. Compared with the whole cohort,
17 patients with clinical fatigue at baseline had worse ECOG scores
(35% had ECOG 0 compared with 79% in all patients), more pain
(71% vs. 37%) and higher incidence of previous surgery (41% vs.
21%) as shown in Supplementary Table 2.
Figure 2shows fatigue, leg strength and fitness level (VO
2peak
)
in patients with baseline clinical fatigue, compared with the
group as a whole. Patients with clinical fatigue who exercised
improved their fatigue scores at 3 months (from 27.7 ± 3.6 to
38.4 ± 5.1), and this was maintained at 6 and 12 months (37.2 ±
5.2 and 34.8 ± 6.1). However, improvements were also seen in
the usual care group (from 25.0 ± 7.8 at baseline to 28.1 ± 10.8 at
3 months, 34.7 ± 7.6 at 6 months and 28.5 ± 5.7 at 12 months,
Supplementary Table 8). In a repeated measures analysis
(baseline up to 6 months), the mean between-group difference
in fatigue score was 6.3 (95% CI: −0.6 to 13.3, p=0.07). There
was a positive trend in leg strength in the exercise group over
time (Fig. 2b).However,legstrengthwasnotsignificantly
different between groups (repeated measures’mean difference
from usual care: −2.5 kg (95% CI: −26.0 to 20.9)). There was no
change in VO
2peak
in the exercise group up to 6 months, and no
material effects on other endpoints (Supplementary Fig. 2).
Table 1. Baseline characteristics of all participants.
Baseline characteristics Control
(n=42)
Randomised to active
intervention (n=89)
Declined active
intervention (n=38)
Accepted active
intervention (n=51)
Completed active
intervention (n=41)
Age, median (range) 63 (40–80) 64 (35–86) 64 (36–86) 63 (35–86) 64 (41–86)
Female sex, n(%) 18 (43%) 41 (46%) 17 (45%) 24 (47%) 18 (49%)
Ethnicity, n(%)
White 36 (86%) 74 (83%) 35 (92%) 29 (77%) 32 (78%)
Black 3 (7%) 9 (10%) 1 (3%) 8 (16%) 5 (12%)
Asian 3 (7%) 4 (5%) 1 (3%) 3 (6%) 3 (7%)
Other 0 (0%) 2 (2%) 1 (3%) 1 (2%) 1 (2%)
Type of myeloma
IgG 27 (64%) 52 (58%) 22 (58%) 30 (59%) 24 (59%)
IgA 5 (12%) 15 (17%) 7 (18%) 8 (16%) 7 (17%)
Light chain 7 (17%) 17 (19%) 8 (21%) 9 (18%) 7 (17%)
Non-secretory/oligo-
secretory
3 (7%) 5 (6%) 1 (3%) 4 (8%) 3 (7%)
Autologous stem-cell transplantation
No 4 (10%) 14 (16%) 7 (18%) 7 (14%) 6 (15%)
Yes 38 (90%) 75 (84%) 31 (82%) 44 (86%) 35 (86%)
On maintenance treatment 4 (10%) 18 (20%) 8 (21%) 10 (20%) 10 (24%)
Bone disease 29 (69%) 61 (69%) 24 (63%) 37 (73%) 29 (71%)
Pain 13 (31%) 35 (39%) 15 (39%) 20 (39%) 16 (39%)
Prior surgery 11 (26%) 16 (18%) 7 (18%) 9 (18%) 8 (20%)
Radiotherapy 8 (19%) 23 (26%) 9 (24%) 14 (28%) 9 (22%)
Time since treatment,
median (range), months
20 (2, 251) 14 (2, 161) 15 (2, 161) 13 (2, 138) 12 (2, 84)
ECOG performance score
0 33 (79%) 70 (79%) 31 (82%) 39 (76%) 31 (76%)
1 9 (21%) 19 (21%) 7 (18%) 12 (24%) 10 (24%)
Fatigue, quality of life and physical fitness following an exercise. . .
DA. Koutoukidis et al.
4
Adverse events
No serious adverse events were reported by study participants.
One participant reported hip pain while performing the home-
exercise programme that was spontaneously resolved. Four
participants reported lower back pain during the intervention
period, but it was unclear if this was related to exercise.
Haematology parameters stayed stable throughout the study
(Supplementary Table 9).
Qualitative feedback
Participants’feedback showed that the main reasons for declining
the intervention were time and travel constraints. Qualitative
interviews helped in understanding the less tangible, yet equally
important, benefits. Box 1shows sample quotes (details in a
separate paper). Participants were generally pleased to participate,
appreciated the opportunity to improve their physical well-being
andreportedincreasedconfidenceinexercisingbecauseof
313 assessed for
eligibility
131 randomised
89 allocated to exercise intervention
4 with disease relapse
51 consented to intervention
10 attended < 6 of the 12
classes, of whom:
6 withdrew
3 withdrew 2 declined
1 withdrew
1 with disease relapse
1 lost to follow-up
1 declined
1 withdrew
1 with disease relapse
1 medically withdrawn
1 declined
2 declined 6-month,
but had 12-month
assessment
1 declined 6-month,
but had 12-month
assessment
5 with disease relapse
2 declined
3 with disease relapse
3 withdrew
5 with disease relapse
4 withdrew
4 with disease relapse
1 withdrew
4 with disease relapse
1 withdrew
1 decline
3 with disease relapse
1 withdrew
1 did not complete Q.
1 declined 3-month,
but had 6-month
assessment
2 declined 3-month,
but had 6-month
assessment
1 declined 3-month,
but had 6-month
assessment
45 had assessment at 3 months
39 had assessment at 6 months
32 had assessment at 12 months
45 included in primary analysis Not included in primary analysis 40 included in primary analysis
20 had assessment at 12 months 31 had assessment at 12 months
25 had assessment at 6 months 35 had assessment at 6 months
29 had assessment at 3 months 40 had assessment at 3 months
20 completed 3/3
Monthly classes
10 completed 2/3
7 completed 1/3
14 completed 0/3
3 unwell
1 with disease relapse
41 completed ≥6/12 classes
10 time commitment
34 declined intervention
7 travel commitment
4 time & travel commitment
4 other medical problem
3 could not contact
3 on long-term holidays
2 other reason
1 withdrawn
42 allocated to usual care
Excluded
80 declined
64 no response
23 medically excluded
8 ineligible
1 withdrawn post baseline
6 relapsed post baseline
Fig. 1 CONSORT flow diagram. The diagram displays the progress of the participants through the MASCOT trial. Q: Questionnaire.
Fatigue, quality of life and physical fitness following an exercise. . .
DA. Koutoukidis et al.
5
professional supervision. Patients also felt fulfilled and described a
sense of achievement. Most of them found the level of exercise
appropriate and maintainable, but reported travelling as the main
attendance barrier.
DISCUSSION
MASCOT was the first RCT to evaluate the benefits of an exercise
intervention in MM survivors who have completed treatment. We
observed significant improvements in leg muscle strength at
Table 2. Primary and secondary outcome measures at 3 months among randomised controls and those patients who agreed to the exercise
program and treatment effects (mean difference between the groups, adjusted for baseline values).
Exercise Control Mean difference (95% CI) P-value
Baseline 3-month NBaseline 3-month N
Quality of life
Fatigue 39.6 (9.3) 40.9 (9.8) 45 41.1 (10.8) 40.9 (9.9) 40 1.6 (−1.1, 4.3) 0.25
FAC T—functional 19.7 (6.7) 20.1 (6.1) 45 21.4 (5.1) 21.8 (6.0) 40 0.0 (−1.5, 1.5) 0.97
FAC T—emotional 19.8 (3.9) 19.6 (3.5) 45 19.5 (3.5) 19.5 (4.4) 40 0.0 (−1.5, 1.5) 0.99
HADS anxiety 4.7 (3.5) 4.3 (3.6) 42 5.4 (3.2) 5.0 (3.3) 39 –0.4 (−1.6, 0.8) 0.49
HADS depression 3.5 (2.7) 3.2 (2.5) 44 3.3 (2.6) 3.5 (3.9) 40 −0.6 (−1.7, 0.5) 0.26
Anthropometry
% Fat 30.5 (8.5) 28.7 (8.3) 43 30.9 (10.2) 31.0 (10.8) 38 −0.9 (−1.9, 0.1) 0.07
Muscle mass (kg) 50.5 (10.9) 51.2 (10.0) 43 52.0 (10.3) 52.3 (10.4) 38 0.4 (−0.3, 1.0) 0.23
Weight (kg) 76.9 (15.2) 76.1 (14.8) 44 80.7 (17.6) 81.4 (18.1) 39 –0.4 (−1.3, 0.6) 0.43
PA and fitness
PA (counts per minute) 312.4 (95.1) 326.5 (96.7) 39 353.5 (87.3) 342.8 (74.7) 30 10.3 (–22.1, 42.6) 0.53
Leg muscle strength (kg) 44.3 (26.0) 63.3 (23.3) 40 53.3 (22.1) 61.1 (19.1) 34 8.4 (0.5, 16.3) 0.04
Grip strength (kg) 28.1 (11.1) 29.4 (9.9) 43 31.3 (10.0) 31.7 (9.8) 37 0.7 (–1.0, 2.4) 0.42
VO
2
peak (ml/kg/min) 18.1 (6.9) 20.1 (6.9) 40 19.3 (7.3) 19.8 (7.1) 37 1.5 (−0.2, 3.2) 0.08
PA physical activity.
Fatigue is on a scale 0–52 (high scores mean less fatigue). FACT—functional is on a scale 0–28, FACT—emotional is on a scale 0–24 and HADS—anxiety and
depression are each on a scale 0–21 (high scores mean better QoL).
Table 3. Primary and secondary outcome measures at 6 months among randomised controls and those patients who agreed to the exercise
program and treatment effects (mean difference between the groups, adjusted for baseline values).
Exercise Control Mean difference (95% CI) P-value
Baseline 6-month NBaseline 6-month N
Quality of life
Fatigue 39.8 (8.7) 41.1 (9.1) 39 43.4 (8.1) 43.7 (8.4) 35 0.3 (–2.6, 3.1) 0.85
FAC T—functional 19.9 (6.7) 20.6 (5.4) 38 22.6 (4.2) 21.3 (6.0) 35 0.1 (–2.4, 2.7) 0.91
FAC T—emotional 19.6 (4.1) 19.5 (4.1) 38 19.9 (3.3) 20.1 (3.5) 35 −0.3 (−1.6, 0.9) 0.59
HADS anxiety 4.9 (3.6) 5.3 (3.9) 39 5.2 (3·0) 4.4 (2.9) 33 1.1 (0.0, 2.1) 0.05
HADS depression 3.6 (2.8) 2.8 (2.4) 38 2.9 (2.4) 2.7 (2.5) 35 –0.3 (−1.2, 0.7) 0.57
Anthropometry
% Fat 28.5 (8.5) 28.6 (8.0) 34 30.0 (10.7) 29.7 (10.8) 34 0.4 (−0.6, 1·4) 0.47
Muscle mass (kg) 51.1 (10.2) 51.6 (9.8) 34 53.1 (10.8) 53.4 (10.6) 34 –0.1 (–0.8, 0.7) 0.84
Weight (kg) 76.0 (14.8) 76.4 (14.3) 35 81.5 (19.0) 81.5 (18.7) 34 0.2 (−1.0, 1.3) 0.77
PA and fitness
PA (counts per minute) 314.2 (92.9) 301.8 (79.2) 32 352.8 (89.2) 342.3 (103.9) 29 −12.4 (−45.9, 21.1) 0.13
Leg muscle strength (kg) 44.8 (25.3) 67.4 (23.9) 33 58.6 (20.6) 61.8 (23.4) 31 10.8 (1.2, 20.5) 0.03
Grip strength (kg) 28.7 (10.0) 30.1 (10.0) 34 33.2 (9.5) 34.0 (9.0) 34 0.5 (−1.3, 2.3) 0.58
VO
2
peak (ml/kg/min) 18.7 (7.6) 19.5 (6.2) 32 20.7 (7.4) 19.4 (7.8) 31 1.2 (−1.0, 3.5) 0.27
PA physical activity.
Fatigue is on a scale 0–52 (high scores mean less fatigue). FACT—functional is on a scale 0–28, FACT—emotional is on a scale 0–24 and HADS—anxiety and
depression are each on a scale 0–21 (high scores mean better QoL).
Fatigue, quality of life and physical fitness following an exercise. . .
DA. Koutoukidis et al.
6
3 and 6 months that remained at 12 months, but little effect on
fatigue, the primary outcome. Post hoc analysis showed that
participants with clinical levels of fatigue reported some
improvement in fatigue following the intervention. The pain and
bone morbidity seen at baseline in many patients would
theoretically make them unlikely candidates for exercise pro-
grammes. However, adherence was good, and uptake was
comparable to other exercise studies.
28
The intervention was safe,
and no notable adverse events were observed. The Zelen design
aimed to avoid contamination bias, thereby producing more
reliable estimates of effect than other cancer trials of exercise.
MASCOT followed on from our single-arm trial, in which fatigue
improved by 4 points at 6 months.
12
A likely reason for the smaller
effect on fatigue in MASCOT is that patients had less fatigue at
baseline than in the pilot study (mean score 40.7 vs. 37.4), hence
less scope for improvement. This is partly supported by our
exploratory analyses, suggesting improvement in fatigue in the
subset of patients with clinical fatigue at baseline, along with
increased leg strength. However, future larger trials in patients
with clinical fatigue are required.
The two previous RCTs of exercise in MM patients involved
home-exercise programmes during high-dose chemotherapy and
autologous stem-cell transplantation.
9,10
They were inconclusive
and had a short follow-up. One had only 24 patients, though the
results suggested improvements in muscle strength (in line with
our data) and sleep. The other study (187 patients) reported no
effect on fatigue, but did not measure strength/physical fitness,
nor analysed subgroups according to baseline fatigue score. Our
study was designed to improve upon these limitations, with a
tailored and supervised programme (once-weekly gym atten-
dance), individualised progression of intensity and accompanied
by behavioural support using Habit theory. We also aimed to
reduce contamination through a blinded control arm, utilising a
modified Zelen design. Further strengths of our MASCOT study
include timing of intervention after treatment to reduce the risk
of fracture and increase the likelihood of participants completing
the strength tests, the use of a theory-based intervention,
Fatigue (FACIT-F scale)
55
a
b
c
50
45
40
35
30
25
20
15
10
5
0
150
125
100
75
50
25
0
50
45
0
10
20
30
03612 03612 03612 03612
03612
03612 0 3612
Months
Exercise — with fatigue
Control — with fatigue
Exercise — all completers
Control — all completers
VO2 peak (ml/kg/min)
Leg strength (kg)
03612 0 3612
03612 0 3612 0 3612
Fig. 2 Tukey plots. Tukey plots for fatigue (a), leg strength (b) and
VO
2
peak (c) for participants with clinical fatigue at baseline (FACIT-F
score < 34), and all participants in the per-protocol analysis (had
high adherence to the exercise programme) at each time point.
Box 1: Participants’experience of the exercise intervention
from interviews
Participants’experience Key quotes
Enjoyment and self-
confidence
“I think the biggest thing has been for me
the confidence to know it’s okay to do
exercise. I was frightened to exercise before,
I was frightened that I was going do some
damage because I’d done so much
damage to my bones. So, the biggest thing
was having the confidence instilled in me
that I can do it. You certainly wouldn’t
have got that through being given a fact
sheet about what’s possible. Having a
really highly skilled physio supporting me
physically, mentally and emotionally
through that was brilliant. It really gave me
the confidence and ability to go out and
have a more active life really.”
Sense of fulfilment and
achievement
“I felt fulfilled, motivated. That’s always
nice to think, ‘I’ve actually achieved
something’.”
“I like the sense of achievement after, I like
the sense of wellbeing because you feel so
alive and engaged and I have a little
twinkle.”
Factors influencing
intervention adherence
“You track that [i.e. Borg Rating of
Perceived Exertion] so that as you come
into each session, you’re –you know, Jo
would have a look and say, ‘Ah. Anything
feel a bit easy? That one looks –yeah, that
one feels a bit easy. Right, well, we’ll
increase the difficulty there.’Or actually,
‘You’re right up at the limit there. Let’s just
keep trying to build up to that one.’You
know, so we’re constantly checking each
exercise in terms of was it stretching you
enough um and you know, do we need to
make it any –any adaptations to help you
build up? So, there’s a few things I had to
have adapted so that I could build up to
it’cause they were too difficult, and you
know, I was able to progress, and other
things that you know, felt quite easy so we
increased the difficulty of those. But it was
you know, very, very personalized every
week, so that was great.”
“The only thing is that it takes quite a long
time, you know, to arrive here, the exercise
and so on. Basically, it’s half of your day
gone.”
Fatigue, quality of life and physical fitness following an exercise. . .
DA. Koutoukidis et al.
7
comprehensive objective outcomes, a more ethnically diverse
sample than previous trials and high adherence to the exercise
sessions.
The limitations of the current trial include the low levels of the
ECOG score at baseline. Despite being open to patients with ECOG
scores of 0–2, all patients in our study had ECOG 0–1. Furthermore,
the mean fatigue score of 37.4 was substantially higher, indicating
less fatigue, compared with a previous study of 88 MM survivors
that reported a mean FACIT-F-fatigue score of 20.2.
7
We were
recruiting from a central London tertiary centre where patients are
referred for autologous stem-cell transplantation, and the majority
of our cohort were in their first line of treatment. Such patients
often have higher functioning and QoL than those in subsequent
treatment phases.
29
Hence, there was less room for improvement
in some of the outcomes we studied.
Even though the exercise programme involved weekly atten-
dance at a central gym, the uptake (57%) was consistent with a
systematic review of 65 cancer exercise trials using a standard RCT
design where uptake was estimated at 63% (range 33–80%).
28
At
6 months, 76% remained in the programme. Of the decliners, 62%
were interested in participating in the intervention, but were not
keen on the extra time/travel commitment. This highlights the
need to design and test exercise programmes with better access
and less burden for patients.
The modified intention-to-treat analysis was used as the decline
rate within the intervention group may otherwise have diluted
any potential intervention effect. Furthermore, we did not
generally observe differences between those who accepted and
declined the intervention. Thus, the modified intention-to-treat
analysis allowed us to explore whether the intervention had an
effect on the outcomes under study.
Our findings of increased leg muscle strength are particularly
relevant to an older group of cancer survivors with osteolytic bone
disease. These were clinically large effects, which could be
expected to help improve patients’general mobility, as well as
providing some lessening of physical fatigue. For MM survivors,
the risk of falls related to advanced age is increased by
deconditioning, resulting from bone morbidity and debilitating
effects of chemotherapy, and the fracture risk is high. Increased
muscle strength reduces the risk of falls; thus, this in itself is an
important benefit of physical exercise. Our preliminary results for
fatigue reflect those of two studies of exercise intervention in
patients undergoing stem-cell transplantation (any haematologi-
cal cancer), which reported no improvement in fatigue,
30,31
though one showed better physical functioning.
30
A third trial in
haematological cancer survivors (37 patients) indicated a large
benefit of exercise (post cancer treatment) on fatigue at 3 months;
however, with a different tool (Schwartz Cancer Fatigue scale),
benefits were lost by 6 months, and only four patients had MM.
32
CONCLUSION
Our RCT in MM survivors demonstrated that a tailored exercise
programme was safe, improved muscle strength in all patients
and indicated preliminary evidence of improved fatigue in those
who had clinical fatigue at baseline. Multiple myeloma survivors
could consider structured exercise programmes, and clinicians
should be encouraged to offer or refer patients for exercise
support. Larger trials should now focus on patients with clinical
fatigue, and modify the intervention delivery format to reduce
barriers to recruitment and attendance providing more support
for home-based activities.
ACKNOWLEDGEMENTS
We would like to thank the participants for taking part in this trial, Professor Fares
Haddad who facilitated the use of facilities at the Institute of Sport, Exercise and
Health (ISEH), Sarah Hayden for administrative support at ISEH, Nicholas Counsel for
statistical support and Rose Wilson for contributing to the intervention development.
Our study results were selected for an oral presentation at the 60th American Society
of Hematology Annual Meeting & Exposition in December 2018.
31
AUTHOR CONTRIBUTIONS
K.Y., A.F., R.J.B., A.H. and B.P. conceived and designed the study. K.Y. and A.F. provided
administrative support. K.Y., D.D., S.D., A.R., N.R., R.P., C.K., X.P. and A.M. provided
materials and patient data. J.L., M.H., D.A.K., O.M. and S.P. collected and assembled
data. D.A.K., A.H., J.L., A.F. and K.Y. did the data analysis and interpretation. D.A.K., J.L.,
R.J.B., A.H., A.F. and K.Y. wrote the paper, and all authors approved the final version of
the paper.
ADDITIONAL INFORMATION
Ethics approval and consent to participate Full ethical approval was obtained by
the National Research Ethics Service Committee London—Queens Square Reference:
13/LO/1105. The study was performed in accordance with the Declaration of Helsinki.
All participants provided written informed consent to participate.
Consent to publish Not applicable.
Data availability The data sets used and/or analysed during the current study are
available from the corresponding author on reasonable request.
Competing interests Professor Kwee Yong reports grants from Celgene during the
conduct of the study. The remaining authors declare no competing interest.
Funding information The study was funded by Cancer Research UK (Programme
grant no. C1418/A14133), Cancer Research UK Development Fund and Celgene,
and supported by the National Institute for Health Research University College
London Hospitals Biomedical Research Centre and by the NIHR Oxford Biomedical
Research Centre. University College London was the study sponsor. They had no
role in study design, data collection, data analysis, data interpretation or the
writing of the report. The corresponding author had full access to all the data in
the study, and had final responsibility for the decision to submit for publication. R.
J.B. is currently supported by Yorkshire Cancer Research. The views expressed are
those of the authors and not necessarily those of the NHS, the NIHR or the
Department of Health and Social Care.
Supplementary information is available for this paper at https://doi.org/10.1038/
s41416-020-0866-y.
Publisher’snoteSpringer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
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Fatigue, quality of life and physical fitness following an exercise. . .
DA. Koutoukidis et al.
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