EXERCISE in pediatric autologous stem cell transplant patients: a randomized controlled trial protocol

BMC Cancer (Impact Factor: 3.36). 09/2012; 12(1):401. DOI: 10.1186/1471-2407-12-401
Source: PubMed
ABSTRACT
Background
Hematopoietic stem cell transplantation is an intensive therapy used to improve survivorship and cure various oncologic diseases. However, this therapy is associated with high mortality rates and numerous negative side-effects. The recovery of the immune system is a special concern and plays a key role in the success of this treatment. In healthy populations it is known that exercise plays an important role in immune system regulation, but little is known about the role of exercise in the hematological and immunological recovery of children undergoing hematopoietic stem cell transplant. The primary objective of this randomized-controlled trial (RCT) is to study the effect of an exercise program (in- and outpatient) on immune cell recovery in patients undergoing an autologous stem cell transplantation. The secondary objective is to determine if an exercise intervention diminishes the usual deterioration in quality of life, physical fitness, and the acquisition of a sedentary lifestyle.

Methods
This RCT has received approval from The Conjoint Health Research Ethics Board (CHREB) of the University of Calgary (Ethics ID # E-24476). Twenty-four participants treated for a malignancy with autologous stem cell transplant (5 to 18 years) in the Alberta Children’s Hospital will be randomly assigned to an exercise or control group. The exercise group will participate in a two-phase exercise intervention (in- and outpatient) from hospitalization until 10 weeks after discharge. The exercise program includes strength, flexibility and aerobic exercise. During the inpatient phase this program will be performed 5 times/week and will be supervised. The outpatient phase will combine a supervised session with two home-based exercise sessions with the use of the Wii device. The control group will follow the standard protocol without any specific exercise program. A range of outcomes, including quantitative and functional recovery of immune system, cytokine levels in serum, natural killer (NK) cells and their subset recovery and function, and gene expression of activating and inhibitory NK cell receptors, body composition, nutrition, quality of life, fatigue, health-related fitness assessment and physical activity levels will be examined, providing the most comprehensive assessment to date.

Discussion
We expect to find improvements in immunological recovery and quality of life, and decreased acquisition of sedentary behavior and fitness deconditioning. The comprehensive outcomes generated in this RCT will provide preliminary data to conduct a multisite study that will generate stronger outcomes.

Trial registration
Gov identification # NCT01666015

Full-text

Available from: Fiona Schulte
ST UD Y P R O T O C O L Open Access
EXERCISE in pediatric autologous stem cell
transplant patients: a randomized controlled
trial protocol
Carolina Chamorro-Viña
1
, Gregory MT Guilcher
2,3,6
, Faisal M Khan
5
, Karen Mazil
2,7
, Fiona Schulte
2
, Amanda Wurz
1
,
Tanya Williamson
1
, Raylene A Reimer
1,3
and S. Nicole Culos-Reed
1,3,4*
Abstract
Background: Hematopoietic stem cell transplantation is an intensive therapy used to improve survivorship and
cure various oncologic diseases. However, this therapy is associated with high mortality rates and numerous
negative side-effects. The recovery of the immune system is a special concern and plays a key role in the success of
this treatment. In healthy populations it is known that exercise plays an important role in immune system
regulation, but little is known about the role of exercise in the hematological and immunological recovery of
children undergoing hematopoietic stem cell transplant. The primary objective of this randomized-controlled trial
(RCT) is to study the effect of an exercise program (in- and outpatient) on immune cell recovery in patients undergoing
an autologous stem cell transplantation. The secondary objective is to determine if an exercise intervention diminishes
the usual deterioration in quality of life, physical fitness, and the acquisition of a sedentary lifestyle.
Methods: This RCT has received approval from The Conjoint Health Research Ethics Board (CHREB) of the University of
Calgary (Ethics ID # E-24476). Twenty-four participants treated for a malignancy with autologous stem cell transplant (5
to 18 years) in the Alberta Childrens Hospital will be randomly assigned to an exercise or control group. The exercise
group will participate in a two-phase exercise intervention (in- and outpatient) from hospitalization until 10 weeks after
discharge. The exercise program includes strength, flexibility and aerobic exercise. During the inpatient phase this
program will be performed 5 times/week and will be supervised. The outpatient phase will combine a supervised
session with two home-based exercise sessions with the use of the Wii device. The control group will follow the
standard protocol without any specific exercise program. A range of outcomes, including quantitative and functional
recovery of immune system, cytokine levels in serum, natural killer (NK) cells and their subset recovery and function, and
gene expression of activating and inhibitory NK cell receptors, body composition, nutrition, quality of life, fatigue,
health-related fitness assessment and physical activity levels will be examined, providing the most comprehensive
assessment to date.
Discussion: We expect to find improvements in immunological recovery and quality of life, and decreased acquisition of
sedentary behavior and fitness deconditioning. The comprehensive outcomes generated in this RCT will provide
preliminary data to conduct a multisite study that will generate stronger outcomes.
Trial registration: Gov identification # NCT01666015
Keywords: Pediatric, Hematopoietic stem cell transplant, Cancer, Exercise, Quality of life, Immune system, Physical
activity levels
* Correspondence: nculosre@ucalgary.ca
1
Faculty of Kinesiology, University of Calgary, 2500 University Drive NW,
Calgary, AB T2N 1N4, Canada
3
Faculty of Medicine, University of Calgary, Calgary, Canada
Full list of author information is available at the end of the article
© 2012 Chamorro et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Chamorro-Viña et al. BMC Cancer 2012, 12:401
http://www.biomedcentral.com/1471-2407/12/401
Page 1
Background
Hematopoietic stem cell transplantation (SCT) is an
intensive therapy used in the treatment of various
oncologic diseases [1]. This treatment has improved
survivorship in recent years, but is associated with nu-
merous negative physical and psychological side-effects
as well as a spectrum of late effects [1-5]. Oeffinger et al.
reported that one-third of childhood cancer survivors
have severe or life-threatening medical complications
30 years after diagnosis, and those who received SCT
compound the high-risk group [5]. Recent research at-
tention has bee n focused on diminishing the impact of
these potential negative side-effects and late-effects
thereby, improving the quality of life (QOL) of pediatric
cancer survivors.
There is increasing evidence that exercise (EX) is
safe, beneficial and feasible in different stages of cancer
treatment [3-6], including in immune-compromised
patients [7]. However, scientific evidence suggests that
children with cancer are more sedentary than their
healthy peers [8,9]. It has been argued that childhood
cancer survivors are subject to an insidious spectrum
of disuse as a result of an overly cautious approach to-
wards EX, fostered by concerned parents and environ-
mental factors [10]. A potential explanation for this
overprotective attitude may stem from a general lack of
education about what a child can be expected to do
after cancer treatments [11].
Huang et al. [3] in a recent review showed that the im-
pact of EX on health and physical function in pediatric
oncology is promising. However, only 15 published stud-
ies (1993-2011) have examined EX as an intervention
[3]. Of these 15, only 4 were RCTs, and only 3 studied
the effect of EX on immunological function [7,12,13].
Overall, these 3 studies found that EX was beneficial and
did not impair immune system recovery in any way that
could provoke concern for health. Furthermore, Chamorro
et al. [7] showed that EX was safe in neutropenic
patients, who were also able to avoid weight lost during
hospitalization. This previous research is limited by small
sample size and limited immunological analyses, including
no assessment of NK cell function or cytokine environ-
ment. In addition, most of the previous EX interventions
were in acute lymphoblastic leukemia patients undergoing
maintenance therapy [3]. To our knowledge, only three
English language publications described the effect of EX
in children with cancer undergoing SCT [7,14,15]. These
articles suggest that EX is sa fe, fe asible and has a promis-
ing role in the recovery of children undergoing SCT.
Despite robust scientific evidence describing the posi-
tive effects of EX in the adult cancer population, limited
research efforts have focused on exploring the transla-
tion of EX therapy to children. Specifically, the role of
EX in the immune system recovery of pediatric patients
undergoing SCT has not been examined sufficiently to
date, however the results from the adult population [16-
18] are promising. It is argued that improved QOL
through an E X program is sufficient rationale to provid-
ing EX programming. However EX will be fur ther sup-
ported if it can be shown to improve immune system
recovery which may result in diminished risk of infec-
tion, hospitalization day s and improve overall survival.
This RCT will significantly add to the evidence on the
effect of EX on the recovery of children undergoing
SCT. A range of outcomes, including quantitative and
functional recovery of immune system, e.g., different
leukocyte cell subset counts in peripheral blood, cyto-
kine levels in serum, NK cells and their subset recovery
and function, and gene expression of ac tivating and in-
hibitory NK cell receptors known as Killer Immuno-
globulin like Receptors (KIR), body composition,
nutrition, QOL, fatigue, health- related fitness assess-
ment and physical activity levels will be examined, pro-
viding the most comprehensive assessment to date.
The purposes of the present study are:
Primary Study the effect of an EX program (in- and
outpatient) on immune cell recovery in patients under-
going an autologous SCT.
Secondary Determine if an EX program performed in
patients undergoing autologous SCT diminis hes the de-
terioration of physical fitness, physical activity levels and
improves QOL.
Tertiary Establish the programs feasibility (uptake and
adherence) to provide the impetus to run multi-centre
research with larger populations in the future.
Methods
Study design
SCORE Stem Cell patients Ongoing Recovery through
Exercise is a RCT of pediatric cancer patients undergo-
ing autologous SCT. Assessors will be blind to partici-
pants condition (EX or control) and all the statistical
analyses will be performed maintaining blindness to con-
dition. Blinding of assessors and statistical analyses
ensures limited bias on outcomes, especially with sub-
jective outcomes of interest. Flow through the study is
depicted in Figure 1.
This study will examine the effect of two phases of an
EX program on several health related outcomes in
pediatric patien ts undergoing autologous SCT (Figure 2).
The first phase of the EX program will be an inpatient
intervention, beginning when the child is hospitalized
undergoing conditioning therapy and continuing until
discharge.
Chamorro-Viña et al. BMC Cancer 2012, 12:401 Page 2 of 12
http://www.biomedcentral.com/1471-2407/12/401
Page 2
The second phase will be a 10-week outpatient inter-
vention, beginning once the child is discharged. We will
utilize a mixed EX program, including supervised (at the
University of Calgary) and home-based training incorp-
orating the use of the Nintendo
W
Wii device (Wii Fit,
Wii Dance and Sports games).
Assessments include measures of QOL, fatigue, health-
related fitness (HRF), physical activity levels and
hematological and immunological reconstitution. Assess-
ments will be completed at baseline, 30, 85 and 180 days
post infusion day (day 0+). Hematological and immuno-
logical reconstitution will be assessed at the time points
described above, plus at 7, 15 and 56 days post reinfusion.
The baseline assessment will be completed within the two-
month period prior to the conditioning regimen. The
30 day assessment is intended to capture the effect of
Phase 1, the EX program during the hospitalization period
(from conditioning regimen up to discharge). The 85 day
assessment is intended to capture the early survivorship re-
covery period after an autologous SCT and the effect of
Phase 2, EX program during the outpatient phase. The
180 day assessment will provide a mid-term follow-up of
physical activity, QOL, fatigue and hematological and im-
munological reconstitution. These outcomes will allow us
to examine the impact of an EX program implemented
early during the SCT process 3 months after finishing the
EX intervention on (i) physical activity levels (ii) QOL and
fatigue iii) hematological and immunological recovery.
Baseline
+7 days
+14 days
+30 days
+56 days
+85 days
+180 days
Stem Cell Collection Day
Hospitalization day
Infusion day (+0)
Hospital discharge
Follow up (+85 days)
Follow up (+180 days)
Randomization
Intervention group Control Group
-56
-6
0
+15
+85
+180
Timeline
(Days)
Assessment
Blood General
BASELINE
+ 30 DAYS
+ 85 DAYS
+ 180 DAYS
Identification of eligible cases through research nurse
Regular care
Phase 1
, Exercise
I
ntervention
Phase 2,
Exercise
Intervention
Research nurse contacts potential participants by phone
Interested Not interested
Lost participant
-65
All participants will be invited to PEER program
Figure 1 Participants flow through SCORE study.
Chamorro-Viña et al. BMC Cancer 2012, 12:401 Page 3 of 12
http://www.biomedcentral.com/1471-2407/12/401
Page 3
Study population
A total of 24 children will be recruited for this RCT; 12
patients will be assigned to an EX training program and
12 subjects will be assigned to a control group (without
any specific training). A sequence to allocate participants
randomly will be generated by the software Research
Randomizer, a research tool provided by the Social
Psychology Network (www.socialpsychology.org). Alloca-
tion concealment will be ensured. After baseline assess-
ments each participant will choose a sealed, non
transparent envelop, which contains a number that will
allocate the subjects to the control or EX group. The re-
search coordinator will be responsible for the random
allocation.
Eligibility criteria includes: (1) autologous SCT at
Alberta Childrens Hospital (ACH) for malignancy, (2)
age 5 to 18 years of age, (3) will be receiving myeloa-
blative conditioning regime n, (4) no evidence of cardiac
or pulmonary failure associated with treatment (short-
ening fraction (SF) 28%, ejection fraction (EF) 50%),
(5) no functional nor cognitive limitation that would
prohibit performance of the home-based training, (6)
approval by treating oncologist for participants, (7) a
parent or legal guardian must sign the consent form,
and (8) children should express verbal assent to partici-
pate. The entire team of assessors and the persons per-
forming the statistical analyses will be blinded to group
assignment.
Recruitment
Children undergoing autologous SCT will be recruited
through the Section of Pediatric Oncology and Blood and
Marrow Transplantation at ACH. ACH is the SCT centre
for Alberta. The referring oncologist will identify potential
subjects and the research nurse will contact them to
present the study at least 4 weeks before the hospitalization
to start autologous SCT treatment. Those subjects who are
interested in the study will be asked to sign the consent
form by the research nurse and will be contacted by the
research assistant to set up the baseline assessment.
This on-site patient recruitment method will be more
likely to enhance recruitment efforts than a mail out or
other off-site method. Also, prospective subjects might
feel more supported if the physician supports the re-
search protocol. In order to obtain a homogenous sam-
ple, is known that the recruitment phase will take
between 2-3 years to reach the sample described.
Intervention and control group
Intervention group
Children in the intervention group will participate in an
inpatient and outpatient mixed EX program including
both resistance and aerobic training.
Control group
These subjects will not participate in any scheduled EX
and will perform the same battery of tests as the
HOSPITAL ADMISSION SCT
CONDITIONING REGIMEN
STEM CELL INFUSSION
NEUTROPENIC PHASE
EARLY PHASE AFTER SCT
Mixed exercise program
(unsupervised/home-based
program and supervised
exercise training).
± 28 days
70 days
FOLLOW UP ASSESMENT
85 days
End of phase 2
Phase 1, EX
Intervention
Phase 2, EX
Intervention
Hospital
discharge
Exercise
program will
be offer to
the entire
participants
Baseline assessment:
- Immune system recovery
-QOL
- Physical activity levels
-HRF
- Dietary intake
30 day assessment:
- Immune system recovery
-QOL
- Physical activity levels
-HRF
- Dietary intake
85 day assessment:
- Immune system recovery
-QOL
- Physical activity levels
-HRF
- Dietary intake
180 day assessment:
-Immune system
recovery
- QOL
- Physical activity levels
Figure 2 SCORE study protocol.
Chamorro-Viña et al. BMC Cancer 2012, 12:401 Page 4 of 12
http://www.biomedcentral.com/1471-2407/12/401
Page 4
intervention group. They will be offered an E X program
upon completion of phase 2, to be held in the Thrive
Centre, University of Calgary.
Medical treatment transp lant protoco l
High dose chemotherapy and autologous SCT will be
performed for a given child as per the recommended
therapy for a given disease and stage risk group. Only
children receiving myeloablative conditioning will be eli-
gible. Most children will have a history of Sarcoma,
Lymphoma, Neuroblastoma or Germ cell tumor. Sup-
portive care will be as per institutional practice.
Sample size
Power calculations were derived using GPower 3.1 [19]
The sample size/power calculation was based on rele-
vant intervention literature [12,20,21] with natural killer
cell activity as the primary outcome measure (Cohens
d = .79). With an α of .05 and power of .80, a minimum
sample size of 20 participants is required. To account
for potential drop out, we will recruit an additional 20%,
for a total of 24 participants.
Data analysis
The raw data analysis will be performed using SPSS
(v. 20.0) and will include descriptive, correlations, and
repeated measures analysis of variance (ANOVA). Specif-
ically, for the primary and second objectives, correlations
will be run to examine the degree of relationship between
the variables, and planned doubly multivariate repeated
measures ANOVAs will be performed to examine group
differences between the intervention and control group.
Descriptive statistics will be conducted for demographics,
medical variables, adherence to the program, and phys-
ical activity behavior using means, standard deviations,
and ranges as appropriate. As was previously mentioned,
the statistician will be blinded to participant condition.
EX intervention
This RCT will be a biphasic EX intervention.
Phase 1 The inpatient phase will be performed at the
ACH during conditioning and the isolated phase of
autologous SCT.
Phase 2 The outpatient phase will take place after
discharge. The participants will participate in a 10 week
mixed supervised and home-based EX program
utilizing the Wii device.
In both phases participants will wear a portable heart
rate monitor (RS300X Polar) when at
the EX sessions to ensure safety and target the aerobic
EX intensity between 50% and 70% of heart rate
reser ve (HRR), depending on the physical status of
each child.
The training session will be cancelled if the child has
platelet levels below 10.000/ μl, hemoglobin levels
below 8 g/dl, fever greater than 38°C, pain, diarrhea,
hemorrhage or any other complication(s) the
oncologist thinks ma y worsen with EX. Additionally, a
session may be cancelled if the child doesnt want to
participate.
Phase One: In-Patient Exercise Program
This program will consist of combined aerobic (20-30
minutes) and resistance training, designed on the basis
of our previous experience with pediatric patients with
cancer, and following the rules of the institutions for
global benchmarks for strength training and aerobic
EX in children and adolescents [7,14,22]. During the
neutropenic phase, all training equipment (including
cycle ergometers) will be sterilized before each training
session, and the instructors will wear appropriate med-
ical attire.
The strength EXs, will engage the major muscle
groups (arm curl, elbow extension, bench press, leg ex-
tension, half squat, abdominals, supine bridge, and row-
ing), performing one set of 12 15 repetitions per EX.
Phase Two: Outpatient Exercise Program
Following the in-patient EX program, the participant s
of the interventio n group will engage in a 10-week
EX program consisting of 3 weekly sessions. The par-
ticipants from Calgary will perform a combined
super vised and unsupervised/home-based exercise
program (2 unsupervised and 1 super vised sessions/
week) w ith an average duration of 60 minutes/ses-
sion. The participants from outside of C algary will
perform only the home-based E X program 3 days/
week. The super vised and unsupervised EX plans will
be individualized based on f itness assessment out-
comes and current health status.
Supervised EX program The supervised training ses-
sion (Calgary-based participants) will be performed at
the Thrive Centre at the Univer sity of Calgary 1 time/
week and will be similar to the inpatient intervention.
Home-Based Exercise Pro gram Designed by exercise
professionals and supervised by the parents, it will in-
clude 20-30 minutes of aerobic EXs and 30 minutes of
strength and stretching EXs using Nintendos Wii con-
sole and Wii Fit/Wii Sports/Wii Dance games (from
now on, named as Wii Fit/Sports/Dance).
Parents and children are going to be instructed on
how to control the intensity of the EXs. Training adher-
ence will be reported in a logbo ok, including reported
training days and reasons for missed EX sessions. Train-
ing sessions will be declared valid if 80% of the planned
Chamorro-Viña et al. BMC Cancer 2012, 12:401 Page 5 of 12
http://www.biomedcentral.com/1471-2407/12/401
Page 5
session were performed. Participants will be reminded
and encouraged to engage in their home-based workouts
when they come to the Thrive Centre, and all partici-
pants (including those residing outside of Calgary) will
receive a weekly phone call (from the research assistant)
to encourage the participants to continue performing
the EX program and answer any questions they or their
parents may have.
Measures
Once consent has been obtained, the research nurse will
be responsible for instructing participants (parents and
pediatric patient) (1) on the use of the accelerometers
and log book, (2) on how to perform the food record,
and (3) on the QOL assessment. The research coordin-
ator will be responsible for contacting participants to
perform the baseline HRF assessment. All ba seline
assessments will be performed before any conditioning
regimen is administered. Additionally, the research co-
ordinator will ensure all assessments are administered
according to the protocol.
We will perform: (1) Hematological and Immuno-
logical Recovery, (2) Health and Lifestyle Assessment
and (3) Health-Related Fitness Assessments (HRF).
Hematological and immunological recovery
Specimen collection
At baseline 2 Buccal Swabs will be collected to use for
deoxyribonucleic acid (DNA) extraction. DNA speci-
mens will be used to perform genotyping of activating
and inhibitory KIR genes. The patient should not eat or
drink anything for one hour prior to the specimens
being taken. We will take one swab and rub the inside of
right and left patients cheek for approximately 10 sec-
onds. The swab will air dry for 1-2 minutes prior to re-
placing it into its container.
The baseline blood draw will be performed at the Unit
1 in the ACH (within 7 days prior to conditioning and
transplant). The maximum blood volume to be drawn
will be determin ed based on patient weight and other
ordered blood work. A minimum of 7 mL will be
required. The blood sample collection will be performed
at baseline, day 7, 14, 30, 56, 85 and 180.
To avoid any acute EX effects, we will discourage any
specific EX training 24 h before blood draws in the sam-
ples that will be collected at baseline and after transplant
on day 14, 30, 56, 85 and 180. Research samples may be
collected via central line or peripheral draw. For this
study, we will store 1 aliquot each for peripheral blood
mononuclear cells (PBMNCs) for e very blood specimen
serum. The aliquoted serum samples will be stored in
our -86°C freezers and PBMNCs will be cryo-preserved
at -150°C using liquid nitrogen based cell storage facility.
All immune functional assays will be performed on cry
preserved PBMNCs.
Hematological and immune system assessment
Assessment of the impact of the EX intervention on the
immune recovery of pediatric autologous SCT patients
will be based on four parameters (a) Recovery of differ-
ent leukocyte cell subset (e.g., T cells, NK cells, B cells,
monocytes, neutrophils etc) in peripheral blood, (b) Ex-
pression of activating and inhibitory KIR s (c) Function
of NK cells and their subsets and (d) Levels of different
pro-inflammatory and regulatory cytokines in serum,
a) Recovery of NK cells and other immune cells subsets
will be performed by flow cytometry enumeration of
different blood leukocyte subsets including NK cells
and its subsets (cytolysis and regulatory NK cells), T
cells and its subsets (CD4, CD8, regulatory, naive
and memory T cells), B cells, monocytes, neutrophils
and dendritic cells.
b) Gene/allele carriage analysis for 8 inhibitory KIR
genes (2DL1, 2DL2, 2DL3, 2DL4, 2DL5, 3DL1, 3DL2
and 3DL3); 6 activating KIR genes (3DS1, 2DS1,
2DS2, 2DS3, 2DS4 and 2DS5) and two pseudo genes
(2DP1 and 3DP1) will be performed for all 24
patients. Gene expression analysis of 14 KIR genes
will be done by RNA based real-time PCR analysis.
Total RNA will be extracted from the PBMNCs for
each time point and cDNA will be prepared using
random primers and M-MLV reverse transcriptase
enzyme. A quantitative real time PCR analysis will be
performed to assess the expression of genes
encoding for 8 inhibitory and 6 activating KIR genes.
Quantitative PCR will be carried out with SYBR
Green PCR method. The mRNA expression of
different KIR genes will be normalized against
GAPDH, and fold change in expression will be
determined using ddCt method. Additionally, a flow-
cytometry based protein expression analysis for 7
KIRs (4 activating and 3 inhibitory KIRs) on NK cells
will also be performed. PBMNCs from each subject
for each time point will be stained with
fluorochrome labeled antibodies against different KIR
molecules and markers specific for NK cells. Cells
will be analyzed by multi-color flow cytometry. To
quantify the amount of KIR expression on NK cells,
we will determine the mean fluorescence intensity
(MFI) for each KIR on NK cells.
c) NK function will be assessed by measuring in vitro
cytokine secretion and degranulation by different
NK cell subsets (cytolysis and regulatory NK cells)
on incubation with K-562 cell lines. PMNCs will be
cultured with and without K562 cell in RPMI
supplemented with 5% fetal bovine serum,
Chamorro-Viña et al. BMC Cancer 2012, 12:401 Page 6 of 12
http://www.biomedcentral.com/1471-2407/12/401
Page 6
glutamine (2 mM), Pen icillin (100 U/ml) and
Streptomycin (0.1 mg/ml) at 37°C in a humidified
atmosphere containing 5% CO
2
. To measure
degranulation, fluorochrome-conjugated antibody
against human CD107a (a surrogate marker of
degranulation) will be added to the cells at the start
of culture as CD107a is only transiently expressed
on T cell surface following activation-induced
degranulation and it becomes internalized over
time. Monessen will also added to the culture from
beginning to ensure blockade of cytokine export
from cells to the extra-cellular space and to provide
neutral pH that maintains the fluorescence of
FITC-conjugated CD107a antibody bound to
CD107a, when internalized into the cell. At the end
of the culture, cells will be stained with
fluorochrome labeled antibodies against CD, CD3,
CD56, CD16 and IFNγ and will be analyzed by
multi-color flow cytometry. A cytolysis NK cell will
be defined as CD3
neg
CD56
dim
CD16
pos
NK cell
while a regulatory NK cell will be defined as
CD3
neg
CD56
dim
CD16
pos
IFNγ
pos
NK cell.
Positivity for IFNγ and CD107a will correspond to
the cytokine producing and degranulation functions
respectively.
d) Assessment of cytokine levels in serum: A total of 30
cytokines including TNF-α, IFN-γ, IL-10, IL-6, IL-1α,
IL-1β, IL-1R, IL-2, IL-12, TGF-β IL-15, and IL-17 etc
will measured in the serum specimens for each time
point using a bead-based array on Luminex.
Health and lifestyle assessment
Baseline health
Baseline demographic and health characteristics of the
study participants will include demographic characteris-
tics , health record information (type of cancer, disease
status, co-morbid conditions, cancer treatment received,
side-effects of treatment) and information related to
SCT (platelet and neutrophil engraftment, conditioning
regimen received, toxicities due to conditioning regimen,
documented infection, incidence of fever). These ques-
tionnaires will be filled out by the physician at baseline,
15, 30, 60, 85 and 180 days after stem cell infusion.
Dietary habits
Usual dietary intake will be assessed at four time points
(baseline, 30, 85 and 180 days after infusion) using a 3-
day dietary record [23]. Dietary records will be analyzed
by a Registered Dietitian using Diet Analysis Plus 10.0
software (Thomson Wadsworth, Toronto, Canada). Par-
ticipants and their parents will be instructed as to how
to fill out these records by the researc h nurse.
Quality of life
Quality of life will be assessed using the Pediatric quality
of life inventory (PedsQL) general and cancer module as
a self-report, and PedsQL and Behavior A ssessment Sys-
tem for Children (BASC-2) as paren t proxy report. The
PedsQL Measurement Model is a modular approach to
measuring QOL in healthy children and adolescents and
those with acute and chronic health conditions. The
PedsQL Measurement Model integrates seamlessly both
generic core scales and disease-specific modules into
one measurement system. The 23-item PedsQL Generic
Core Sca les were designed to measure the core dimen-
sions of health a s delineated by the World Health
Organization, including physical, emotional, social and
school functioning. In addition, the cancer module will
be assessed to provide greater measurement sensitivity.
The reliability and validity of the PedsQL general and
cancer module has been shown in pediatric cancer popu-
lations [24]. Participants will complete this measure.
The BASC-2 [25] is a standardized report measure of
child behavior consisting of 150 items with self, parent
proxy, or teacher report forms. The BASC yields scores
for externalizing (i.e., hyperactivity, aggression, conduct
problems) and internalizing (i.e. anxiety, depression, and
summarization) behavior problems as well as for adaptive
skills. Items are rated using a 4-point ordinal scale. Raw
scores are converted into T scores. T-scores of 60 or
greater are indicative of clinically significant behavior
problems. Parents will be asked to complete this mea sure
as a means of enhancing QOL measurement sensitivity.
Fatigue
Fatigue will be assessed using the multidimensional
PedsQL fatigue scale. The recently developed 18-item
PedsQL Multidimensional Fatigue Scale was designed to
measure fatigue in pediatric patients and comprises the
General Fatigue Scale (6 items), Sleep/Rest Fatigue Scale
(6 items), and Cognitive Fatigue Scale (6 items). Reliabil-
ity and validity of the pediatric multidimensional fatigue
scale has been shown in cancer population [24]. Partici-
pants will complete this measure.
Objective measurements of physical activity
A triaxial accelerometer (Actual Phillips respironics)
will be used as an objective assessment of physical activ-
ity le vels. Actual measures and records time-stamped ac-
celeration in all directions, providing an index of
physical activity intensity. The digitized values are
summed over a user-specified interval of 1 min, resulting
in a count value per minute (counts per minute). Accel-
erometer signals are also recorded as steps per minute.
This gold standard measure provides a reliable and ob-
jective measure of physical activity levels, previously vali-
dated and tested for reliability [26,27].
Chamorro-Viña et al. BMC Cancer 2012, 12:401 Page 7 of 12
http://www.biomedcentral.com/1471-2407/12/401
Page 7
The activity monitor (AM) will be put on when the
participant gets up from bed each day and worn until
the participant is ready to fall asleep. Participants can go
about their normal, daily activities, including rigorous
EX, swimming or bathing. Participants will be instructed
to wear the activity monitor over their right hip on an
elasticized belt for seven consecutive days. The AM can
be worn over or under clothing. Additionally, partici-
pants will be asked to record, in a daily log, the time
they put on and took off the monitor each day. This
protocol and device was recently used in a study to asses
physical activity among healthy Canadian children be-
tween 6-19 yr [28]. The research nurse will explain the
instructions about how to use the AM and daily log at
their first meeting.
Health-related fitness assessments
The HRF assessments will be performed by a certified
exercise physiologist. Participant s will complete the
assessments in the following order: resting blood pres-
sure (BP), heart rate (HR) and electrocardiogram; body
composition; musculoskeletal fitness (flexibility, muscu-
lar strength and endurance); functional mobility test and
cardiorespiratory fitness. Adequate recovery and hydra-
tion will be provided, with the total fitness assessment
time approximately 2.0 hours.
Submaximal aerobic test
Resting HR will be measured using a heart rate monitor
(Polar Electro RS300X, Finland) and resting BP (mmHg)
will be measured following the Fourth Report published
by the U.S. Department of Health and Human Services
[29]. All participants will perform a submaximal EX test
on a treadmill. A modified protocol suggested by Bar-Or
(1993) adjusted by height will be used. The initial vel-
ocity of the test will be determined upon child height
(Table 1) based on Bar-Or suggestion for healthy kids
maximal testing [30]. All participants will start the test
with an upgrade of 5%. Every 2 minutes (Tanner stages
I-IV) and every 3 minutes (Tanner stage V), the slopes
will increase 2.5% until 80% of age-predicted maximal
HR is achieved. Age-predicted maximal HR will be cal-
culated usin g the equation 208- (0.7× age) [31].
All the children will be verbally encouraged during the
test. Gas-exchange data will be measured in a mixed
metabolic cart (True One Metabolic Cart, ParVo Me dics
Inc, Utah, U.S.) and specific pediatric face-masks (Hans
Rudolph Model 8930, 8940, 8950, 8960 ). The duration of
the test, the maximal load reached (velocity and slope),
and the maximal distance walked will be recorded. In
addition, parameters including ventilation (VE), ventila-
tory equivalent of carbon dioxide (VCO
2
), respiratory ex-
change ratio (RER), and Respiratory Quotient (RQ) will be
recorded.
Oxygen uptake and HR will be determined at Ventila-
tory threshold (VT). VT will be determined using the
criteria of an increase in both the ventilatory equivalent
of oxygen (VE . VCO
2
-1
) and end-tidal pressure of oxygen
(PetO
2
) with no increase in the VCO
2
while RER
remained below 1.0 [32]. All the EX tests will be per-
formed under similar environmental conditions and at
the same time of the day (10:00 am 13:00 pm). Partici-
pants will be directed to consume their usual breakfast
3 hours prior to the testing.
Previous familiarization sessions will not be possible
due to the nature of the study population (i.e., approxi-
mately ½ of parti cipants will be from outside of Calgary).
To diminish the anxiety and fear that fitness tests may
generate, participants and parents will have the oppor-
tunity to watch a video explaining and showing all
assessments.
Functional mobility test
This test is used to measure the capacity of the children
to perform daily activities. We will perform the timed up
and go test (TUG) in 3 m [33,34]. For the TUG, the
child is sitting with 90° hip and knee flexion and at a
given signal the child will get up, walk 3 m, turn and
come back as fast as possible without running. The re-
searcher measures the time spent performing this test.
The test will be performed three times and the best time
will be registered. Between each attempt the child will
rest for 2 minutes.
Musculoskeletal fitness
Muscular endurance Muscular endurance is described
as the ability of a muscle or a muscle group, to generate
force repeatedly or for an extended period of time. Mus-
cular endurance can be determined by measuring the
number of repetitions or time to fatigue. We are going
to ask the children to perform three tests: (a) partial
curl-up, (b) modified push-up and (c) sit and stand test.
a) Partial curl-up will assess the muscular endurance of
the abdominal muscles. The FITNESSGRAM
protocol will be used [35]
b) Modified push-up: This test measures the endurance
of upper body muscles.
Table 1 Sub maximal aerobic test; setting speed
according to height of each participant
STATURE (cm) SPEED (km/h)
109.9 cm 3 km/h
110129.9 cm 4 km/h
130 cm 4.8 km/h
Chamorro-Viña et al. BMC Cancer 2012, 12:401 Page 8 of 12
http://www.biomedcentral.com/1471-2407/12/401
Page 8
The modified push-up will require the participant to
start with hands shoulder-width apart with the
elbows and body straight. The knees will be flexed
90° and the ankles crossed. The test consists of doing
as many repetitions as possible continuously until
failure. To ensure the participant is properly
completing the push up, they will have to lower their
torso until they come into contact with a foam roller
(10 cm diameter) on the ground (rather than a fist).
c) Squat test: Will assess the muscular endurance of the
lower body. The participant stands in front of a
chair, facing away from it, with their feet shoulder
width apart . The participant squats down lightly
touching the chair (located at 90 ˚ hip flexion) with
their backside before standing back up and repeats
this sequence of movements for 30 seconds [36]. The
assistant counts and records the number of
successfully completed squats.
Strength assessment Strength is defined as the maximal
force or torque developed by a muscle, or a muscle
group. Maximum isometric contraction values will be
done by assessing (a) knee extension and (b) grip
strength.
a) Knee extension will be performed by using the
break technique, in which the examiner gradually
overcomes the muscle force and stops at the
moment the extremity gives away [37,38]. All tests
will be performed with the tested limb segment in a
position that will be not affected by gravity. The
tester will manually stabil ize the body part proximal
to the tested limb segment during testing. Before the
test, the assessor will demonstrate to the patient the
muscle contraction. The piston of the dynamometer
will be held perpendicular to the anterior surface of
leg. The plate of the dynamometer will be placed just
proximal to the ankle on the anterior surface of the
leg. The subject will be seated on the edge of a
padded mat table with the knee flexed 90°. Measures
of strength of the right and left sides will be assessed.
A sum will be determined in kilograms from the best
score of 2 trials recorded for each muscle group.
b) Grip strength will also be assessed using a hand-
dynamometer (Baseline
W
). Measures of strength of
the right and left sides will be assessed. A sum will
be determined in kilograms from the best score of 2
trials recorded for each muscle group, according to
the CPAFLA protocol [39].
Flexibility
Sit and reach test measures the flexibility of the ham-
strings and lower back muscles [39]. CPAFLA protocol
will be followed [39].
Body composition
Standing height and body mass will be measured. We
will measure standing height to the nearest 0.1 cm with
a clinical stadiometer (SECA, Birmingham, UK), while
children stand barefoot. Body mass will be measured to
the nearest 0.01 kg using a balance scale (Health o
Meter, Illinois, US) with the subjects in the ir underwear
and will calculate body mass index (BMI) as weight
height [mass (kg)/height (m
2
)]. Estimated childrensfat-
free mass (FFM) will be calculated from the following
equation (1): FFM = body mass fat mass (FM), where
FM = 4.95 x Body density (BD) x body mass. Childrens
BD will be estimated from skin fold thickness at the tri-
ceps, biceps, sub scapular, and suprailiac area. In all sub-
jects, each skin fold will be obtained in duplicate by the
same researcher using standard equipment (Harpender
skin fold caliper, Bath international, UK) and the mean
value per skin fold utilized for statistical analysis [39]. A
third skin fold measure will be taken if the difference be-
tween the first two measures is greater than 4 mm. Dif-
ferent equations depending on childrens age and gender
will be used to calculated BD (1) BD = 1,169 - 0,0788 *
log Σ 4 skin folds and BD = 1,2063 - 0,0999 * log Σ 4
skin folds (for boys and girls, respe ctively, aged 12 yr)
and (2) BD = 1,1533 - 0,0643 * log Σ 4 skin folds and
BD = 1,1369 - 0,0598 * log Σ 4 skin folds (for boys and
girls, respectively, aged 13 yr) [40].
Discussion
The primary focus of the SCORE study will be to iden-
tify the effect of an early EX intervention in the immune
system recovery of pediatric patients undergoing autolo-
gous SCT. Other important health outcomes will include
the intervention impact on QOL and fatigue. We will
also be able to examine the mediators and moderators of
any observed associations between PA, HRF, and health
outcomes after SCT at a mid-term assessment point. Fi-
nally, we will be able to identify if an early intervention
will be able to diminish the acquisition of a sedentary
lifestyle,
Taken together, these data will provide a detailed and
complete understanding of the effect of an EX program
in pediatric cancer patients undergoing autologous SCT.
From our knowledge, this study will be one of the most
comprehensive studies in this population, and will pro-
vide an initial database along with the impetus to pro-
mote a multisite study. A multisite study is the ideal
approach to examine the impact of EX on immuno-
logical and patient-reported outcomes in the pediatric
oncology population, due to relatively small sample sizes
at any one centre.
The SCORE study is designed to address the following
research themes through pilot data:
Chamorro-Viña et al. BMC Cancer 2012, 12:401 Page 9 of 12
http://www.biomedcentral.com/1471-2407/12/401
Page 9
1. Hematological and immunological reconstitution and
exercise. The primary aim of this project is to
examine the associations between EX, recovery of
hematological and immunological reconstitution, and
the relation with some disease outcomes in pediatric
cancer patients undergoing autologous SCT
(including duration of neutropenia,
thrombocytopenia, anemia, fever, toxicity degree,
chemotherapy completion rate infectious
complications and event free survival) [41]. The
clinical utility of autologous SCT is limited in part by
treatment related toxicity [42]. Also, an absolute
lymphocyte recovery of 500 cells/μl or more at day
15 after autologous SCT has been reported as a
powerful and independent prognostic indicator of
clinical outcomes. NK cells have antitu mor activity,
therefore an early NK cell engraftment with an early
anti-tumor immune-surveillance might have a direct
impact on survival post autologous SCT. Preliminary
studies in children with cancer showed a decrease in
NK lytic activity before and after cessation of cancer
chemotherapy, especially in those with progressive
disease [43,44]. Physical activity has the ability to
promote an immune modulation that may involve
multiple biological pathways, including a reduction in
inflammation, an enhancement of anti-tumor
response and may modulate killer cell
immunoglobulin-like receptors (KIRs) [45]. Neither
of the aforementioned mechanism has been studied
in detail [46]. More research is needed to determine
which inflam matory mediators and antitumor
immune mechanism are more sensitive to EX.
2. Exercise, health-related fitness, quality of life and
fatigue questionnaires. The specific objectives of this
study are to examine the effect of an EX program on
(a) QOL and fatigue outcomes across the SCT
process and immediately after discharge, (b) to
examine the associations between HRF indices,
physical act ivity and QOL and fatigue outcomes.
Pediatric cancer patients undergoing SCT have an
elev ated risk for poor QOL and fatigue both during
treatment and into survivorship, however this issue
has to be studied in depth [4]. Some evidence
suggests that EX may be a beneficial tool to improve
fatigue and QOL in children with cancer [47]. New
research suggest that fatigue is strongly associated
with a diminish in physical activity levels [48], thus it
is imperative to break the vicious cycle of fatigue in
this population.
Systematic reviews support the promising role of EX
as a safe and eff ective intervention to improve HRF
and quality of life and fatigue outcomes in children
with cancer [3,4]. However, most of the research was
performed in children with ALL. Only three articles
have been published showing the effect of an EX
intervention in children undergoing SCT and the
outcomes are promising including improve in cardio
respiratory capacity, strength, fatigue and QOL
[7,14,15]. This study will provide details about the
effect of an EX program on fatigue and QOL as a
self-report outcome and also will be compared with
parents proxy report.
3. The effects of an EX intervention on body
composition
The aim of this study is to determine if an early EX
intervention during SCT will (a) avoid loss of body
weight. Survivors of pediatric patients who went
undergoing a SCT are at an increased risk to have
less lean mass and an excess of fat mass compared
with healthy peers [49].
Given the scarcity of literature on the effect of an EX
program on the immune system recovery, QOL,
physical act ivity levels and HRF measures for
pediatric cancer patients undergoing SCT, the
SCORE study will generate new knowledge and be
instrumental in developing future clinical and
community-based programming for this population.
This will be the largest known study in children
undergoing autologous SCT and will provide us with
valuable information for a future multisite study.
This research could add biologic plausibility to the
association between EX and immune system recovery
after autologous SCT that may identify new targets
for interventions, and inform clinical
recommendations for improving survival. Ultimately,
this project will enable us to achieve more effective
targeted interventions that help pediatric cancer
patients achieve healthy levels of PA and HRF and
with the hope of optimizing disease and treatment
related outcomes.
Abbreviations
SCORE, (Stem Cell patients Ongoing Recovery through Exercise);
SCT, Hematopoietic stem cell transplantation; QOL, Quality of life;
EX, Exercise; RCT, Randomized controlled trial; NK, Natural Killer; KIR, Killer
immunoglobulin like receptor; HRF, Health-related fitness; PBMNC, Peripheral
blood mononuclear cell; DNA, Deoxyribonucleic acid; MFI, Mean
fluorescence intensity; PedsQL, Pediatric quality of life inventory; BASC-
2, Behavior assessment system for children; AM, Activity monitor; BP, Blood
pressure; HR, Heart rate; VE, Ventilation; VCO2, Ventilatory equivalent of
carbon dioxide; VT, Ventilatory threshold; RER, Respiratory exchange ratio;
RQ, Respiratory quotient; PetO2, End tidal pressure of oxygen.
Competing interests
The entire authors listed in this manuscript declare that they have no
competing interests.
Authors contributions
CC-V conceived the study and participated in its design and coordination as
well as helped draft the manuscript. GG participated in the design of the
study, facilitated the in-hospital setting and helped to draft the manuscript.
FK was responsible for choosing the methods to carry out the immune
system assessment. Additionally he will carry out the immunoassays, data
analysis of immune system assessment and he helped to draft the
Chamorro-Viña et al. BMC Cancer 2012, 12:401 Page 10 of 12
http://www.biomedcentral.com/1471-2407/12/401
Page 10
manuscript. KM as a research nurse who will help us in the recruitment of
the participants and ensure the entire participant will have done the blood
draw properly. She helped to draft the manuscript. FS will participate in the
analysis of the quality of life and fatigue questionnaires. AW will participate
in the development of the exercise intervention and will help coordinate
testing times. She also helped to draft the manuscript. TW will be
responsible to perform and interpret the health-related fitness assessments.
RR will be responsible for analyzing the 3 day dietary intake records. NCR as
a PI will be responsible to oversee the study and data analysis and all
subsequent manuscripts and dissemination of the work. She also conceived
and participated in the design and coordination of the study. All authors
read and approved the final manuscript.
Acknowledgments
Dr. Chamorro-Viña is a CIHR and PORT-funded post-doctoral fellow.
Dr. Khan is an ACHF investigator in Pediatric Hematology.
Dr. Reimers research is funded by CIHR and the Bank of Montreal Program
in Healty Living in conjunction with the Alberta Childrens Hospital Research
Insitute.
Dr. Culos-Reeds research program is supported by the Canadian Imperial
Bank of Commerce, CIHR and AHS.
Childhood Cancer Collaborative and Alberta Childrens Hospital Foundation
support this research project.
We thank Dr. Doug Strother and the pediatric oncology group for
supporting this study at the Alberta Childrens Hospital.
We thank Jessica Danyluk who will perform the Health-related fitness
assessments and has collaborated in its design.
We thank Rosemary Neil who provided assistance in the design of the
health-related fitness assessment (Faculty of Kinesiology, University of
Calgary).
We thank Dr. Antonio Perez who helped us conceive of this study.
Author details
1
Faculty of Kinesiology, University of Calgary, 2500 University Drive NW,
Calgary, AB T2N 1N4, Canada.
2
Section of Pediatric Oncology, Alberta
Childrens Hospital, Calgary, Canada.
3
Faculty of Medicine, University of
Calgary, Calgary, Canada.
4
Department of Psychosocial Resources, Tom Baker
Cancer Centre, Calgary, Canada.
5
Department of Pathology & Laboratory,
Faculty of Medicine, University of Calgary, Heritage Medical Research, 3300
Hospital Drive NW . Room 269, Calgary, Canada.
6
Division of Pediatric and
Oncology, Alberta Childrens Hospital, 2888 Shaganappi Trail NW, CalgaryAB
T3B 6A8, Canada.
7
Hematology, Oncology, Transplant Program, Alberta
Childrens Hospital, 2888 Shaganappi Trail NW44, Calgary, AB T3B 6A8,
Canada.
Received: 27 August 2012 Accepted: 28 August 2012
Published: 10 September 2012
References
1. Miano M, Labopin M, Hartmann O, Angelucci E, Cornish J, Gluckman E,
Locatelli F, Fischer A, Egeler RM, Or R, et al: Haematopoietic stem cell
transplantation trends in children over the last three decades: a survey
by the paediatric diseases working party of the European Group for
Blood and Marrow Transplantation. Bone Marrow Transplant 2007,
39(2):8999.
2. Oeffinger KC, Hudson MM, Landier W: Survivorship: childhood cancer
survivors. Primary care 2009, 36(4):743780.
3. Huang TT, Ness KK: Exercise interventions in children with cancer: a
review. International journal of pediatrics 2011, 2011:461512.
4. San Juan AF, Wolin K, Lucia A: Physical activity and pediatric cancer
survivorship. Recent results in cancer research Fortschritte der Krebsforschung
Progres dans les recherches sur le cancer 2011, 186:319347.
5. Oeffinger KC, Mertens AC, Sklar CA, Kawashima T, Hudson MM, Meadows
AT, Friedman DL, Marina N, Hobbie W, Kadan-Lottick NS, et al: Chronic
health conditions in adult survivors of childhood cancer. N Engl J Med
2006, 355(15):15721582.
6. Oeffinger KC, Robison LL: Childhood cancer survivors, late effects, and a
new model for understanding survivorship. Jama 2007,
297(24):27622764.
7. Chamorro-Vina C, Ruiz JR, Santana-Sosa E, Gonzalez Vicent M, Madero L,
Perez M, Fleck SJ, Perez A, Ramirez M, Lucia A: Exercise during
hematopoietic stem cell transplant hospitalization in children. Med Sci
Sports Exerc 2010, 42(6):10451053.
8. Warner JT, Bell W, Webb DK, Gregory JW: Daily energy expenditure and
physical activity in survivors of childhood malignancy. Pediatr Res 1998,
43(5):607613.
9. Reilly JJ, Ventham JC, Ralston JM, Donaldson M, Gibson B: Reduced energy
expenditure in preobese children treated for acute lymphoblastic
leukemia. Pediatr Res 1998, 44(4):557562.
10. Aznar S, Webster AL, San Juan AF, Chamorro-Vina C, Mate-Munoz JL, Moral
S, Perez M, Garcia-Castro J, Ramirez M, Madero L, et al : Physical activity
during treatment in children with leukemia: a pilot study. Appl Physiol
Nutr Metab 2006, 31(4):407
413.
11. Robertson AR, Johnson DA: Rehabilitation and development after
childhood cancer: can the need for physical exercise be met? Pediatr
Rehabil 2002, 5(4):235240.
12. Shore S, Shepard RJ: Immune responses to exercise in children treated
for cancer. J Sports Med Phys Fitness 1999, 39(3):240243.
13. Ladha AB, Courneya KS, Bell GJ, Field CJ, Grundy P: Effects of acute
exercise on neutrophils in pediatric acute lymphoblastic leukemia
survivors: a pilot study. J Pediatr Hematol Oncol 2006,
28(10):671677.
14. San Juan AF, Chamorro-Vina C, Moral S, Fernandez Del Valle M, Madero L,
Ramirez M, Perez M, Lucia A: Benefits of intrahospital exercise training
after pediatric bone marrow transplantation. Int J Sports Med 2008,
29(5):439446.
15. Rosenhagen A, Bernhorster M, Vogt L, Weiss B, Senn A, Arndt S, Siegler K,
Jung M, Bader P, Banzer W: Implementation of structured physical activity
in the pediatric stem cell transplantation. Klin Padiatr 2011,
223(3):147151.
16. Peters C, Lotzerich H, Niemeier B, Schule K, Uhlenbruck G: Influence of a
moderate exercise training on natural killer cytotoxicity and personality
traits in cancer patients. Anticancer Res 1994, 14(3A):10331036.
17. Na YM, Kim MY, Kim YK, Ha YR, Yoon DS: Exercise therapy effect on
natural killer cell cytotoxic activity in stomach cancer patients after
curative surgery. Arch Phys Med Rehabil 2000, 81(6):777779.
18. Kim SD, Kim HS: Effects of a relaxation breathing exercise on anxiety,
depression, and leukocyte in hemopoietic stem cell transplantation
patients. Cancer Nurs 2005, 28(1):7983.
19. Faul F, Erdfelder E, Lang AG, Buchner A: G*Power 3: a flexible statistical
power analysis program for the social, behavioral, and biomedical
sciences. Behavior research methods 2007, 39(2):175191.
20. Fairey AS, Courneya KS, Field CJ, Mackey JR: Physical exercise and immune
system function in cancer survivors: a comprehensive review and future
directions. Cancer 2002, 94(2):539551.
21. Fairey AS, Courneya KS, Field CJ, Bell GJ, Jones LW, Mackey JR: Randomized
controlled trial of exercise and blood immune function in
postmenopausal breast cancer survivors. J Appl Physiol 2005,
98(4):15341540.
22. Faigenbaum AD, Kraemer WJ, Blimkie CJ, Jeffreys I, Micheli LJ, Nitka M,
Rowland TW: Youth resistance training: updated position statement
paper from the national strength and conditioning association. J Strength
Cond Res 2009, 23(5 Suppl):S60S79.
23. Tremblay A, Sévigny J, Leblanc C, Bouchard C: The reproducibility of a
three-day dietary record. Nutr Res 1983, 3(6):819830.
24. Varni JW, Burwinkle TM, Katz ER, Meeske K, Dickinson P: The PedsQL in
pediatric cancer: reliability and validity of the Pediatric Quality of Life
Inventory Generic Core Scales, Multidimensional Fatigue Scale, and
Cancer Module. Cancer 2002, 94(7):20902106.
25. Wolfe-Christensen C, Mullins L, Stinnett T, Carpentier M, Fedele D: Use of
the Behavioral Assessment System for Children 2nd Edition: Parent
Report Scale in Pediatric Cancer Populations. Journal of Clinical Psychology
in Medical Settings 2009, 16(4):322330.
26. Puyau MR, Adolph AL, Vohra FA, Zakeri I, Butte NF: Prediction of activity
energy expenditure using accelerometers in children. Medicine and
science in sports and exercise 2004, 36(9):16251631.
27. Pfeiffer KA, McIver KL, Dowda M, Almeida MJ, Pate RR: Validation and
calibration of the Actical accelerometer in preschool children. Med Sci
Sports Exerc 2006, 38(1):152157.
28. Colley RC, Janssen I, Tremblay MS: Daily step target to measure adherence
to physical activity guidelines in children. Med Sci Sports Exerc 2012,
44(5):977982.
Chamorro-Viña et al. BMC Cancer 2012, 12:401 Page 11 of 12
http://www.biomedcentral.com/1471-2407/12/401
Page 11
29. The fourth report on the diagnosis, evaluation, and treatment of high
blood pressure in children and adolescents: Pediatrics 2004,
114(2 Suppl 4th Report):555576.
30. Docherty D: Measurment in pediatric exercise sciences. Champaign, Illinois:
Human Kinetics; 1996.
31. Mahon AD, Marjerrison AD, Lee JD, Woodruff ME, Hanna LE: Evaluating the
prediction of maximal heart rate in children and adolescents. Res Q Exerc
Sport 2010, 81(4):466471.
32. Caiozzo VJ, Davis JA, Ellis JF, Azus JL, Vandagriff R, Prietto CA, McMaster WC:
A comparison of gas exchange indices used to detect the anaerobic
threshold. J Appl Physiol 1982, 53(5):11841189.
33. Gocha Marchese V, Chiarello LA, Lange BJ: Strength and functional
mobility in children with acute lymphoblastic leukemia. Med Pediatr
Oncol 2003, 40(4):230232.
34. San Juan AF, Fleck SJ, Chamorro-Vina C, Mate-Munoz JL, Moral S, Garcia-
Castro J, Ramirez M, Madero L, Lucia A: Early-phase adaptations to
intrahospital training in strength and functional mobility of children with
leukemia. J Strength Cond Res 2007, 21(1):173177.
35. The Cooper Institute: Fitnessgram & Activitygram Test Administration Manual .
Dallas, Texas: United States of America: Human Kinetics; 2010.
36. Jones CJ, Rikli RE, Beam WC: A 30-s chair-stand test as a measure of lower
body strength in community-residing older adults. Res Q Exerc Sport 1999,
70(2):113119.
37. Beenakker EA, van der Hoeven JH, Fock JM, Maurits NM: Reference values
of maximum isometric muscle force obtained in 270 children aged
4-16 years by hand-held dynamometry. Neuromuscular disorders: NMD
2001, 11(5):441446.
38. Ness KK, Morris EB, Nolan VG, Howell CR, Gilchrist LS, Stovall M, Cox CL,
Klosky JL, Gajjar A, Neglia JP: Physical performance limitations among
adult survivors of childhood brain tumors. Cancer 2010, 116(12):3034
3044.
39. CSEP-Health & Fitness Programs Health-Related Appraisal and Counselling
Strategy: The Canadian Physical Activity. Third edition © 2003rd edition.
Ottawa, Ontario: Fitness & Lifestye Approach Protocol (CPAFLA); 2003.
40. Durnin JV, Rahaman MM: The assessment of the amount of fat in the
human body from measurements of skinfold thickness. Br J Nutr 1967,
21(3):681689.
41. Courneya KS, Segal RJ, Mackey JR, Gelmon K, Reid RD, Friedenreich CM,
Ladha AB, Proulx C, Vallance JK, Lane K, et al
: Effects of aerobic and
resistance exercise in breast cancer patients receiving adjuvant
chemotherapy: a multicenter randomized controlled trial. J Clin Oncol
2007, 25(28):43964404.
42. Kalwak K, Gorczynska E, Toporski J, Turkiewicz D, Slociak M, Ussowicz M,
Latos-Grazynska E, Krol M, Boguslawska-Jaworska J, Chybicka A: Immune
reconstitution after haematopoietic cell transplantation in children:
immunophenotype analysis with regard to factors affecting the speed of
recovery. Br J Haematol 2002, 118(1):7489.
43. Gallego-Melcon S, Espanol Boren T, Sanchez De Toledo J, Prats Vinas J:
Natural killer cell function in children with malignant solid neoplasias.
Med Pediatr Oncol 1991, 19(3):175181.
44. Alanko S, Salmi TT, Pelliniemi TT: Recovery of natural killer cells after
chemotherapy for childhood acute lymphoblastic leukemia and solid
tumors. Med Pediatr Oncol 1995, 24(6):373378.
45. Maltseva DV, Sakharov DA, Tonevitsky EA, Northoff H, Tonevitsky AG: Killer
cell immunoglobulin-like receptors and exercise. Exerc Immunol Rev 2011,
17:150163.
46. Walsh NP, Gleeson M, Shephard RJ, Woods JA, Bishop NC, Fleshner M,
Green C, Pedersen BK, Hoffman-Goetz L, Rogers CJ, et al: Position
statement. Part one: Immune function and exercise. Exerc Immunol Rev
2011, 17:663.
47. Keats MR, Culos-Reed SN, Courneya KS, McBride M: An examination of
physical activity behaviors in a sample of adolescent cancer survivors.
J Pediatr Oncol Nurs 2006, 23(3):135142.
48. Keats MR, Culos-Reed SN: A community-based physical activity program
for adolescents with cancer (project TREK): program feasibility and
preliminary findings. J Pediatr Hematol Oncol 2008, 30(4):272280.
49. Mostoufi-Moab S, Ginsberg JP, Bunin N, Zemel BS, Shults J, Thayu M,
Leonard MB: Body composition abnormalities in long-term survivors of
pediatric hematopoietic stem cell transplantation. J Pediatr 2012,
160(1):122128.
doi:10.1186/1471-2407-12-401
Cite this article as: Chamorro-Viña et al.: EXERCISE in pediatric
autologous stem cell transplant patients: a randomized controlled
trial protocol. BMC Cancer 2012 12:401.
Submit your next manuscript to BioMed Central
and take full advantage of:
Convenient online submission
Thorough peer review
No space constraints or color figure charges
Immediate publication on acceptance
Inclusion in PubMed, CAS, Scopus and Google Scholar
Research which is freely available for redistribution
Submit your manuscript at
www.biomedcentral.com/submit
Chamorro-Viña et al. BMC Cancer 2012, 12:401 Page 12 of 12
http://www.biomedcentral.com/1471-2407/12/401
Page 12
    • "Specific physical therapy, adapted to individual performance limitations, is essential for this patient group, as well as a general promotion of enjoyable exercises to maintain adequate activity levels and physical fitness [40]. Some ongoing studies about the role of exercise interventions in specific groups of pediatric cancer entities like solid tumors [33] and patients treated with autologous stem cell transplan- tation [7] may help to develop entity-related exercise recommendations in the future. The association between vincristine treatment and motor performance was examined because a previous study suggested a possible influence on motor skills [29] , and vincristine is known to induce peripheral neuropathy [28]. "
    [Show abstract] [Hide abstract] ABSTRACT: Reduced motor performance may particularly limit reintegration into normal life after cessation of treatment in pediatric cancer patients. This study aimed at analyzing motor performance at the end of the acute treatment phase and reveals potential risk factors for motor deficits. A childhood cancer population with different tumor entities was assessed with the MOON test, which allows for comparison with age- and gender-matched reference values of healthy children, at the end of the acute treatment phase. Forty-seven patients were tested at 7.0 ± 2.6 months after diagnosis. Significant reductions of motor performance affected muscular explosive strength (P < 0.001), handgrip strength (P < 0.001), muscular endurance of legs (P = 0.035), hand-eye coordination (P < 0.001), static balance (P = 0.003), speed (P = 0.012), and flexibility (P < 0.001). Loss of upper extremity coordination did not achieve statistical significance. Associations between single motor deficits and the tumor entity, age, body mass index, and inactivity during treatment were revealed, whereas no associations were found for gender and vincristine application. Conclusion: Overall, motor performance was low in the patient group studied. We recommend that individualized exercise interventions to attenuate motor deficits and promote physical activity are needed during cancer treatment in order to enhance motor performance and improve social participation during and after cancer therapy.
    No preview · Article · Nov 2014 · European Journal of Pediatrics
  • Source
    • "Active video games have been studied also in children with cerebral palsy [35,36], developmental delay [37] or disability [38], acquired brain injury [39] and lower limb amputations [40] with promising results [30] but, to the best of our knowledge, active video games have not yet been studied in children with cancer alone. However, there is a protocol published in which active video gaming is used for exercise purposes in pediatric autologous stem cell transplant patients [41]. "
    [Show abstract] [Hide abstract] ABSTRACT: Low levels of physical activity, musculoskeletal morbidity and weight gain are commonly reported problems in children with cancer. Intensive medical treatment and a decline in physical activity may also result in reduced motor performance. Therefore, simple and inexpensive ways to promote physical activity and exercise are becoming an increasingly important part of children's cancer treatment. The aim of this study is to evaluate the effect of active video games in promotion of physical activity in children with cancer. The research is conducted as a parallel randomized clinical trial with follow-up. Patients between 3 and 16 years old, diagnosed with cancer and treated with vincristine in two specialized medical centers are asked to participate. Based on statistical estimates, the target enrollment is 40 patients. The intervention includes playing elective active video games and, in addition, education and consultations for the family. The control group will receive a general recommendation for physical activity for 30 minutes per day. The main outcomes are the amount of physical activity and sedentary behavior. Other outcomes include motor performance, fatigue and metabolic risk factors. The outcomes are examined with questionnaires, diaries, physical examinations and blood tests at baseline and at 2, 6, 12 and 30 months after the baseline. Additionally, the children's perceptions of the most enjoyable activation methods are explored through an interview at 2 months. This trial will help to answer the question of whether playing active video games is beneficial for children with cancer. It will also provide further reasoning for physical activity promotion and training of motor skills during treatment.Trial registration: ClinicalTrials.gov identifier: NCT01748058 (October 15, 2012).
    Full-text · Article · Apr 2014 · BMC Pediatrics
  • [Show abstract] [Hide abstract] ABSTRACT: Hematopoietic stem-cell transplant (SCT) is increasingly used to treat children with cancer, and survival following SCT is improving. One predominant consequence of childhood cancer therapy is increased physical morbidity, which is worse in pediatric SCT recipients compared to children treated with chemotherapy or radiation alone. There are many factors that contribute to exercise intolerance and reduced physical function during the pre-transplant, peri-transplant, and post-transplant phases. These include side-effects from chemotherapy or radiation, excessive immobility due to bed rest, infections, the negative effects of immunosuppressants, and graft vs. host disease; all of which can impair cardiorespiratory fitness, muscle strength, and muscle function. Few studies have investigated the effects of exercise in childhood SCT recipients. In a small number of published studies, exercise interventions have been demonstrated to improve cardiorespiratory fitness, preserve or increase muscle mass, and improve muscle strength in children following SCT. The use of exercise as medicine may be a non-invasive and non-pharmaceutical treatment to target physical complications post-SCT. Researchers and health-care professionals should work together to develop exercise prescription guidelines for this unique and important population.
    No preview · Article · Apr 2014 · Pediatric exercise science