Proefschrift PDF. Braam

the qlim study
Improving physical fitness in children with cancer:
a steep mountain to climb
Katja Braam
This thesis provides information on a study on the physical fitness
of children with cancer during and shortly after cancer treatment.
It presents the design and effects of a new 12-weeks intervention
program, which includes physical exercise and psychosocial training
sessions. In addition, this thesis gives insight into the cost-effective-
ness of the program and the willingness of children and their parents
to participate in the trial.
Katja Braam is a health scientist at the VU University Medical Center,
with specific interest in health care innovations and interventions
aiming to minimize the negative effects of childhood cancer.
theqlimstudyImprovingphysicalfitnessinchildrenwithcancer:asteepmountaintoclimbKatjaBraam
Omslag QLIM Study.indd 1Omslag QLIM Study.indd 1 22-03-16 07:2722-03-16 07:27

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The QLIM study
Binnenwerk QLIM Study Mix 1Binnenwerk QLIM Study Mix 1 21-03-16 15:5721-03-16 15:57

2 the qlim study

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The QLIM study
Improving physical ﬁtness
in children with cancer:
K ATJ A I R E N E B R A A M
2016

4 the qlim study
The QLIM study – Improving physical ﬁtness in children with cancer:
Thesis,VU University, Amsterdam, the Netherlands
© Katja Irene Braam, Amsterdam, the Netherlands, 2016
The printing of this thesis was supported by:
CIT Technics
Lode Holding B.V.
Research Fonds Kindergeneeskunde
Cover Marjolein Triesscheijn
Editing Eefje Gerits, www.redactiepunt.nl
Lay-out Andre Klijsen, www.villay.nl
Printed by Drukkerij Wilco, www.wilco.nl
ISBN 978-90-9029647-0

5
V R I J E U N I V E R S I T E I T
The QLIM study
Improving physical ﬁtness in children with cancer:
ACADEMISCH PROEFSCHRIFT
ter verkrijging van de graad Doctor aan
de Vrije Universiteit Amsterdam,
op gezag van de rector magniﬁcus
prof. dr.V. Subramaniam,
in het openbaar te verdedigen
ten overstaan van de promotiecommissie
van de Faculteit der Geneeskunde
op maandag 23 mei 2016 om 13.45 uur
in de aula van de universiteit,
De Boelelaan 1105
door
Katja Irene Braam
geboren te Nijmegen

6 the qlim study
promotor: prof. dr. G.J.L. Kaspers
copromotoren: dr.T.Takken
dr. E. van Dulmen-den Broeder
dr. M.A.Veening

7
Contents
Chapter 1 General introduction
Chapter 2 Cardiorespiratory fitness and physical activity in children with
cancer
(Supportive Care and Cancer, 2015: DOI 10.1007/s00520-015-2993-1)
Chapter 3 Physical exercise training interventions for children and young
adults during and after treatment for childhood cancer
(Cochrane Database of Systematic Reviews 2013, issue 4;
Review updated 2015: accepted)
Chapter 4 Design of the Quality of Life in Motion (QLIM) study: a randomized
controlled trial to evaluate the effectiveness and cost-effectiveness
of a combined physical exercise and psychosocial training program
to improve physical fitness in children with cancer
(BMC Cancer 2010, 10:624)
Chapter 5 Factors influencing childhood cancer patients to participate in a
combined physical and psychosocial intervention program: Quality
of Life in Motion
(Psycho-Oncology 2015, 24(4):465-471)
Chapter 6 Effects of a combined physical exercise and psychosocial training
program for children with cancer: a randomized controlled trial
(Submitted)
Chapter 7 Cost-effectiveness of a combined physical exercise and psycho-
social training program for children with cancer
(Submitted)
Chapter 8 Application of the steep ramp test for aerobic fitness testing in
children with cancer
(European Journal of Physical and Rehabilitation Medicine 2015,
51(5):547-555)
9
25
41
95
109
123
137
151

8 the qlim study
Chapter 9 General discussion
References
Chapter 10 Summary
Nederlandse samenvatting
Appendix Chapter 3: Cochrane review search strategies
Curriculum vitae
List of publications
Dankwoord
165
175
191
197
203
213
215
219

9
c h a p t e r 1
General introduction

10 the qlim study
Epidemiological aspects of childhood cancer
Yearly, approximately 600 children (0-18 years old) in the Netherlands are diagnosed
with cancer.1 More speciﬁcally, the incidence of childhood cancer is 16 per 100,000 in
boys aged 0 till 14 years old and 13 per 100,000 in girls with the same age range.1
For adolescents, numbers are slightly higher: 27 and 21 per 100,000 for boys and girls
between 15 and 24 years old, respectively.1
Childhood cancer is a rare disease which can develop in different systems or organs.
The incidence per cancer type differs by age. In addition, such as is shown in Figure 1.1
and 1.2 the deviation of cancer types changes when the age increases.1,2
In general, childhood cancer can be divided in hematological malignancies and solid
cancers. Hematological malignancies are childhood cancer types that particular
develop in cells of the immune system, or in blood forming tissue such as the bone
marrow.3,4 Hematological malignancy can be further divided into two groups: leuke-
mia and lymphoma, all with different sub-types.5
Figure 1.1 Age-speciﬁc childhood cancer incidence 0-14 years

11i: general introduction
Figure 1.2 Age-speciﬁc childhood cancer incidence 15-19 years
A solid cancer is a cluster of malignant cells (tumor) which has the ability to invade sur-
rounding tissue and to metastasize.3 A solid cancer can develop in any place or tissue
of the body3 leading to a wide range of solid cancer types which can occur during
childhood (Figure 1.1 and 1.2). In children the most common types of solid cancer are:
Central Nervous System (CNS) tumors, renal tumors, soft tissue sarcoma’s and bone
tumors, but especially in older children also carcinomas and melanomas frequently
occur (Figure 1.2).3
Each type of cancer has its own incidence peak.Table 1.1 shows the incidences accord-
ing to the Dutch Cancer Registries by age group at 2013 as a recent year, showing a
yearly incidence of 631 childhood cancer cases.

12 the qlim study
Table 1.1: Childhood cancer incidence per type of cancer in 2013.
Diagnosis Total Age 0-4 Age 5-9 Age 10-14 Age 15-17
Leukemia
Lymphoma
Brain/CNS tumor
Soft tissue sarcoma
Bone tumor
Nephroblastoma
Others
total
187
78
76
40
50
28
172
631
79
2
22
20
4
14
52
193
41
6
27
4
12
10
4
104
33
21
17
8
18
2
24
123
34
49
10
8
16
2
92
211
Childhood cancer treatment
In general, children are treated with surgery, chemotherapy and radiotherapy, or a
combination of these treatment modalities. Sometimes treatment also involves a
bone marrow or stem cell transplantation.
Surgery, as a treatment modality in childhood cancer patients, is used for diagnosis
(biopsy), remove the tumor, or to replace a bone or to implant a prothesis. It is rarely
used as the only treatment modality. Nowadays, surgery in children is preferably per-
formed with minimally invasive surgery techniques, leading to smaller incisions and
faster recovery.3
Radiotherapy uses ionizing radiation to treat cancer.6 Compared to 1896, the year
in which the ﬁrst patients were treated with radiotherapy, current radiotherapy is
administered far more accurate and precise.7 By stereotactic irradiation and proton
therapy it is currently possible to deliver high-dose radiation from multiple directions
towards the tumor,with minimal damage to the healthy surrounding tissue,resulting
in increased survival and better health-outcomes.7 Radiation can be used as a single
treatment modality to destroy the whole tumor.8 It, furthermore, can also be used in
combination with other types of treatment; for example as post-surgery treatment
to kill remaining cancer cells after tumor resection or combined with chemotherapy.8
Finally it can be used as palliative treatment to relieve cancer-related pain.8
Surgery and radiotherapy dominated the ﬁeld of cancer therapy into the 1960s, but
cure rates plateaued at about 33%, showing the need for new treatment modali-
ties.9 In 1955 new chemotherapy agents were developed to cure patients with various
advanced cancers.9 Nowadays, most children with cancer are treated with chemo-
therapy. Chemotherapy, or cytostatic drugs, have the ability to prevent growth and
proliferation of cells,and to kill cells.6,10 The best results are found when different cyto-
static drugs are combined, provided in cycles and administered over a longer period

of time.5,11 For each type of cancer a different chemotherapy combination is needed to
cure the disease.11,12
Stem cell transplantation is the procedure of replacing abnormal stem cells with
healthy stem cells.6 Stem cells can be harvested from either bone marrow or blood.6 A
stem cell transplantation can be allogeneic (from either a related, or unrelated donor)
or autologous (patient’s own cells).13 In children with cancer, a stem cell transplanta-
tion is performed in children with aggressive leukemia13,14, or when the cancer treat-
ment is so aggressive that next to the cancer also all stem cells are destroyed.15
Adverse side effects of childhood cancer treatment
Childhood cancer treatment is increasingly successful in the last decades and cur-
rently approximately 77% of the children who are diagnosed with cancer will be alive
five years post-diagnosis.16 However, the treatment required to establish these high
survival rates has its consequences. Patients are at increased risk for premature death
and adverse health problems.It has become clear that almost 75% of the 5-years child-
hood cancer survivors have one or more (severe) chronic adverse health-outcomes.17 A
survivors of childhood cancer can be at increased risk for heart problems, lung or
kidney problems, but also psychosocial dysfunction and negative effects of inactivity
such as obesity, diabetes and cardiovascular disease.17 Therefore, when possible, it is
important to develop interventions both to reduce organ failure as well as to promote
healthy behavior to eliminate some of the risks. Below, per treatment type, often
occurring adverse side effects are described.
Surgery as the oldest therapy method may lead to clear but long-term effects with
adverse implications. For instance, an amputation of a limb, or other body part to
remove a bone tumor will have life-long consequences18,as will ataxia following brain
tumor surgery.19
Radiotherapy may lead to negative short- and long-term consequences. One of the
common short-term consequences of radiotherapy is fatigue.20 Reported long-term
adverse effects of radiotherapy are second malignancies, organ deficits, bone and
body growth problems and neuro-cognitive problems depending on the radiation
location.21
Finally, chemotherapy can have negative short- and long-term effects. It commonly
leads to bone marrow suppression, resulting in low erythrocyte, platelet and leu-
kocyte counts, leading to anemia, increased risk of bleeding, an impaired immune
response and muscle function and decreased physical fitness.3 Since the physiological

14 the qlim study
characteristics of cancer cells hardly differ from healthy cells,cytostatic drugs affect all
dividing cells.10,22 In the short -term they especially affect those cells with a rapid turn-
over,such as hair cells,and mucosa membrane cells,leading to hair loss and mucositis
with nausea with subsequent vomiting.10,22 In the long-term, chemotherapy may also
affect organ function. For example: use of antracyclines can impair cardiac function
especially when higher cumulative doses are used and when antracyclines are given
to young children23, bleomycine may result in a decreased lung function due to pul-
monary fibrosis24 and vincristine, can result in peripheral neuropathy with pain and
muscle weakness, especially in feet and hands.25
Physical fitness in childhood cancer patients
As stated above , children with cancer are known to have an impaired muscle func-
tion and reduced physical fitness.26 Yet, additionally, they also are found to have a low
physical activity level.27–30 Low physical fitness, muscle atrophy and inactivity during
cancer treatment may persist if inactivity becomes a habit and then may lead to seri-
ous diseases later in life. 31–34
Physical fitness combines multiple components: strength, endurance, body compo-
sition and flexibility, but can also be related to athletic competence.35 It, overall, is
known as a combination of cardiorespiratory fitness and muscle strength.36
Muscle strength is important for the ability to perform activities.37 cardiorespiratory
fitness is important for the maintenance of activities36, and has been described as a
strong indicator for health.36
Physical activity commonly reflects someone’s physical fitness. It is any bodily move-
ment produced by skeletal muscles that results in energy expenditure.35 Sedentary
behavior, on the other hand, is passive behavior, requiring very low energy expendi-
ture, for example sitting, lying in bed and watching TV.38 While physical activity posi-
tively affects health39,40, sedentary behavior negatively affects physical functioning
through increased risk for obesity,cardiovascular disease and type 2 diabetes.17,41 Pedi-
atric physical activity recommendations state that children need to perform a mini-
mum of sixty minutes of moderate-to-vigorous physical activity per day.42–44 Meet-
ing these recommendations is difficult for most children of the general population
but especially difficult for children with cancer. These children are ill, have to face a
highly intensive treatment and related hospitalizations with fear and uncertainties
about the future; cure than is more important than participating in sports.26 But the
problem of inactivity remains. Also after childhood cancer treatment, the survivors
of childhood cancer are found to be less physically active when compared to healthy
others.29,30,44

There are different factors influencing physical activity and sedentary behavior.46 In
general female sex, being an adolescent , lower self-esteem, perceived barriers, urban
environment, winter season, and higher parental age are found to negatively affect
physical activity.47–49 Children with cancer face additional factors such as the cancer
diagnosis, treatment, hospitalization, and low, unbalanced or extensive nutritional
intake50; all further decreasing physical activity in this population.28,51–53
Overall, childhood cancer treatment negatively affects the child’s daily function-
ing both in the short- as well in the long run. Pain, fatigue, anemia, infection risks,
nausea and a reduced muscle function decreases the child’s possibility to participate
in sports, school and social events and this may ultimately reduce the overall health-
related quality of life (HrQoL).
Health-related quality of life and fatigue
HrQoL on its own has been recognized as an important outcome measure during
and after childhood cancer. It combines the experienced quality of someone’s physi-
cal, psychological and social functioning.54 The HrQoL of children with cancer is lower
than the norm when they are during treatment.55 Children with cancer experience
problems on different domains, such as school functioning, problem solving, social
relations and family functioning.56 They have to simultaneously deal with a deadly
disease, bodily changes, worries about the future and changes in the family.56 The
HrQoL scores tend to return to normal after cessation of treatment.54,57 Apart from
being better,this may result from an enhanced self-esteem,becoming aware of (nega-
tive) thoughts or feelings and obtaining adequate coping strategies.56
HrQoL can also be influenced by fatigue. Fatigue is a symptom related to both physi-
cal, psychological and emotional functioning.58 Fatigue is a frequently encountered
symptom in cancer patients.58,59 This cancer-related fatigue is an unexpected tired-
ness that is more intense and more severe than normal fatigue and unlike normal
fatigue, is not relieved by sleep or rest.59 Physical fitness, physical activity and can-
cer-related fatigue are closely related. Children with a low physical fitness experience
fatigue. This might lead to more sleep and rest and a further reduction of physical
activity and physical fitness60,61, resulting in a vicious circle which is often observed in
cancer patients.58,60 As physical exercise has been reported to decrease cancer-related
fatigue62, it has been hypothesized that a physical exercise intervention will help to
escape from the vicious circle.

16 the qlim study
Rehabilitation
Physical exercise intervention can be introduced with various aims and contents. Pos-
sible aims include the need to increase cardiorespiratory ﬁtness63–65, physical activ-
ity66,67, bone mineral density65,68–70, immune recovery71,72, and/or psychosocial func-
tioning and HrQoL73–75, but also the need to decrease cancer-related fatigue76–78, or
reduce total body fat mass68.To reach these goals different interventions are needed.
Physical exercise interventions can, for example be high (i.e. aerobic and weight bear-
ing exercises)79–86, or low intensive (i.e. walking and yoga)87–90, group-based77,91, or
provided individually65,84,92. Physical exercise interventions can be provided hospital-
based79,80,86,87,90,93, home –based63–65,76,81,89,90,94, or in a rehabilitation, sport, or physi-
cal therapy center77,92.
In adult cancer patients, exercise interventions are more and more incorporated in
standard health care.95 The clinical importance of exercise during cancer treatment
was underscored by a recent publication which showed that breast cancer patients
had less chemotherapy dose-reductions during therapy when they participated in
an exercise program, compared to the control group receiving usual care.82 Also in
children with cancer attention towards and requests for exercise related care is grow-
ing.96 However, in children with cancer no effective evidence-based exercise program
exists. Studies performed before 2009,assessing the effectiveness of physical exercise
interventions in children with cancer,included small patient numbers,primarily diag-
nosed with acute lymphoblastic leukemia, and often performed as non-controlled
study or with a case-control study design, leading to results and conclusions based on
low quality study data97 (Table 1.2).
All but two86,98 of the described studies in Table 1.2 used a training program includ-
ing aerobic and muscle strengthening exercises. Yet, there seems to be no consensus
on the best duration of the intervention (ranging from 2 days to 2 years), nor on the
frequency of exercises (range: twice per day for 30 min, to twice per week for 45 min).
Former study results indicate that high-intensive exercise training protocols (training
above 70% of the maximal heart rate reserve) provide the best, and most
effective training.64,79,92,93,98 Yet, included patient numbers were small and especially
Takken et al. (2009) showed a high drop-out rate.92

Table 1.2: Studies evaluating the effectiveness of exercise interventions in children with cancer
during or shortly after cancer treatment, published before or in 2009.
Author (year),
design
Patients Intervention Duration Intensity
Sharkey (1993),95
Case-series
Type: all childhood
cancer types (n=12)
After treatment
a) Hospital-based
b) home-based:
aerobic exercises
a) 12 weeks
b) week 7-12
a) 2x p/w; 60 min
b) 60 min
Shore (1999),108
Case-control
Type: all childhood
cancer types (n=6);
healthy control (n= 11)
After treatment
a) Hospital-based
b) home-based;
aerobic exercises
12 weeks a) 1x p/w; 30 min
b) 2x p/w; 30 min
70-85% of HRmax
Marchese (2004),64
RCT
Type: ALL (n=28)
During treatment
Home-based:
aerobic and muscle
strengthening
exercises
4 months 7x p/w; min NM
San Juan (2007),94
Case-series
Type: ALL (n=7)
During treatment
Hospital-based;
strength and aero-
bic exercises
16 weeks 3x p/w; 90-120
min
>70% of HRmax
San Juan (2008),80
Case-series
Type: BMT (n=8)
After treatment
Hospital-based;
strength and aero-
bic exercises
8 weeks 3x p/w; 90-120
min
>70% of HRmax
Hinds (2007),87 RCT Type: Solid tumor or
AML (n=29)
During treatment
Hospital based;
pedaling on a sta-
tionary bike
2-4 days 2x p/d; 30 min
Takken (2009),93
Case-series
Type: ALL (n=9)
After treatment
a) Local physical
therapy center
b) home-based
exercise; strength
and aerobic exer-
cises
a and b) 12
weeks
a) 2x p/w; 45 min
b) >2x p/w; 11 min
77-90% of HRmax
Moyer-Mileur
(2009),65 RCT
Type: ALL (n=15)
During treatment
Home-based: aero-
bic and strengthen-
ing exercises
12 weeks 3x p/w; 15-20 min
MVPA
Hartman (2009),66
RCT
Type: ALL (n=51)
During treatment
Home-based: aero-
bic and strengthen-
ing exercises
2 years 2x p/d; min NM
Abbreviations: RCT: randomized controlled trial; n: number; ALL: acute lymphoblastic leukemia;
AML: acute myeloid leukemia; p/w: per week; p/d: per day; min: minutes; NM: not mentioned;
HRmax: maximum heart rate; MVPA: moderate-to-vigorous physical activity.

18 the qlim study
Combination of physical exercise and psychosocial training
intervention
In adult cancer patients, some studies assessed the effectiveness of combined physi-
cal exercise and psychological intervention99–101, most of them with modest positive
effects. A study by Van Weert et al. (2010) was performed to compare two interven-
tions arms.77 The first was a group-based exercise training intervention without psy-
chosocial support, the second was a combined program of both exercise and psycho-
social training sessions.77 This study showed comparable results in both intervention
groups.77 It was discussed that, possibly related to the group-based physical exercise
training and the provided peer support during that training, the psychosocial inter-
vention did not increase the intervention effect.77
In children with cancer it is difficult to provide a group-based exercise intervention
due to the low childhood cancer incidence. Nonetheless children with cancer might
be at increased risk for dropping out a physical exercise intervention when confidence
and support is lacking.92 According to the findings of the study by Takken et al. (2009),
parents of children with cancer seem to put low demands on their child and children
themselves stop easily when it comes to demanding activities or pushing bounda-
ries.92 For a training program to be more effective with a lower drop-out rate,it may be
helpful for children with cancer to increase their self-esteem, beliefs of athletic com-
petence and to learn how to coop with difficult cancer-related situations. Especially
when participating in a challenging physical exercise intervention. An additional
psychosocial intervention to increase self-esteem, beliefs of athletic competence and
coping skills,parallel to a physical exercise program,might increase psychosocial well-
being and decrease participation drop-out.
The QLIM study (Quality of Life in Motion)
The QLIM study described in this thesis is part of a large consortium called A-CaRe:
Alpe d’HuZes Cancer Rehabilitation which is sponsored by the Dutch Cancer Society/
Alpe d’HuZes foundation.
The design of the A-CaRe trial is based on a conceptual model, presented in Figure 1.3.
According to this model, cancer treatment influences four health outcomes: physical
activity,physical fitness,fatigue and HrQoL.A physical exercise intervention is thought
to improve physical fitness (cardiorespiratory fitness and muscle strength), which
decreases fatigue and subsequently improves HrQoL. The physical exercise interven-
tions as well as physical fitness may also directly influence fatigue and HrQoL.

Figure 1.3: Conceptual model of the A-CaRe trials
There are four RCTs included in A-CaRe program which all primarily focus on physi-
cal fitness, assessed by approximately the same outcome measures. In addition, all
include a cost-effectiveness analysis of the intervention program.The study described
in the current thesis is the only one, however, to enroll children and to include both a
physical and psychosocial intervention program.
Assessment of physical exercise intervention effects
To assess the effects of a physical exercise intervention it is important to primarily
incorporate assessment of cardiorespiratory fitness and muscle strength, but also to
assess physical activity, body composition, bone mineral density, fatigue, psychosocial
functioning and HrQoL, because they all can be influenced by exercise.
Cardiorespiratory fitness describes the endurance or aerobic capacity of a child, thus
the capacity to perform physical exercise or activity at a higher intensity level or
longer duration. Cardiorespiratory fitness can be assessed by the Cardiopulmonary
Exercise Test, which is the gold-standard test.102,103 This test is performed on a cycle
ergometer or treadmill with gas-exchange analysis to determine peak oxygen uptake
(VO2peak).103 The test protocol includes a gradual increase in workload; depending on
the body height of the child, the workload increases with 10, 15 or 20 Watt per min.102
Besides the heart rate, ventilation and the respiratory exchange ratio changes during
the test, the test provides the volume of oxygen consumed, per minute with (ml·kg-
1·min-1) or without correction for body weight (L/min).102,103
In contrast to the Cardiopulmonary Exercise Test, cardiorespiratory fitness tests with-
out respiratory gas analysis don’t directly measure cardiorespiratory fitness but pro-
vide an estimate.36 However, these tests can easily be performed outside specialized

20 the qlim study
clinics and can therefore be used in general sports centers and physical therapy clin-
ics. Examples of such tests are: the Cooper test, shuttle run test, the Steep Ramp Test,
and the 6, 9 or 12-minute run-walk test.36
Asreportedbefore,musclestrengthisnecessarytoperformphysicalactivities.37 During
a physical exercise program one of the primary aims is to increase muscle strength.
Muscle strength can be measured objectively by two methods: isokinetic testing and
hand-held dynamometry.104 Muscle strength assessment by isokinetic measurement
is the gold-standard method 104 and is performed by a computerized device report-
ing peak and maximal force, muscle endurance, and muscle power.104 However, this
instrument is expensive and often not available outside specialized clinics. A port-
able hand-held dynamometer used to measure muscle strength is also found to be
reliable, valid, and less expensive. Especially when the follow-up measurements are
performed by the same outcome assessor.104 Therefore hand-held dynamometry is
commonly used in non-clinical settings.104 Muscle strength can also be determined by
field tests, such as the sit-to-stand test, 10-repetition maximum, up-and-down stairs
test, standing long jump test, or a muscle power sprint test.36,105,106 These tests are
simple and non-noninvasive,but require careful guidance by an experienced observer
to obtain valid information.
An increase in cardiorespiratory fitness and muscle strength increases someone’s
potential to perform physical and social activities. Physical activity can best be
assessed using an accelerometer.107–110 An accelerometer is a device that measures
acceleration (g-force). Most of the available accelerometers are validated in children,
are small, light and very sensitive by triaxial censoring.111–113 Obtained data from the
device include activity counts per minute, step counts, categorical physical activity
levels (sedentary, light, moderate and vigorous), activity energy expenditure, and met-
abolic equivalents (METs; 1 MET = sitting, 10 METs = rope jumping).114,115
As physical exercises increase energy expenditure, participating in a physical exercise
intervention might also influence weight and fat mass. Fat mass can be assessed by:
whole-body Dual Energy X-Ray Absorptiometry (DXA), skinfold measurement, waist
circumference or bioelectrical impedance analysis.116 Whole-body DXA is a scanning
method that is performed by low amounts of ionizing radiation (0.1-6 μSv). It is per-
formed without special preparations such as iodinated contrast.117 During the scan-
ning, performed in approximately five minutes, the child is allowed to wear (one layer
of) clothing. 118 Due to its validity, the wide accessibility, and low invasiveness of the
technique, this method is the preferred method to use when assessing fat mass.116
117,119

The second method to assess fat mass is skinfold measurement. During this meas-
urement the skinfold thickness is measured by a caliper which is placed on different
standardized body sites.120 The test is simple and is cheap, yet it also is vulnerable for
inter-observer variances, and possibly underestimates the total percentage of body
fat when compared to DXA results.121
A third method to assess fat mass is waist circumference.Waist circumference can be
measured by a tape-measure at a midpoint between the ribs and the top of the iliac
chest, the amount of centimeters presents information on the weight status: normal,
overweight or obese.121 However, in case of distension of the abdomen the measure-
ment is invalid.
Finally fat mass can be measured by bioelectrical impedance analysis. Bioelectrical
impedance analysis is based on the relationship between the volume of a person and
the impedance value.122 Although this technique is simple, fast and can be used in
children122, there are different measurement errors described123 suggesting that this
method is not the advised method for accurate assessment of the percentage body
fat.123
Another important outcome of body composition is bone mineral density. Bone min-
eral density can be assessed by DXA, quantitative computed tomography, magnetic
resonance imaging (MRI), and bone markers in blood.117 Although DXA estimates
bone density by measuring bone mineral areal density, the DXA has been described
as the gold standard method to assess bone mineral density.124 Quantitative com-
puted tomography, as second best, uses normal x-ray computed tomography to
measure compartmental volumetric bone mineral density and additionally geomet-
ric bone structure. This technique provides high quality data, however, the debits are
higher than the proﬁts. The quantitative computed tomography, for example, uses
ten to twelve times more ionizing radiation than DXA. As a second debit it provides
bone mineral density information of small bone parts due to the restricted scanning
options.117,125
MRI is a third method to measure bone density.126 MRI uses no ionizing radiation, but
magnetic resonance and provides volumetric measures by signaling lipid and water
protons to image the bone.117 The correlation with the DXA is high126; nonetheless, the
MRI also has its limitations, such as high costs, long duration (20-30 min), an uncom-
fortable noise and claustrophobic effect during scanning, for which sedation is often
needed in young children.
It is hypothesized that a physical exercise intervention program can also decrease
fatigue.Fatigue in children can be determined by questionnaires such as the PedsQLTM
multidimential fatigue scale,or the Fatigue Scale for children and adolescents.57,127 The
Dutch version of the PedsQLTM multidimential fatigue scale has an adequate feasibil-

22 the qlim study
ity, reliability and validity and can be used to assess fatigue, both in healthy and ill
children.128
Finally, most physical exercise interventions are aimed to ultimately increase
HrQoL. Because HrQoL reflects the quality of someone’s total functioning and well-
being54, it is recognized as an important study outcome in many intervention stud-
ies.73,74,84,87,89,91,129,130 HrQoL in children with cancer is often determined by the use of
the pediatric quality of life inventory generic core scale (PedsQLTM).57 This is a reliable
and valid questionnaire for children (ages 5-7, 8-12, 13-18), as well as for parents.57 The
Dutch version of this questionnaire has adequate properties and Dutch normative
scores.131
Difficulties when performing intervention studies
In order to provide reliable evidence, intervention studies can best be conducted by
well-designed and well-performed (randomized controlled) trials.132 However, design-
ing and performing high-quality trials is not always possible, and biases are easily
introduced.
Selection bias, for instance, refers to systematic differences between characteristics of
children that participated in the study and those who did not.133 It is possible that the
specific intervention triggered those patients who expected to gain the most,or those
with the most positive association towards the intervention.134
Detection bias,as a systematic difference between the study groups to detect the out-
come,can also be a problem when assessing the effects of a physical exercise interven-
tion. It is possible that children who participate in the intervention are better trained
to perform the tests, leading to better scores based on learned skills, instead of better
scores by increased physical fitness.135
Participants drop-out, resulting in incomplete outcome data is another issue (attri-
tion bias).133 Drop-out can be related to the study; for instance a particularly increased
drop-out in one of the study arms, or can be at random. The effects of random drop-
outs will be less disturbing than drop- outs related to the study.133
The transition from study results towards implementation is another point of inter-
est when studying the effects of a new intervention. This includes acceptance and
support by care-providers, as well as additional health-care resources to cover the
possible extra costs. Despite the growing interest in physical exercise interventions

for childhood cancer patients, no randomized controlled trial in this area of research
has estimated the economic benefits of such an intervention. Both expensive (new)
medication and medical technology used in pediatric oncology have high impact on
the available health-care resources. As a result decision makers should make critical
analyses on the costs and benefits of,especially,new interventions.136 By exploring the
cost-effectiveness of an exercise intervention program in children with cancer, recom-
mendations can be made on: if, how and when to incorporate exercise interventions
in childhood cancer health-care.137
Outline of this thesis
The aim of this thesis is to assess the physical fitness and activity levels of children
with cancer, and to assess the effects of a combined physical exercise and psychoso-
cial 12-week training intervention for children with cancer, during or within the first
12-months after treatment, in order to improve physical fitness and HrQoL.
In this thesis we explore the physical activity of children with cancer and determine
the influence of childhood cancer on physical activity as well as physical fitness. We
furthermore compare children and parents who were willing and not-willing to par-
ticipate in this prospective intervention study to investigate if the study introduced
selection bias.
We validate a relatively new physical fitness test (Steep Ramp test) in children with
cancer, in order to be able to objectively monitor training progression for this popula-
tion outside specialized clinics.Finally,we study whether a combined physical exercise
and psychosocial training program is effective and cost-effective in increasing physi-
cal fitness when compared to usual care.
Chapter 2 describes the physical fitness of children with cancer.It explores the number
of children with a low physical fitness level and those with an inactive lifestyle. It fur-
thermore describes the associated behavioral component of physical fitness and sed-
entary behavior. Chapter 3 presents the results of a systematic review to summarize
the currently published clinical (randomized) controlled studies assessing effects of
physical exercise interventions on physical fitness, body composition and psychoso-
cial functioning of children with cancer. In chapter 4 we describe the study design
of the QLIM study. This chapter aims to increase clarity on the used methods during
the trial and to present the study protocol to all researchers in the field. In chapter 5
we describe the longitudinal effects of the QLIM intervention on physical fitness (car-
diorespiratory fitness and muscle strength) and secondarily on body composition,
psychosocial functioning, fatigue and HrQoL. This chapter also provides information

24 the qlim study
about the mediating role of psychosocial and physical factors on the direct relation
between the intervention and its effects on HrQoL after 12 months. In chapter 6 we
assess the differences between children who want to participate in the QLIM study
compared with those who refuse participation. We present the reasons of both chil-
dren and their parents to refuse study participation.This is done in order to optimize
the intervention for a large group of eligible children aiming at increasing the partici-
pation rate in future studies, or increase the area of support during implementation
of the QLIM intervention in general healthcare.
Chapter 7 contains an economic evaluation of the QLIM intervention. For this study
both direct and indirect cost data are gathered through cost-diaries.Medication infor-
mation is provided by local pharmacies. All the information is collected over a period
of 12-months. Based on the QLIM intervention effects, as described in chapter 5, the
reported costs and the medication information,this chapter also provides cost-beneﬁt
information for health-care decision makers.In chapter 8 we compare the gold-stand-
ard Cardiopulmonary Exercise Test with the Steep Ramp Test and present data on the
methods, outcomes, comparability and the applicability of this cycle ergometry in
children with cancer.The Cardiopulmonary Exercise Test uses gas-analysis to measure
peak oxygen uptake; and therefore can only be performed in specialized clinics. The
Steep Ramp Test estimates cardiorespiratory ﬁtness without the use of gas-analysis
and could thus be of value in local physical therapy centers or non-specialized clinics.
Finally, in chapter 9 the results of this thesis are discussed and put into perspective
and in chapter 10 an overall summary is provided.

c h a p t e r 2
Cardiorespiratory ﬁtness
and physical activity in
children with cancer
Katja I. Braam, Elisabeth M. van Dijk-Lokkart, Gertjan J.L. Kaspers,Tim Takken,
Jaap Huisman, Marc B. Bierings, Johannes H.M. Merks, Marry M. van de Heuvel-Eibrink,
Eline van Dulmen-den Broeder, Margreet A.Veening
Supportive Care in Cancer 2015. DOI 10.1007/s00520-015-2993-1

26 the qlim study26 the qlim study
abstract
Purpose. This study assessed cardiorespiratory fitness (CRF), physical activity (PA) and
sedentary behavior (SB), as well as factors associated with these outcomes in children
during or shortly after cancer treatment.
Methods. Cross-sectionally, CRF data, obtained by the cardiopulmonary-exercise-test,
and PA and SB data, obtained by an accelerometer, were assessed in children with
cancer (8-18 years old). Linear regression models were used to determine associations
between CRF, PA or SB and patient characteristics.
Results.Among 60 children with cancer,mean age 12.6 years,35 boys,28% were during
cancer treatment. CRF, reported as the Z-score of VO2peak, showed that 32 children had
a VO2peak Z-score which was -2 below the predicted value. CRF was significantly asso-
ciated with PA and SB: each additional activity count per min resulted in 0.05 ml·kg-
1·min-1 VO2peak increase and each additional min sedentary reduced VO2peak by 0.06
ml·kg-1·min-1.
Multiple linear regression models of PA and SB showed that decreased activity was sig-
nificantly associated with higher age, being fatigued, being during childhood cancer
treatment (p<0.001), or having a higher percentage of fat mass. The multiple linear
regression model showed that lower CRF was significantly associated with increased
fatigue, being during cancer treatment, having a higher percentage of fat mass and
lower belief of own athletic-competence (p<0.001).
Conclusion.This study revealed that children during or shortly after cancer treatment
have low CRF-scores.The most inactive children had a higher fat mass, were fatigued,
older and during childhood cancer treatment. Unexpectedly, treatment-related fac-
tors showed no significant association with activity behavior.

27ii: cardiorespiratory fitness and physical activity in children with cancer
introduction
Cardiorespiratory fitness (CRF) and muscle strength, have shown to be reduced both
during and after childhood cancer treatment.32,34,138 Both are considered important
health markers, since they represent the functional status of most body functions
involved in the performance of daily physical activities (PA). A reduction in CRF and
muscle strength can be caused by physical inactivity.27,28 When inactivity persists it
will put the patient at risk for obesity,cardiovascular disease,reduced muscle strength,
decreased bone mineral density,and subsequently,a reduced health-related quality of
life (HrQoL).28,52,94,139,140
In childhood cancer patients, the cancer treatment may adversely interfere with the
patients’physical and mental ability to engage in PA. Several determinants are known
to influence motor function. Chemotherapy can result in anemia, decreased oxygen
transport to the muscles, and reduced muscle function141, the use of vincristine can
result in peripheral-neuropathy with muscle weakness in hands and feet, while
anthracyclines may impair cardiac function, and bleomycine may result in decreased
lung function due to pulmonary fibrosis.24 Also mechanical factors are important,
such as decreased motor function after an amputation in bone tumor patients18, or
ataxia following brain tumor treatment19. Apart from clear physical factors, being
fatigued, as well as having depressive symptoms, may also negatively influence PA.61
Previous studies,using an accelerometer to objectively measure PA,showed that child-
hood cancer patients have low PA levels.27–30 These studies, however, were performed
in small groups and did not study the association between PA and CRF.
Only recently, both in children and adults, sedentary behavior (SB) has been intro-
duced as a new important negative factor for health.142 SB is defined as activities that
typically require low-energy expenditure,such as sitting on the couch.143 Frequent and
prolonged sitting periods puts a person at risk for obesity and other metabolic condi-
tions that enhance the risk of chronic diseases (e.g. type 2 diabetes, cardiovascular
disease, breast and colon cancer).144–146 Children with cancer are already at increased
risk for chronic diseases, and therefore assessing SB in children with cancer is impor-
tant.17 Through questionnaires, one study found that 9% of the children with cancer
left their bed for less than 1-hour, while 44% of the questioned patients reported to
leave their bed over 10 hours per day during home-stays.147 Up till now no studies
objectively measured SB in childhood cancer patients.
This study aimed to assess CRF in childhood cancer patients during or shortly after
treatment and to evaluate the association with objectively measured PA and SB. In
addition, the impact of several physical and psychosocial factors on PA and SB were
assessed in order to identify targets for future interventions aimed at stimulating PA,
decreasing SB to ultimately increase CRF and HrQoL.

28 the qlim study
methods
Study population
This study is a cross-sectional study using the baseline data of a randomized con-
trolled trial (RCT), evaluating the effects of a combined 12-week exercise and psycho-
social training program for children with cancer on physical fitness and HrQoL (The
Quality of Life in Motion (QLIM)-study). Details on the design of this study had been
described previously.148
Eligible children were 8-18 years old, diagnosed with any type of malignancy, treated
with chemotherapy and/or radiotherapy, during or within the first year after cancer
treatment. Patients who were not able to make self-reflections (children <8 years old,
or with a mental retardation), who received growth hormones, who were planned for
stem cell transplantation, and those who were not able to ride a bike, or read and
write Dutch were excluded.
Patients were recruited between March 2009 and July 2013. Eligible patients were
identified through patient databases by pediatric oncologists, the study-researcher
or research nurse of the pediatric oncology/hematology departments within four
University hospitals in the Netherlands: VU University Medical Center Amsterdam,
Academic Medical Center Amsterdam, Erasmus MC Rotterdam and University Medi-
cal Center, Utrecht. Patient records and the clinic data were weekly reviewed to verify
eligibility.When children needed to be hospitalized, and when clinical conditions (low
blood counts, infections, or others) made participation impossible (as assessed by
their treating physician),children were considered unable to start study participation,
and therefore the start of the study was postponed.Both patients and their parents or
legal representatives received spoken and written information and provided written
informed consent as by approval of the medical ethics committees of the four par-
ticipating hospitals and was performed according to the 1964 Declaration of Helsinki.
Register; Dutch Trial Registry number NTR1531.
Procedure
Study data were obtained at the university hospital of the child. Children were
assessed on CRF, muscle strength, and body composition. Child-report questionnaires
were used to measure psychosocial functioning. In the week after the study measure-
ments an accelerometer was used to measure PA and SB. Clinical data,such as data on
cancer diagnosis,treatments,and complications,were obtained from medical records.

Measures
Cardiorespiratory fitness was assessed during a cardiopulmonary exercise test on an
electronically braked cycle ergometer (Lode,Corival P,ProCare B.V.Groningen,the Neth-
erlands) using the Godfrey protocol. During the test ventilatory gas exchange data
were determined breath-by-breath. The peak oxygen uptake (VO2peak) was calculated
as the mean value of the final thirty seconds of the test, and expressed in milliliters
per kilogram per min (ml·kg-1·min-1). Predicted values for VO2peak were calculated from
an age- and sex-based equation.103 Measured VO2peak results were compared with
these predicted values.
Physical activity and sedentary behavior of each patient were measured by the Actical
activity monitor (B series, Philips Respironics Actical Mini Mitter, Murrysville, PA, USA).
The Actical is an accelerometer (37 x 29 X 11 mm) which has been validated in children
between 7-18 years old.109 The receiver operating characteristic curves were 0.85, 0.93
and 0.95 for a sedentary to light, light to moderate, and a moderate to vigorous activ-
ity level, respectively.109 The Actical accelerometer was attached to an elastic waist
belt, and worn on the left hip during daytime at waking-hours (between 6:00 am
and 11:59 pm) on 4 consecutive days (Wednesday- Saturday). The device was removed
while bathing or swimming.
When the device was worn less than 500 min/day, the measurement of that day was
considered invalid. Time not wearing the accelerometer was defined as 60-min of
consecutive zero’s on the read-out and this time during waking hours was excluded
from the analyses. The acceleration signal of the Actical is summed over a specific
time interval (epoch).149 A 15-sec epoch was used in the study.
Physical activity (PA) was expressed as mean counts-per-minute (cpm). For the present
study we used the following cpm range to define the different activity intensities:
sedentary status corresponds with an activity count of less than 100 cpm,light activity
with 100-1599 cpm, moderate activity corresponds with 1600-4760 cpm and 4760 or
more cpm was considered as a vigorous activity level.150 Children who participated at
least 60 min per day at an activity level of >1600 cpm were categorized as fulfilling the
international PA recommendations.43
Sedentary behavior (SB), defined as a cpm below 100, was presented as mean minutes
sedentary (out of 1080 measured minutes per/day) and as accelerometer-based sed-
entary bouts. Sedentary bouts were defined as periods of at least 5, 10, 20, 30 and 60
min of SB.142,151

30 the qlim study
Possible associated factors
Physical factors
For all study participants, height and weight were measured to the nearest millimeter
(mm) and 0.1 kilogram (kg), respectively. Body mass index (BMI; kg/m2) was calculated
as well as the BMI-Z-scores using the growth calculator for professionals.152
Muscle strength was measured by the use of hand-held dynamometry (CITEC, CT 3001,
Haren, the Netherlands)153 using the break-method.154 The highest out of three scores
were used in the analyses. Lower body muscle strength was calculated as the sum of
the best (left or right) upper-leg,lower-leg and foot scores.Upper body muscle strength
was calculated as the sum of the best shoulder, elbow and grip strength scores.
Body fat was assessed by dual energy X-ray absorptiometry (DXA).The assessment was
performed on a Hologic Delphi/ Discovery, or a Lunar Prodigy scanner. Differences in
percentage of fat mass were corrected accordingly the equation of Shepherd et al.
(2012).119
Fatigue was self-assessed by the use of the PedsQL™ Multidimensional fatigue scale
(acute version)128,with lower scores indicating more fatigue (range:0-100); the results
of the sub-scale‘general fatigue’were included in the study analyses.
Psychosocial factors
The participation in sports of the study participant before the cancer diagnosis was
evaluated by the use of a questionnaire which was developed for this study.
Athletic competence, was assessed with a subscale of the Self Perception Proﬁle ques-
tionnaire for children aged 8-11 years old (CBSK) and for adolescents aged 12-18 years
old (CBSA).155 Higher scores reﬂect a more positive perception of the athletic compe-
tence (range between 0-100 points).
Depressive symptoms were assessed by the use of the Children’s Depression Inven-
tory (CDI).This questionnaire for children aged 7-18 years old, contains 27 items which
assesses self-reported depressive symptoms.156 For this study we used the total scores
(range: 0-54).
Statistical analysis
Normality of the data was assessed by normality plots and the Shapiro-Wilk test.When
data showed a normal distribution, continuous outcomes were expressed as mean
(standard deviation [SD] or range), in case of non-normal distribution, median (inter-
quartile range [IQR]) scores were reported. Paired sample t-test was used to assess
differences between the observed and predicted VO2peak (ml·kg-1·min-1) values.103

Univariate regression analyses were performed to identify association between and
additional associated factors for CRF (VO2peak), PA (cpm) and SB (min sedentary p/d).
Because the sample size (N=60) did not allow us to simultaneously include all poten-
tial variables into the multiple linear regression model, we preselected a maximum
of 6 variables with p < 0.15 from the univariate regression analyses and include them
in the multiple linear backward regression analyses. By hand factors with the highest
p-value were removed until all factors were statistically significant. The coefficient of
determination and the standard error of the estimate (SEE) are included to present a
measure for variance and accuracy of the regression models. A 2-sided P-value < 0.05
was considered statistically significant in all analyses.IBM SPSS Statistics forWindows
(Version 20.0. Armonk, NY: IBM Corp., USA) was used for the statistical analyses.
Figure 2.1: Flow chart of the Quality of Life In Motion study, a randomized controlled trail evaluating
the effects of a 12-week combined physical and psychosocial training program for children with
cancer.

32 the qlim study
results
General and medical characteristics
A total of 174 children were invited to participate in the QLIM study, of whom 68 (37
boys) were included (Figure 2.1). Due to missing accelerometer data in eight patients,
the current study, therefore, analyzed the results of 60 children (35 boys) with a mean
age of 12.6 years (SD: 3.1; range: 8.0-18.0 years). A total of 17 children (28%) were during
cancer-treatment at time of the study (Table 2.1).Thirty-seven (62%) were treated with
chemotherapy alone.
Both the general and medical characteristics of the eight children who were excluded
from the analyses, as well as characteristics of the 106 non-participants157, were not
signiﬁcantly different from the 60 children who were analyzed (data not shown).
Table 2.1: Demographic and clinical characteristics of the 60 Dutch 8-18 year old
participants of the Quality of Life In Motion study
Variable Patients included: N = 60
mean ± SD / median (IQR)
Gender (male)
Age, years
Height, cm
Weight, kg
BMI SDS score (SDS)
Fat mass SDS score (SDS)
Diagnoses:
Acute lymphoblastic leukemia
Acute Myeloid Leukemia
Brain tumor
Hodgkin’s lymphoma
Bone tumor
Non-Hodgkin lymphoma
Rhabdomyosarcoma
Chronic Myeloid Leukemia
Others
Treatment:
CT
CT + RT
CT + S
CT + RT + S
Vincristine
Location of the bone tumor:
Upper limp with prosthetic device
Lower limp with prosthetic device
Trunk with prosthetic device
35
13.8 (10 - 16)
156 ± 17.3
50.7 (34 – 63)
0.4 (-0.2 – 1.4)
0.8 (0.1 – 1.4)
17
8
8
7
7
5
3
2
3
37
7
8
8
36
0/3
2/3
1/1
Legend: N: number; SD: standard deviation; IQR: interquartile range; SDS: standard deviation
score; cm: centimeter; kg: kilogram; CT: chemotherapy; RT: radiotherapy; S: surgery

Cardiorespiratory ﬁtness (CRF), expressed asVO2peak (ml·kg-1·min-1),in the study popula-
tion was 31.7 ml·kg-1·min-1 (SD 9.2). The mean predicted value of the study group was
45.1 ml·kg-1·min-1 (SD 3.6), resulting in a mean absolute difference between the meas-
ured and predicted values of -13.4 ml·kg-1·min-1 (SD 9.2) (p<0.001). Results for boys and
girls separately are presented in Figure 2.2A and 2.2B.
A total of 32 children (53%) had a Z-score ≤ -2; approximately 12 ml·kg-1·min-1 below the
predicted value.103 The 17 children who were during treatment, all belonged to the -2
Z-scores group.
Figure 2.2a: Measured versus predicted VO2peak in boys (according to age and sex matched norm
values) in the Quality of Life In Motion study (N=35)
Figure 2.2b: Measured versus predicted VO2peak in girls (according to age and sex matched norm
values) in the Quality of Life In Motion study (N=25)
Legend:VO2peak: peak
oxygen uptake;
Z-score: standard deviation
from the mean ;
* Based on age matched
norm values
Legend:VO2peak:
peak oxygen uptake;
Z-score: standard deviation
from the mean;
* Based on age matched
norm values

34 the qlim study
Physical activity and sedentary behavior
Physical activity (PA) was monitored over a median period of 4 days (IQR: 3.5 - 4 days).
Overall, the median PA level was 127 cpm (IQR: 80-219) (Table 2.2). The children spent
16% of their day-time on light-activities,were 7% (SD 4.4) moderately active,and spent
only 0.1% (SD 0.2) of the day on a vigorous activity level.
Evaluation of sedentary behavior (SB) showed that children were sedentary in 80%
of all waking hours: median of 869 min (IQR: 785 - 911) of the 1080 min which were
analyzed per day. Study results also showed that prolonged sitting periods without
interruptions (≥ 20 or 30 min) were common (Table 2.2).
Table 2.2: Median scores on physical activity levels and time spent sedentary in childhood cancer
participants of the Quality of Life In Motion study
Variables Patients (n = 60)
physical activity* Median (IQR)/ n/total %
Counts per minute
Daytime minutes spent on
Sedentary (min)
Light activities (min)
Moderate activities (min)
Vigorous activities (min)
Meeting MVPA recommendations
Boys
Girls
127 (80-219)
869 (785-911)
195 (150-263)
18 (5-39)
0 (0 - 1)
9/60
7/35
2/25
76 a
16 a
7 a
0.1a
15b
20b
8b
sedentary behavior*
Sedentary period
≥ 5 min
≥ 10 min
≥ 20 min
≥ 30 min
≥ 60 min
26 (22 - 29)
15 (13 - 18)
8 (6 - 10)
4 (3 - 6)
1 (0 – 2)
Legend: *Assessment between 6.00 am and 23.59 pm (a total of 1080 min); N: number;
IQR: interquartile range; min: minutes; %: percentage of the day during waking-hours;
MVPA: moderate-to-vigorous physical activity
a: percentage of the day during waking-hours
b: percentage of the total group of children
Cardiorespiratory ﬁtness, physical activity/ sedentary behavior
and associated factors
In either way, CRF, PA and SB showed highly signiﬁcant associations (Table 2.3). A posi-
tive association was found between CRF (VO2peak) and PA (cpm) (β 0.05; 95% CI: 0.0;0.1;
p<0.001): every additional cpm resulted in a 0.05 ml·kg-1·min-1 increase in CRF. SB had
a negative association with CRF (β -0.06; 95% CI: -0.1;-0.0; p< 0.001): every additional
minute of sedentary time per day decreased the CRF by 0.06 ml·kg-1·min-1 (Table 2.3).

Table2.3:Resultsofunivariateandmultiplelinearregressionanalysesforcardiorespiratoryfitness,physicalactivityandsedentarybehaviorinchildrenwithcancer
Physicalactivity
(activitycountsperminute)
Sedentarybehavior
(minsedentary)
Cardiorespiratoryfitness
(VO2peak;ml·kg-1·min-1)
UnivariateregressionMultipleregression
Model1
Model2
Model3
IndependentvariablesB(95%CI)B(95%CI)B(95%CI)B(95%CI)B(95%CI)B(95%CI)
Age(years)
Sexa(0/1)
Musclestrength
*Upperbodystrength
*Lowerbodystrength
Percentageoffatmass
Leanbodymass
Cancerb(0/1)
Treatmentc(0/1)
Amputationd(0/1)
VCRused(0/1)
Glucocorticoidused(0/1)
During/aftercancertreatmente(0/1)
SportspartbeforeDXf(0/1)
Fatigueg
Depressivesymptoms
Athleticcompetence
-15.4(-23.6to-7.2)***
-43.5(-99.7to12.8)
-0.1(-0.3to0.2)
-0.0(-0.2to0.1)
-5.4(-9.0to-1.7)**
-0.0(-0.0to0.0)
-18.6(-77.7to40.5)
-15.9(-73.9to42.1)
-34.6(-122.2to53.0)
-38.2(-95.4to19.0)
3.6(-53.0to60.2)
63.9(3.4to124.3)*
27.2(-41.8to96.1)
2.6(1.5to3.7)***
-6.2(-11.9to-0.5)*
0.9(-0.1to1.8)
-11.9(-19.8to-4.0)**
68.0(18.1to118.0)**
1.8(0.7to2.9)**
14.6(7.8to21.5)***
28.4(-20.5to77.2)
0.1(-0.1to0.3)
0.1(-0.1to0.2)
4.9(1.8to7.9)**
0.0(0.0to0.0)*
10.4(-40.6to61.4)
3.4(-46.7to53.5)
25.9(-49.7to101.5)
35.0(-14.8to84.8)
6.7(-42.0to55.4)
-47.9(-100.4to4.7)
-14.5(-74.5to45.5)
-2.1(-3.1to-1.1)***
5.8(0.9to10.7)*
-0.6(-1.4to0.2)
10.0(3.5to16.5)**
3.7(1.1to6.3)**
-1.2(-2.2to-0.2)*
-0.1(-0.9to0.6)
-4.0(-8.7to0.8)
0.0(-0.0to0.0)
0.0(0.0to0.0)
-0.8(-1.0to-0.5)***
0.0(0.0to0.0)
-3.6(-8.5to1.3)
-3.1(-8.0to1.8)
-3.3(-10.7to4.1)
-4.7(-9.7to0.2)
1.1(-3.7to6.0)
7.4(2.4to12.3)**
1.5(-4.2to7.2)
0.2(0.1to0.3)***
-0.8(-1.3to-0.4)**
0.2(0.1to0.2)***
-0.5(-0.7to-0.2)***
3.9(0.3to7.5)*
0.2(0.1to0.3)***
0.1(0.0to0.1)*
Physicalactivity
Sedentarybehavior
Cardiorespiratoryfitness
--------------------------------------------------------------------------
-0.99(-1.1to-0.8)***
6.99(4.4to9.6)***
-0.73(-0.9to-0.6)***
--------------------------------------------------------------------------
-5.87(-8.0to-3.7)***
0.05(0.0to0.1)***
-0.06(-0.1to-0.0)***
--------------------------------------------------------------------------
P-value:*<0.05;**<0.01;***<0.001;CI:confidenceinterval;B:regressioncoefficient;VCR:vincristine;DX:diagnosis;a0:boys;a1:girls;b0;hematologicalmalignancyb1:solidtumor;c0:
chemotherapyc1:chemotherapyincombinationwithoneormoreothertreatmentmodalities;d0:no;d1:yes;e0:duringtreatment;e1:aftertreatment;f0:nosportbeforediagnosis;f1:
didsportbeforecancerdiagnosis;ghigherscoresindicatelessfatigue;R2:r-squared;SEE:standarderrorofthemean
Model1:factorsbeforebackwardselection:1)age,2)percentageoffatmass,3)leanbodymass,4)beingduring/aftercancertreatment,5)fatigue,and6)depressivesymptoms
Model2:factorsbeforebackwardselection:1)age,2)percentageoffatmass,3)leanbodymass,4)beingduring/aftercancertreatment,5)fatigue,and6)depressivesymptoms
Model3:factorsbeforebackwardselection:1)lowerbodymusclestrength2)percentageoffatmass,3)beingduring/aftercancertreatment,4)fatigue,5)depressivesymptoms,and6)
athleticcompetence

36 the qlim study
Physical activity
Single factor associations showed that PA was significantly associated with: age
(β -15.4; 95% CI: -23.6;-7.2; p<0.001), percentage of fat mass (β -5.4; 95% CI: -9.0;-1.7;
p=0.005),being during (0)/after (1) cancer treatment (β 63.9;95% CI:3.4;124.3;p=0.039),
fatigue (β 2.6; 95% CI: 1.5;3.7; p<0.001), and depressive symptoms (β -6.2; 95% CI: -11.9;-
0.5;p=0.034) (Table 2.3). For the multivariate analysis a 6th factor was added:lean body
mass (β 0.0; 95% CI: -0.0;0.0; p=0.056).
The multiple linear regression analysis for PA showed that age (β -11.9; 95%CI: -19.8;-
4.0; p=0.004), being during (0)/after (1) cancer treatment (β 68.0; 95% CI: 18.1;118.0;
p=0.008), and fatigue (β 1.8; 95%CI: 0.7;2.9; p=0.002; i.e. higher scores indicate less
fatigue) were significantly associated with PA (Table 2.3). Thus, younger children who
were following cancer treatment and who were less fatigued were more active.These
factors explained 41.8% of the variance in PA; SEE = 85.0 (model P<0.001).
Sedentary behavior
Significant univariate associated factors for SB (min sedentary p/d) were age (β 14.6;
95% CI: 7.8; 21.5; p<0.001), percentage of fat mass (β 4.9; 95% CI: 1.8;7.9; p= 0.002), lean
body mass (β 0.0; 95%CI: 0.0; 0.0; p=0.016), fatigue (β -2.1; 95%CI: -3.1; -1.1; p<0.001), and
depressive symptoms (β 5.8; 95% CI: 0.9; 10.7; p=0.021) (see Table 2.3). For the multi-
ple regression analyses also being during/after treatment (β -47.9; 95% CI: -100.4; 4.7;
p=0.074) was added as an independent variable.
After backward elimination the final multiple regression model for SB included age
(β10.0; 95% CI: 3.5;16.5; p=0.003), percentage of fat mass (β 3.7; 95% CI: 1.1;6.3; p=0.007),
and fatigue (β -1.2; 95% CI: -2.2;-0.2; p=0.015) (Table 2.3). Older age, being fatigued and
having an increased percentage of fat mass was associated with more minutes of SB
per day. The three factors together explained 43.0% of the variance in SB; SEE = 71.0
(model P<0.001).
Univariate, CRF furthermore was significant associated with percentage of fat mass
(β -0.8; 95% CI: -1.0;-0.5; p<0.001), being during (0)/after (1) cancer treatment (β 7.4;
95% CI: 2.4;12.3; p=0.004), fatigue (β 0.2; 95% CI: 0.1;0.3; p<0.001), depressive symptoms
(β -0.8; 95% CI: -1.3;-0.4; p=0.001), and athletic competence (β 0.2; 95% CI: 0.1; 0.2;
p<0.001) (Table 2.3). For the multiple regression analyses also lower body muscle
strength (β 0.0; 95% CI: 0.0;0.0; p=0.055) was added as an independent variable.
The multiple linear regression analysis for CRF showed that fat mass (β -0.5; 95%
CI: -0.7; -0.2; p<0.001), being during/after treatment (β 3.9; 95% CI: 0.3;7.5; p=0.035),
fatigue (β 0.2;95% CI:0.1;0.3;p<0.001),and beliefs of athletic competence (β 0.1;95% CI:
0.0;0.1; p=0.034) were significantly associated with CRF. Thus, fatigued children with
increased fat mass,and reduced beliefs in athletic competence,and those during can-

cer-treatment had the lowest CRF. These four factors explained 64.8% of the variance
in CRF; SEE = 5.7 (model P<0.001).
discussion
The present study shows that the CRF is low in the majority of children during as well
as after cancer treatment when compared to healthy Dutch children. Furthermore,
this is the first study performed in children with cancer that clearly demonstrates that
decreased CRF is significantly associated with objectively assessed low PA and high
SB. Children at risk for reduced PA had the highest percentage of fat mass, were older
and fatigued and were during childhood cancer treatment. Unexpectedly treatment
related factors did not significantly influence activity behavior. These results indicate
that intervention studies should focus on preventing or reducing fatigue and over-
weight, in order to improve PA behavior and ultimately increase CRF.The most seden-
tary children of the study were older and during childhood cancer treatment,pointing
out an important target population.
Our finding that older age and fatigue were significantly associated with reduced
PA, is in line with previous findings among healthy children.61,158,159 In children with
cancer however, next to an older age and being fatigued, Hooke et al. (2011) also found
that children who exhibit emotional dysfunction were more sedentary.61 The latter
could not be confirmed with our data. Psychological factors in our study did not show
a clear association pattern with PA and SB.In univariate models,depressive symptoms
showed a significant associated with the two outcomes; however, in multiple regres-
sion models, this factor did not remain significant.This indicates that this association
was weak, or possibly mediated by other factors.51
International recommendations for children advice 60 min of moderate-to-vigorous
physical activity per day.43 The current study showed that 20% of the boys and 7%
of the girls, during or shortly after childhood cancer treatment, met the activity rec-
ommendations. Which, however, is in line with the worrisome results of the normal
Dutch population.67 This indicates that only a small percentage of all children, with or
without cancer, reach the international PA recommendation. Yet, related to the given
cancer treatment and possible late-complications and diseases, the impact of inactiv-
ity in children with cancer may be worse than in healthy children.17
Despite positive attitudes towards PA160, the current study showed that children with
cancer were highly sedentary. Especially the prolonged periods of SB are striking, i.e.
the sitting periods of 20 min or more were approximately four times higher in this
study population, compared to reported data of healthy children.161 The activity cpm
were also considered lower than those reported in healthy children.39 We found a
median cpm score of 127 (IQR: 80-219 cpm) equally distributed among sex, whereas a

38 the qlim study
meta-analysis among 20,871 healthy children reported that girls had a mean PA of 540
cpm (193 SD) and boys a mean PA of 642 cpm (226 SD).39 However, such as for PA data,
the SB data of the study among healthy children were obtained with a different accel-
erometer (Actigraph) using different cut-off points for activity intensities, decreasing
comparability.39
Strength and Limitations of this study
The strength of this study is the number of included children; 60 is a relatively large
population compared to patient numbers used in the four earlier studies which
reported PA accelerometer data (range: 7 to 38 patients).27–30 Furthermore, this study
is the first in children with cancer to combine CRF data with activity data and to show
associations between activity behavior and patient characteristics.Finally,most of the
data were obtained during a visit to the hospital for study purpose, increasing quality
of the measurements.
This study also had some limitations that should be noted. First, the cross-sectional
design does not allow for the assessment of the causal relation between study out-
comes and factors.Longitudinal data of the QLIM RCT will provide further information
regarding the relation between increased PA and CRF, and possible confounding or
mediating factors.
Secondly,in this study accelerometer data were obtained for a period of 4 days instead
of 7. The memory-capacity of the accelerometer did not allow assessment of PA by
15-s epoch for a length of 7-days. It was possible to use 15-s epochs when we limited
the assessment period to four days. The use of a short epoch in children is important
because children are known to perform short and intermitted actions.149 Missing data
of three days within the measurement week is a limitation. However, accelerometer
data were obtained from Wednesdays until Saturdays, which are the most common
days in the week in the Netherlands to participate in (team) sports during childhood.
Sport participation before diagnosis was questioned retrospectively. However, the
time period at which they participated in sports was not specified.This led to unclear
information. To increase validity of the data we dichotomized sport participation
before diagnosis (yes/no), however thereby losing some valid information.
Finally, this study included children with any type of cancer, aged between 8-18 years
old and children both during and within the first year after cancer-treatment. There-
fore our study group was a heterogeneous one with potentially additional influenc-
ing factors. However, as a result of this heterogeneity, we now were able to say that
children with any type of cancer had reduced CRF and PA levels.

conclusion
In conclusion, the present study shows that CRF is low in children during
as well as shortly after cancer treatment and that this low ﬁtness is associ-
ated with reduced PA levels and increased SB across all cancer and treatment
types. It revealed that older children, more fatigued children who were during
cancer treatment were the least active. Increased SB, in addition, was signiﬁ-
cantly associated with older age, more fatigue and having a higher percent-
age of fat mass.This indicates that especially the fatigued,overweight or obese
adolescents with cancer, and those who are during cancer treatment, need to
be informed about the health risks of a prolonged sedentary lifestyle and be
advised in how to increase their PA level. In the QLIM RCT we will assess the
causal relation between CRF, PA, SB, fatigue, age, and treatment-related fac-
tors in children with cancer, to develop an optimal exercise intervention for
this population, in order to increase PA, and CRF to ultimately decrease chronic
diseases and impaired HrQoL later in life.

40 the qlim study

c h a p t e r 3
Physical exercise training
interventions for children
and young adults during
and after treatment for
childhood cancer
Katja I. Braam, Patrick van der Torre,Tim Takken, Margreet A.Veening,
Eline van Dulmen-den Broeder, Gert-Jan J.L. Kaspers
Cochrane Database of Systematic Reviews 2013, Issue 4. Art.
Update: 2015 accepted

abstract
A decreased physical fitness has been reported in patients and survivors of childhood
cancer. This is influenced by the negative effects of the disease and the treatment
of childhood cancer. Exercise training for adult cancer patients has frequently been
reported to improve physical fitness. In recent years, literature on this subject has also
become available for children and young adults with cancer, both during and after
treatment.This is an update of the original review that was performed in 2011.
This review aims to evaluate the effect of a physical exercise training intervention
(at home, at a physical therapy practice, or in-hospital) on physical fitness of children
with cancer, in comparison with the physical fitness of children in a care as usual con-
trol group.The intervention, with a minimal duration of four weeks, had to be offered
within the first five years after diagnosis.
The second aim was to assess the effects of a physical exercise training intervention in
this population on fatigue, anxiety, depression, self-efficacy, and health-related qual-
ity of life and to assess the adverse effects of the intervention.
For this review the electronic databases of Cochrane Register of ControlledTrials (CEN-
TRAL), MEDLINE, EMBASE, CINAHL, PEDro, ongoing trial registries and conference pro-
ceedings were searched on 6 September 2011 and updated in 11 November 2014. In
addition, a hand search of reference lists was performed in that same period.
The review included randomized controlled trials (RCTs) and clinical controlled trials
(CCTs) that compared the effects of physical exercise training with no training, in
people who were within the first five years of their diagnosis of childhood cancer.
Two review authors independently identified studies meeting the inclusion criteria,
performed the data extraction,and assessed the risk of bias using standardized forms.
Study quality was rated by the Grading of Recommendation Assessment, Develop-
ment and Evaluation (GRADE) criteria.
Apart from the five studies in the original review, this update included one additional
RCT. In total 171 participants were included in the analysis, all during treatment for
childhood acute lymphoblastic leukemia (ALL).
The duration of the training sessions ranged from 15 to 60 minutes per session. Both
the type of intervention and intervention period varied in all the included studies.
However, the control group always received usual care.
All studies had methodological limitations, such as small numbers of participants,
unclear randomization methods, and single-blind study designs in case of an RCT and
all results were of (very) low quality (GRADE).
Cardiorespiratory fitness was evaluated by the 9-minute run-walk test,timed up-and-
down stairs test, the timed up-and-go time test and the 20-m shuttle run test.Data of
the 9-minute run-walk test and the timed up-and-down stairs test could be pooled.
The combined 9-minute run-walk test results showed significant differences between

43iii: physical exercise training interventions for children and young adults 43iii: physical exercise training interventions for children and young adults
the intervention and the control group, in favor of the intervention group (standard-
ized mean difference (SMD) 0.69;95% confidence interval (CI):0.02 to 1.35).Pooled data
from the timed up-and-down stairs test showed no significant differences in cardi-
orespiratory fitness (SMD -0.54; 95%CI: -1.77 to 0.70). However, there was considerable
heterogeneity (I2 = 84%) between the 2 studies on this outcome. The other 2 single-
study outcomes, 20-m shuttle run test and the timed up-and-go test, also showed
positive results for cardiorespiratory fitness in favor of the intervention group.
The effect of exercise on bone mineral density (total body) was assessed in one study
only, showing a statistically significant positive intervention effect (SMD 1.07; 95% CI:
0.48 to 1.66). The pooled data on body mass index did not show a statistically sig-
nificant end-score difference between the intervention and control group (SMD 0.59;
95%CI: -0.23 to 1.41).
Flexibility was assessed in 3 studies. Two studies assessed ankle dorsiflexion. One
study assessed active ankle dorsiflexion, while the other assessed passive ankle dor-
siflexion. No statistically significant difference between the intervention and control
group was identified with the active ankle dorsiflexion test; however, in favor of the
intervention group, they were found for passive ankle dorsiflexion (SMD 0.69; 95% CI:
0.12 to 1.25). The 3rd study assessed body flexibility using the sit-and-reach distance
test,but identified no statistically significant difference between the intervention and
control group.
Muscle strength was assessed in 3 studies (knee, ankle, back and leg, and inspiratory
muscle strength). Only the back and leg strength combination score showed statisti-
cally significant differences on the muscle strength end-score between the interven-
tion and control group (SMD 1.41; 95%CI: 0.71 to 2.11).
Apart from 1 sub-scale of the cancer scale (Worries;P=0.03),none of the health-related
quality of life scales showed a significant difference between both study groups on the
end-score. For the other outcomes fatigue, level of daily activity, and adverse events
(all assessed in one study) no statistically significant differences were found between
the intervention and control group.
None of the included studies evaluated activity energy expenditure, time spent on
exercise, anxiety and depression, or self-efficacy as an outcome.
The effects of physical exercise training interventions for childhood cancer partici-
pants are not yet convincing. Possible reasons are the small numbers of participants
and insufficient study designs, but it can also be that this type of intervention is not
as effective as in adult cancer patients. However, the first results show some positive
effects on physical fitness in the intervention group compared to the control group.
Positive intervention effects were seen for body composition, flexibility, cardiorespira-
tory fitness, muscle strength and health-related quality of life (cancer-related items).
As measured by some assessment methods, but not all. However, the quality of the
evidence is (very) low and these positive effects were not found for the other assessed

outcomes, such as fatigue, level of daily activity, and adverse events. There is a need
for more studies with comparable aims and interventions, using a higher number of
participants which also include diagnoses other than ALL.

45iii: physical exercise training interventions for children and young adults
plain language summary
Physical exercise training interventions for children and young
adults during and after treatment for childhood cancer
Childhood cancer is less common than adult cancer at a rate of 144 to 148 cases per
one million children. An intensive treatment, including combined treatment modali-
ties such as surgery, chemotherapy, radiotherapy, or a combination, is often needed
for cure. These treatment modalities are frequently accompanied by adverse events,
such as nausea,serious infections,organ damage (heart,lung,kidney,liver),decreased
bone mineral density, but also decreased muscle strength and physical fitness.
In the past, children were advised to recover in bed, and to take as much rest as pos-
sible. Nowadays, it is considered that too much immobility may result in a further
decrease of physical fitness and physical functioning. These adverse effects might
be prevented or minimized by introducing a physical exercise training intervention
during, or shortly after, childhood cancer treatment.
This review includes 5 randomized controlled trials and 1 clinical controlled trial that
evaluated the effects of a physical exercise training program in children during cancer
treatment.Childhood acute lymphoblastic leukemia (ALL) is the most common type of
childhood cancer. For that reason, researchers often focus on this type of cancer since
it will provide the largest number of a homogeneous group of patients in the short-
est time-span. In total 171 participants with ALL were included in the analysis of this
review. The results of the review show that there are some small benefits of physical
exercise training on body composition (percentage of fat mass, muscles, and bones),
flexibility, cardiorespiratory fitness (endurance capacity), muscle strength and cancer-
related health related quality of life, but the evidence is limited.This can be related to
an unsuitable intervention for children with cancer, or due to methodological limita-
tions of the included studies. More studies assessing the effects of exercise on body
composition,muscle functioning,daily activity,psychological functioning,or a combi-
nation of these,are needed in a variety of childhood cancer populations. Furthermore,
the current findings do not provide enough evidence to identify an optimal physical
exercise training program for children with cancer, neither do they provide informa-
tion on the characteristics of people who will,or will not,benefit from such a program.
These important issues still need to be clarified.

46 the qlim study
background
Description of the condition
Only a small percentage of the total population suffer from childhood cancer; approx-
imately 144 to 148 cases per million children.162,163 However the impact of childhood
cancer is significant. Many studies report a decreased physical fitness (aerobic capac-
ity and muscle strength), in patients and survivors of acute lymphoblastic leukemia
(ALL), which is the most common type of childhood cancer29,45,63–65,164–168 and also in
childhood cancer patients in general34,53,169–173. Reduced daily energy expenditure and
lower levels of physical activity have been described as the most important cause of
this reduced state of physical fitness in childhood cancer patients.166 In addition, a
considerable number of survivors of childhood cancer suffer from motor function dis-
ability17,138,which is mostly related to negative motor signs,such as insufficient muscle
activity, or muscle weakness168,171.
Positive effects of exercise training on physical fitness have been reported in studies
with adult cancer patients.174–177 It is hypothesized that similar results are possible in
children with cancer, or survivors of childhood cancer.64
Description of the intervention
The intervention under consideration was a physical exercise training program, intro-
duced within the first five years following the diagnosis of childhood cancer.The exer-
cise training should aim to increase physical fitness by aerobic, anaerobic, strength, or
mixed fitness training.
How the intervention might work
Cancer and cancer treatment induce lean tissue degeneration and can, therefore,
potentially cause abnormalities in the cardiac and skeletal muscle.178 A decline in
protein synthesis and protein degeneration by cancer and its treatment, can reduce
muscle mass.This can result in a decreased oxidative enzyme activity and a decreased
number of proteins necessary for metabolism.178 Cancer patients often experience
muscle weakness, a decreased functional capacity, decreased flexibility, reduced
mobility, and diminished health-related quality of life (HrQoL).171,178 In addition, a
decreased psychosocial functioning and HrQoL as a result of cancer has impact on a
person’s motivational drive and can result in a poorer self-perception of one’s ability
to perform physical activity.166,167

Physical activity can prevent or diminish the negative effects of a sedentary life-style
such as obesity, poor skeletal health, fatigue, and poor mental health, thereby increas-
ing HrQoL of the individual. Increasing physical activity is possible by adopting a less
inactive life-style and increasing sports participation. Beneficial effects of physical
activity during or shortly after cancer therapy are an increase in muscle mass and
plasma volume, improved lung ventilation and lung perfusion, and also an increased
cardiac reserve.
This was seen in the study by Dimeo et al (2001);the children with cancer who received
cancer treatment with glucocorticoids in combination with resistance exercises,
showed less muscle mass loss than the children who did not receive the additional
physical exercise training intervention.179
Why it is important to do this review
Despite the positive results of exercise interventions on fatigue and physical fitness in
adult cancer patients,the evidence for benefits in childhood cancer patients is limited.
Studies within the population of childhood cancer patients and survivors are emerg-
ing and the first data have recently been published. However, the number of partici-
pants in the various publications is small and the variety in type of cancer limited,
making it difficult to draw more generalized conclusions. In making healthcare man-
agement decisions, participants and clinicians must weigh the benefits and draw-
backs of supportive care. Pooled data can help in this decision-making process.
The purpose of this Cochrane review is to summarize the existing literature on the
effectiveness of physical exercise training interventions in children with cancer,
implemented within the first five years from diagnosis and to provide a best-evidence
synthesis or meta-analysis of the reported results. This is an update of the original
review that was performed in 2011.180
Objectives
Primary objective
To evaluate the effect of a physical exercise training intervention on the physical fit-
ness (i.e. aerobic capacity, muscle strength, or functional performance) of children
with cancer within the first five years from their diagnosis (performed either during
or after cancer treatment), compared to a control group of childhood cancer patients
who did not receive an exercise intervention.

48 the qlim study
Secondary objectives
To determine whether physical exercise within the first five years of diagnosis has
an effect on fatigue, anxiety, depression, self-efficacy, and HrQoL and to determine
whether there are any adverse effects of the intervention.
methods
Criteria for considering studies for this review
Types of studies
We included randomized controlled trials (RCTs) and controlled clinical trials (CCTs)
comparing the effects of physical exercise training within the first five years following
the diagnosis of childhood cancer with no training.
A CCT was included in the review when the study included a well-defined and com-
parable control group. Factors that were taken into account regarding comparability
were: being childhood cancer patients or survivors, age, sex, and country of origin.
We included cluster-randomized trials when the intervention and control groups
were comparable in each aspect except for the location of cancer treatment and study
recruitment.
We included cross-over trials when the study results were available for each separate
intervention period.The data of the first randomization period were then used.
Reviews were not included but were checked for relevant references. In addition, we
excluded observational studies (including case reports, case-control studies) and sur-
veys from this review.
Types of participants
Study participants were under 19 years of age at diagnosis of any type of childhood
cancer. Participants in the physical exercise training program needed to be no more
than five years from diagnosis. We only included studies that also included adult
cancer participants when the results of the childhood and adult study populations
were reported separately.
Types of interventions
Studies that were included compared a physical exercise training intervention for
childhood cancer patients or survivors with a control group receiving care as usual.
Care as usual is defined as care when needed, but no specific exercise program or
alternative intervention prescribed to increase physical fitness,HrQoL,self-perception,
or a combination of these, or to decrease adverse events, fatigue, anxiety, depression,
or a combination of these in childhood cancer patients.

The physical exercise training interventions that were offered included different types
of training or exercise programs. For instance,muscle strength or stretching exercises,
aerobic exercises, or sports such as gymnastics, swimming, running, or bicycling.
The exercise training intervention could have been additional care during therapy or
could have been offered after the standard cancer therapy in a form of rehabilitation.
The goals of this exercise training intervention were preventing motor disabilities and
a decline in physical fitness, or treating motor function problems which developed
during childhood cancer therapy.
The exercise training intervention could have taken place in any setting or location:
at home, at a physical therapy center, in a hospital, or elsewhere. It could either have
been a group intervention, or an individual program.
The duration of the exercise training intervention needed to be at least four weeks, in
order to be able to report on exercise training effects. The upper limit of the training
duration was not fixed for this review. In addition, the duration of physical activities
(daily time spent on activities or sports) could differ per protocol.
Types of outcome measures
We included studies evaluating the effect of physical exercise training interventions
on physical fitness, HrQoL, fatigue, self-efficacy, anxiety and depression. Furthermore
adverse effects of the intervention program were studied.
Primary outcomes
The primary outcome of this review was physical fitness measured by:
1 cardiorespiratory fitness (e.g. peak oxygen uptake (VO2peak), peak work rate (Wmax),
endurance time): aerobic or anaerobic exercise capacity tested by ergometry on a
cycle ergometer or treadmill, the Wingate anaerobic test, the steep-ramp-test,
maximal anaerobic running/cycling test, the Cooper test, or another valid instru-
ment;
2 muscle endurance/strength: assessed with a hand-held dynamometer, the Biodex,
the spring scale, the lateral step-up test, the sit-to-stand test, 10 repetitions maxi-
mum, the up-and-down stairs test, the minimum chair height test, the muscle
power sprint test, a 10 x 5-m sprint test, the six-minute walk test, the incremental
shuttle walking test, or another valid instrument;
3 body composition: using body mass index (BMI), skin-fold measurement, a dual
energy x-ray absorptiometry (DXA) scan, waist circumference, or the waist-to-hip-
ratio;
4 flexibility: conducted with a goniometer, flexometer or with the sit-and-reach test,
V-sit test, shoulder or trunk rotation test, straight leg raise, the passive and active
ankle dorsiflexion test, or another valid instrument;
5 activity energy expenditure: for example by using an accelerometer;

50 the qlim study
6 level of daily activity: assessed by an exercise diary, questionnaire, or by accelero-
metry;
7 time spent exercising (more than daily activity): assessed by an exercise diary,
questionnaire, or by accelerometry
Secondary outcomes
Secondary outcomes of the review were:
1 HrQoL: measured by the Pediatric Quality of Life Inventory (PedsQL), Child Health
Questionnaire (CHQ), and DISABKIDS;
2 fatigue: assessed by the PedsQL Multidimensional Fatigue Scale, Childhood Cancer
Fatigue Scale (CCFS), or the Fatigue Scale for a child (FS-C), the same scale for ado-
lescents (FS-A), and for parents (FS-P);
3 anxiety and depression: measured by the Childhood Depression Inventory (CDI)
and the Center of Epidemiological Studies Depression Scale (CES-D);
4 self-efficacy: assessed using the Confidence Scale, the Self-Efficacy Questionnaire
for Children (SEQ-C), or the Children’s Self-Efficacy Scale;
5 adverse effects during the study period by collecting information on the occur-
rence of sport injuries, infections, fractures, heart failure, the recurrence of cancer,
and fever.
Search methods for identification of studies
Electronic searches
For this review electronic databases ofThe Cochrane Register of ControlledTrials (CEN-
TRAL) (The Cochrane Library, 11 November 2014, Issue 3), MEDLINE/PubMed (from 1945
to 11 November 2014), EMBASE/Ovid (from 1980 to 11 November 2014), CINAHL (from
1982 to 11 November 2014), and Physiotherapy Evidence Database (PEDro; from 1929 to
11 November 2014) (www.pedro.org.au) were searched.
The search strategies for the different electronic databases (using a combination of
controlled vocabulary and text words) are stated in the appendices (see appendix
chapter 3).
Searching other resources
We located information about trials not registered in CENTRAL, MEDLINE, EMBASE,
CINAHL,and PEDro,either published or unpublished,by searching the reference lists of
relevant articles and reviews.We scanned the conference proceedings of the Interna-
tional Society for Pediatric Oncology (SIOP), the American College of Sports Medicine
(ACSM), the International Congress on Physical Activity and Public Health (ICPAPH),

and the American Physical Therapy Association (APTA) electronically, or otherwise by
hand searching from 2005 till 2014.
A search was performed in the ISRCTN register (www.controlled-trials.com), and the
clinical trial database (www.clinicaltrials.gov) for ongoing trials on 11 November 2014.
We did not impose language restrictions and will update the searches every two years.
The search included “children”, “childhood cancer”, “cancer”, “exercise training ther-
apy”, and“outcome”or any related word combination.
Data collection and analysis
Selection of studies
After employing the search strategy described previously, identification of studies
meeting the inclusion criteria was undertaken by two review authors (KB, PT) inde-
pendently.We obtained in full any study that seemed to meet the inclusion criteria on
title and abstract, for closer inspection. Reasons for exclusion were noted on a sepa-
rate form. Discrepancies between review authors were solved by reaching consensus.
In one case, a third party arbitrator (TT) was needed: we required another opinion
on the study of De Macedo 2010.181 This discussion resulted in inclusion of that study
because the training corresponded with the described criteria of the protocol.
Data extraction and management
Dataextractionwasperformedindependentlyby the tworeviewauthors(KB,PT)using
standardized forms. For each study we collected information on the study design,
participant baseline characteristics, settings, sample size, number of participants in
each study arm, type of intervention(s), duration of intervention, randomization and
blinding procedure, type of control group, type and duration of cancer treatment and
stage of cancer treatment (for example, during or after treatment), and duration of
participant follow-up.
The extracted outcome measures included: changes in cardiorespiratory fitness,
muscle strength/endurance, body composition, body flexibility, daily energy expendi-
ture per time period (for example, day, week, or month), and changes in the level of
daily activity and time spent exercising.In addition,we used a separate form to collect
information on psychosocial outcomes such as HrQoL, fatigue, anxiety and depres-
sion, and the child’s self-efficacy. To collect data regarding any other adverse effect of
the intervention, we collected all information reported on adverse events during the
intervention period in the included studies. Authors of the studies of which only an
abstract was available were contacted for additional study information.
In the process of data extraction consensus was reached on all items.

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