CLINICAL SCIENCES

Exercise Intervention in Pediatric Patients with

Solid Tumors: The Physical Activity in
Pediatric Cancer Trial
CARMEN FIUZA-LUCES1,2, JULIO R. PADILLA3, LUISA SOARES-MIRANDA4, ELENA SANTANA-SOSA1,3,
JAIME V. QUIROGA5, ALEJANDRO SANTOS-LOZANO1,6, HELIOS PAREJA-GALEANO1,3, FABIÁN SANCHIS-GOMAR1,
ROSALÍA LORENZO-GONZÁLEZ7, ZORAIDA VERDE3, LUIS M. LÓPEZ-MOJARES3, ALVARO LASSALETTA7,
STEVEN J. FLECK8, MARGARITA PÉREZ3, ANTONIO PÉREZ-MARTÍNEZ5,9, and ALEJANDRO LUCIA1,3
1
Research Institute of the Hospital _12 de Octubre_ (i + 12), Madrid, SPAIN; 2Spanish Network for Biomedical Research in
Rare Diseases (CIBERER), U723, SPAIN; 3School of Doctorate Studies and Research, European University, Madrid, SPAIN;
4
Research Centre in Physical Activity, Health and Leisure, Faculty of Sport, University of Porto, PORTUGAL; 5Innate Immune
Research Group, IdiPAZ, Madrid, SPAIN; 6Department of Health Sciences, GIDFYS, European University Miguel de Cervantes,
Valladolid, SPAIN; 7Department of Hematology-Oncology and Stem Cell Transplantation, Children_s Hospital Niño Jesús,
Madrid, SPAIN; 8Andrews Research and Education Foundation, Gulf Breeze, FL; and 9Department of Pediatric
Hemato-Oncology and Stem Cell Transplantation, University Hospital La Paz, Madrid, SPAIN

ABSTRACT
FIUZA-LUCES, C., J. R. PADILLA, L. SOARES-MIRANDA, E. SANTANA-SOSA, J. V. QUIROGA, A. SANTOS-LOZANO,
H. PAREJA-GALEANO, F. SANCHIS-GOMAR, R. LORENZO-GONZÁLEZ, Z. VERDE, L. M. LÓPEZ-MOJARES, A.
LASSALETTA, S. J. FLECK, M. PÉREZ, A. PÉREZ-MARTÍNEZ, and A. LUCIA. Exercise Intervention in Pediatric Patients with
Solid Tumors: The Physical Activity in Pediatric Cancer Trial. Med. Sci. Sports Exerc., Vol. 49, No. 2, pp. 223–230, 2017.
Introduction: The randomized controlled trial ‘‘Physical Activity in Pediatric Cancer’’ determined the effects of an inhospital
exercise intervention combining aerobic and muscle strength training on pediatric cancer patients with solid tumors undergoing
neoadjuvant chemotherapy. Methods: Participants were allocated to an exercise (n = 24, 17 boys; mean T SEM age, 10 T 1 yr) or control
group (n = 25, 18 boys; 11 T 1 yr). Training included three sessions per week for 19 T 2 wk. Participants were assessed at treatment
initiation, termination, and 2 months after end treatment. The primary endpoint was muscle strength (as assessed by upper and lower-
body five-repetition-maximum tests). Secondary endpoints included cardiorespiratory fitness, functional capacity during daily life
activities, physical activity, body mass and body mass index, and quality of life. Results: Most sessions were performed in the
hospital_s gymnasium. Adherence to the program averaged 68% T 4% and no major adverse events or health issues were noted.
A significant interaction (group–time) effect was found for all five-repetition maximum tests (leg/bench press and lateral row; all P G
0.001). Performance significantly increased after training (leg press: 40% [95% confidence interval [CI], 15–41 kg); bench press: 24%
[95% CI, 6–14 kg]; lateral row 25% [95% CI, 6–15 kg]), whereas an opposite trend was found in controls. Two-month post values
tended to be higher than baseline for leg (P = 0.017) and bench press (P = 0.014). In contrast, no significant interaction effect was
found for any of the secondary endpoints. Conclusion: An inhospital exercise program for pediatric cancer patients with solid tumors
undergoing neoadjuvant treatment increases muscle strength despite the aggressiveness of such therapy. Key Words: CANCER,
EXERCISE, MUSCLE STRENGTH, FITNESS, QUALITY OF LIFE

W
ith the improvement in treatments over the last
Address for correspondence: Alejandro Lucia, M.D., Ph.D., European
University, 28670 Villaviciosa de Odón, Madrid, Spain; E-mail: decades, cure rates of children with cancer have
alejandro.lucia@universidadeuropea.es. increased, and now almost 80% of children and
Submitted for publication June 2016. adolescents diagnosed with cancer will survive the disease
Accepted for publication August 2016. (17). However, this increase in survival carries an enhanced
0195-9131/17/4902-0223/0 risk for severe and life-threatening therapy-related late ef-
MEDICINE & SCIENCE IN SPORTS & EXERCISEÒ fects that can severely deteriorate survivors_ functional ca-
Copyright Ó 2016 by the American College of Sports Medicine pacity and muscle strength as well as quality of life (QoL)
DOI: 10.1249/MSS.0000000000001094 (17). Consequently, more attention is now being given to

223

Copyright © 2017 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
 minimize the late effects of chemotherapy and radiation in
survivors and to prevent second malignancies and future
health problems.
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Interest in exercise intervention has focused primarily on
its potential to ameliorate the short-term and long-term side
effects of treatments. This nonpharmacological therapy has
beneficial effects on a broad range of physiological func-
tions and systems that are typically affected by the tumor or
by the different therapies, including the musculoskeletal,
the central nervous, and the cardiorespiratory systems (28).
Available data on the effects of an exercise program on pe-
diatric cancer patients are much more scarce compared with
studies with adult cancer patients and the great majority
come from studies in children with acute lymphoblastic
leukemia (ALL) (28). Moreover, less than a handful of
these studies were randomized controlled trials (RCTs)
(1,4,6,10,11). Of these, three were performed in children
with hematological malignancies (4,10,11) and two were
performed in a mixed group of pediatric cancer patients
(1,6). Differences between study endpoints, patients_ cohorts,
and design, as well as the heterogeneous results, make the
drawing of conclusions challenging. Thus, evidence is lack-
ing for the efficacy of an exercise program in pediatric cancer
patients, particularly in children with solid tumors undergoing
more aggressive treatments.
The aim of this RCT (‘‘Physical Activity in Pediatric
Cancer’’) was to determine the effect of regular supervised
exercise combining aerobic and muscle strength training
on pediatric cancer patients with solid tumors during the
neoadjuvant chemotherapy period. The primary endpoint
was muscle strength with secondary endpoints of cardiore-
spiratory fitness, functional capacity during activities of
daily living (ADL), physical activity (PA) levels, body mass
and body mass index (BMI), and QoL. We also determined
the effects on the abovementioned outcomes of a detraining
period that followed the exercise intervention. Our main
hypothesis, based on what is known on childhood hemato-
logical cancer (28), was that the intervention would induce
significant benefits, at least in the primary endpoint from
which we powered the study, that is, muscle strength.
METHODS
The present study is a RCT (ClinicalTrials.gov ID:
NCT01645436) designed to comply with the recommenda-
tions of the Consolidated Standards of Reporting Trials
statement (21). The study protocol adheres to the ethics
guidelines of the Declaration of Helsinki and was approved by
the Research Ethics Committee of the Children_s Hospital
Niño Jesús (Madrid, Spain; approval number R-0007/13). All
participants, together with their parents/guardians, gave their
written informed consent. The RCT was conducted from
September 2012 to September 2015 (with recruitment ending
in March 2015) at the abovementioned hospital, which is
where all training and assessment sessions took place.
224 Official Journal of the American College of Sports Medicine
Copyright © 2017 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
All participants were assessed at three separate time points:
i) baseline, that is, upon initiation of treatment (consisting of
neoadjuvant chemotherapy); ii) at treatment termination; and
iii) 2 months after the end of treatment.
Participants
Eligibility criteria included: age 4–18 yr; new diagnosis of
an extracranial solid tumor; not having received previous
therapy other than surgery; good performance status, that is,
for patients age Q 12 yr, score e 2 on the Eastern Coopera-
tive Oncology Group scale, and for patients age e 12 yr,
score Q 50% on the Lansky scale. A consort diagram of the
study is shown in Figure 1.
Seventy-four children met all the eligibility criteria. To-
gether with their parents/guardians, they were provided with
sufficient information concerning the study characteristics to
provide informed consent and were invited to participate.
Forty-nine children finally entered the study. After enroll-
ment and completion of a baseline evaluation, patients were
randomly assigned using a computer-generated list of ran-
dom numbers to a control (n = 25) or intervention (n = 24)
group. The researchers responsible for assessing eligibility,
baseline measures, and outcome assessment were blinded to
group allocation.
Exercise Intervention
All patients in the exercise arm followed an inhospital training
program, which took place during the entire neoadjuvant che-
motherapy treatment period. The intervention included three
sessions per week (Monday–Wednesday–Friday), each last-
ing approximately 60–70 min. Make up sessions (performed
on a Tuesday or Thursday) were allowed if an originally
planned session was missed. Depending on the physician_s
recommendations, exercise sessions were held in the ward
room (especially during neutropenic episodes) or in the hos-
pital gymnasium, which is appropriately equipped for this
purpose as previously described (21). The gymnasium in-
cludes: weight training machines specifically designed for the
size of children (Strive, Inc., McMurray, PA) which we have
previously used for training very young patients, for example,
children with ALL age only 4–7 yr (16); cycle-ergometers (Rhyno
Magnetic H490; BH Fitness Proaction, Victoria, Spain); arm
crank ergometers (Monark Rehab Trainer model 881E; Monark,
Varberg, Sweden); dumbbells; treadmills (Technogym Run
Race 1400HC; Gambettola, Italy); and heart rate (HR) monitors
(Xtrainer Plus; Polar Electro OY, Kempele, Finland). For inward
training sessions, HR monitors, cycle/arm crank ergometers,
and dumbbells were sterilized and used in the patient_s room.
Training was supervised and individualized for each pa-
tient (one supervisor per patient) by fitness instructors with
previous experience in the training of children with cancer.
As for determination of adherence to training, we considered
a session completed when Q 90% of the prescribed exercises
were successfully performed (18). Each session included a
conditioning period of approximately 30 min of aerobic
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FIGURE 1—Flow diagram of study participants.
exercise (cycle-ergometer pedaling, treadmill running, or arm
cranking in those children missing a lower limb due to the
disease, and aerobic games). The training load was gradually
increased depending on the age, capacity, and health status of
each child. Exercise intensity (60%–70% of maximum HR
obtained during cardiorespiratory exercise testing (see below)
for each child) was recorded continuously with HR monitors.
Aerobic exercise was followed by approximately 30 min of
strength training, which included the following exercises
performed against resistance involving a wide range of joint
movements: shoulder, chest and leg presses, upper limb row-
ing exercises, knee extension and flexion, and abdominal,
EXERCISE AND PEDIATRIC SOLID TUMORS
Copyright © 2017 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
CLINICAL SCIENCES
lumbar and shoulder adduction. Participants performed two to
three sets (eight to 15 repetitions) per exercise with a rest period
of 1–2 min between sets and exercises. In the ward sessions,
dumbbell exercises were performed similar to the weight-
training machine exercises performed in the gymnasium.
Participants in the two groups received regular hospital
care, which included physiotherapy as needed. Information
was given to families of all participants on the benefits of
following a healthy lifestyle that comprises when possible
(i.e., for outpatients) sports, playing in the park and in school
with other children, and walking Q 60 minIdj1. The occur-
rence of control group contamination (i.e., the possibility of
Medicine & Science in Sports & Exercised 225
 some children in the group actually performing training
sessions) was largely discarded because all the training
sessions (whether in the gym or in the ward) were super-
CLINICAL SCIENCES
vised by fitness specialists who were in charge of the train-
ing equipment. Thus, only children allocated to the exercise
group had access to the training equipment (ergometers and
weight training machines, or sterilized equipment in the case
of the ward sessions).
Primary Endpoint (Muscle Strength)
Muscle strength was assessed in the hospital gymnasium
with the aforementioned pediatric-specific machines (Strive
Inc.). Baseline assessment was preceded by three sessions of
familiarization with the exercise equipment. Children_s dy-
namic upper and lower body muscle strength endurance was
measured using the same seated bench, row, and leg press
machines that were used for training in the gymnasium. The
five-repetition maximum (5RM), that is, the maximum
strength capacity to perform five repetitions until momen-
tary muscular exhaustion was measured as previously de-
scribed (18). The testing protocol consisted of three warm-up
sets at 50%, 70%, and 90% of the perceived 5RM sepa-
rated by 1-min rest periods (8). A 2-min rest period
followed the last warm-up set after which a 5RM attempt
was made at 100%–105% of perceived 5RM depending on
the effort needed to perform the last warm-up set at 90% of
the perceived 5RM. If the first 5RM attempt was success-
ful, the resistance was increased by 2.5%–5%, and after 2 min
of rest, another 5RM attempt was made. If the second 5RM
attempt was successful, a second testing session was sched-
uled after 24 h of rest. If the first 5RM attempt was not
successful, the resistance was decreased 2.5%–5%, and af-
ter 2 min of rest, another 5RM attempt was made. If the
second 5RM attempt was successful, the weight used was
considered the 5RM. If the second 5RM attempt was not
successful, another testing session was scheduled after 24 h
of rest. Each subject was instructed to perform each exercise
to momentary muscular exhaustion. Any repetitions not
performed with a full range of motion were not counted.
Children with an amputated lower limb did not perform the
leg press test.
Secondary Endpoints
Cardiorespiratory fitness. Peak oxygen uptake (V̇O2peak)
and ventilatory threshold were determined using ‘‘breath-by-
breath’’ analysis with a metabolic cart (Vmax 29C; SensorMedics
Corp., Yorba Linda, CA) and pediatric masks during a ramp-
like treadmill testing protocol (Technogym Run Race 1400HC)
as previously described (21). For those children missing a
lower limb and who were unable to perform the treadmill
testing, we applied the following arm crank ergometer test
(Monark Rehab Trainer model 881E): starting at 5 W, the
load was increased by 5 W every 20 s while cadence was kept
constant at 50 rpm. Baseline tests were preceded by a famil-
iarization session.
226 Official Journal of the American College of Sports Medicine
Copyright © 2017 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
Body mass and BMI. Body mass was determined to
the nearest 0.05 kg using a balance scale (Ano Sayol SL,
Barcelona, Spain) with the participants in their underwear.
BMI (kgImj2) was also calculated.
Functional capacity in ADL. After a familiarization
session, the children performed the Timed Up and Go tests
of 3 m and the Timed Up and Down Stairs test (21). All
patients used a hand railing in the Timed Up and Down
Stairs test to reduce the risk of falling. Performance time was
measured by the same investigator with the same stopwatch
to the nearest 0.1 s.
PA levels—accelerometry. We used a triaxial accel-
erometer (GT3X model, Actigraph Manufacturing Tech-
nology Inc., Fort Walton Beach, FL). Monitor devices were
set as predefined epochs of 15 s and 30 Hz sample rate. PA
was monitored for up to seven consecutive days (Thursday
to Wednesday or Friday to Thursday). A minimum of 4 d
of monitoring (including 1 d of the weekend) and minimum of
10 h of data were considered necessary for adequate assess-
ment of PA. Data were analyzed using ActiLife6 (Actigraph
Manufacturing Technology Inc., Fort Walton Beach, FL).
Outcome variables were expressed as average intensity (counts
per minute) and count ranges for the various activity intensities
were determined using the following cut-points: G100 counts
per minute) for light PA, 2296–4011 counts per minute for
moderate PA and 94012 counts per minute for vigorous PA (3).
QoL. We used the validated Spanish version of _The
Pediatric Quality of Life Inventoryi (PedsQL) Cancer
Module 3.0_ (http://pedsql.org/), which has been designed to
determine health-related QoL dimensions specifically tai-
lored for pediatric cancer (24). This questionnaire was self-
administered for parents and for children age 8–18 yr and
interviewer-administered for children age 5–7 yr (only one
child in the sample was younger than 5 yr). Of note, because
of the potential bias of evaluating QoL twice within only
8 wk (i.e., at post-intervention and detraining), we only
evaluated QoL at baseline and postintervention.
Statistical Analysis
We used a two-factor (group and time) ANCOVA with
repeated measures. We repeated the analyses using the fol-
lowing covariates: baseline values of the study variables,
length of the treatment (since the duration of the coadjuvant
chemotherapy, which equaled training duration, varied
depending on the type of tumor), type of tumor, and total
days of in-room isolation. For each study endpoint, we
reported the level of significance corresponding to the main
group (between-subjects), time (within-subjects) and inter-
action (group–time) effects. To minimize the risk of type I
error, i) we only performed within-group post hoc compar-
isons (with the Bonferroni test) when a significant time
or group–time effect was present and, ii) we corrected all
the analyses for multiple comparisons using the stringent
Bonferroni method, that is, dividing 0.05 by the number of
comparisons. Thus, the P value for primary and secondary
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TABLE 1. Main demographic and clinical characteristics of the two groups at the moment RESULTS
of diagnosis.
P Value for Patient characteristics. Baseline characteristics did

CLINICAL SCIENCES
Exercise Control the Comparison not significantly differ between the two groups (Table 1).
(n = 24) (n = 25) between Groups*
Solid tumors included Hodgkin and non-Hodgkin lymphoma,
Sex, n (% boys) 17 (71%) 18 (72%)
Age (yr) 10 T 1 (4–16) 11 T 1 (5–17) 0.227 soft tissue sarcomas, bone tumors, neuroblastoma, Wilm_s
Tanner maturation stage 0.331 tumors, and germ cell tumors. All tumors were treated as per
I 42% 32% 0.484
II 4% 8% 1.000
current International Society of Pediatric Oncology (or
III 21% 8% 0.247 Spanish Pediatric Hematology-Oncology Society protocols
IV 8% 28% 0.138 if available or, if not, as per standard of care guidelines at
V 25% 24% 0.920
Types of tumors our institution).
Hodgkin_s lymphoma 4% 20% 0.189 Adherence and exercise adverse effects. The du-
Non-Hodgkin_s lymphomas 0.196
Burkitt_s lymphoma 21% 4% 0.545 ration of the training program equaled the total duration of
T-lymphoblastic lymphoma 13% 4% 1.000 the neoadjuvant treatment, that is, 19 T 2 wk (range, 9–41).
Diffuse large B-cell 0% 8% 0.091
lymphoma
Adherence to the intervention averaged 68% T 4%. Of note,
Soft tissue sarcomas 1.000 except in one case, adherence was not low in the younger
Rhabdomyosarcoma 8% 8% 1.000 children (age e 6 yr), that is, equaling 83% (in a 4-yr-old),
Nonrhabdomyosarcoma 4% 8% 1.000
(synovial sarcoma) 88% (5-yr-old), 33% (5-yr-old), and 66% (6-yr-old). The
Bone tumors 0.689 mean proportion of sessions performed in the patients_ rooms
Ewing_s sarcoma 25% 16% 0.637
Osteosarcoma 13% 16% 0.637 in the ward (due in the vast majority of cases to patient iso-
Neuroblastomas 0.609 lation secondary to neutropenia) was 18% T 3%. The main
Neuroblastoma 4% 8% 1.000
Ganglioneuroblastoma 0% 4% 1.000
reasons for missing one or more sessions were as follows:
Wilm_s tumor 0% 4% 1.000 inability to attend a session because parents were unavailable
Germ cell tumors 0.235 to bring their children to the hospital (34%), extreme fatigue
Germinomas 4% 0% 1.000
Nongerminomas 4% 0% 1.000 or relevant side effects associated with the treatment (27%),
(embryonic carcinoma) concurrent chemotherapy session (17%), physician_s advice
Main treatment characteristics
Total duration (wk) 19 T 2 (9–41) 21 T 2 (8–49) 0.416 due to poor functional status of the child or a very low he-
Chemotherapy cycles 7T1 7T1 0.615 moglobin level (8%), lumbar puncture procedure (4%), severe
In-room isolation episodes 3T0 4T1 0.207
due to neutropenia
viral infection during in-room isolation (4%), pneumonia
(3%), and hospitalization in the intensive care unit (3%). There
Data are mean T SEM, % or range.
*Comparisons between groups were performed with: (i) the unpaired Student_s t test, for were in total 26 make-up sessions, which equaled approxi-
data presented as mean T SD; or the W2 test (or the Fisher_s test when G80% of the cells mately 3% of the total number of training sessions in the study
had the expected frequency of n Q 5), for data presented as %).
(n = 837). Importantly, no major adverse events or health-
related issues attributable to the testing sessions or prescribed
outcomes was set at 0.017 (=0.05/3) and 0.005 (=0.05/10), training sessions were noted.
respectively. We used the ‘‘intention-to-treat’’ approach, that Primary endpoint. Results and statistical power for 5RM
is, all the children originally randomized in the trial were strength tests are shown in Table 2. A significant group–time
considered to be part of it regardless of whether they had ac- interaction effect was found for all the tests, that is, leg press
tually completed the trial (i.e., undergoing both post-treatment (P G 0.001, effect size [Gp2] = 0.306, power = 99.7%), bench
and detraining assessments) or the totality of the intervention press: (P G 0.001, Gp2 = 0.245, power = 99.8%), and lateral
(in the case of the exercise group). Missing individual data row (P G 0.001, Gp2 = 0.215, power = 99.4%). In post hoc
were imputed using the ‘‘baseline-observation-carried for- analyses, performance significantly increased in the exercise
ward’’ method. Thus, when posttreatment or detraining end- group after training compared with baseline, that is, P G 0.001
point data were missing, baseline scores were used. All for posttraining versus baseline in the three tests, with 40%
statistical analyses were performed with the IBM SPSS 22.0 increase for leg press (95% confidence intervals (CI) for the
package for MAC (SPSS, Inc., Chicago, IL). mean difference posttraining minus baseline = 15–41 kg),

TABLE 2. Results of primary endpoint (muscle strength) by group.

Endpoint Group n with Data Baseline Posttreatment Detraining Group (P) Time (P) Interaction (P) Statistical Power*
5RM Control n= 17 72.1 T 9.4 63.8 T 9.7 69.8 T 8.5 0.275 0.021 G0.001 42.3%
leg press (kg) Exercise n= 16 41.4 T 7.6 69.4 T 8.5 56.0 T 8.2
5RM Control n= 24 37.3 T 4.3 34.6 T 4.1 38.3 T 4.3 0.819 0.005 G0.001 99.5%
bench press (kg) Exercise n= 22 30.3 T 3.8 40.1 T 4.1 35.6 T 3.8
5RM Control n= 24 39.3 T 4.4 35.8 T 4.1 39.3 T 4.1 0.880 0.045 G0.001 100%
lateral row (kg) Exercise n= 22 31.9 T 4.5 42.8 T 4.7 36.8 T 4.6
Data are mean T SEM. Significant P values are in bold (threshold P value was set at 0.017, i.e., 0.05 divided by number of primary outcomes (0.05/3 = 0.017).
*Statistical post hoc power analysis to detect differences between group means with a significance level (alpha) of 0.05 (2-tailed).

EXERCISE AND PEDIATRIC SOLID TUMORS Medicine & Science in Sports & Exercised 227

Copyright © 2017 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
 24% (95% CI, 6–14 kg) for bench press and 25% (95% CI, [Hodgkin_s lymphoma, nonrhabdomyosarcoma, ganglioneuro-
6–15 kg) for lateral row. By contrast, an opposite trend was blastoma, Wilm_s tumor, germ cell tumors] or high [rest of
found in controls (leg press: P = 0.044; bench press: P = tumors]), that is, all P values 9 the threshold P value of 0.005).
CLINICAL SCIENCES

0.067; lateral row: P = 0.003). In the exercise group, perfor-

mance tended to decrease with detraining (P values for post
DISCUSSION
vs detraining = 0.040 [leg press], 0.008 [bench press], and
The results of this RCT show that an inhospital exercise
0.009 [lateral row]), yet detraining values still tended to be
program can be safely applied to increase muscle strength in
higher compared with baseline for leg (P = 0.017) and bench pediatric cancer patients with solid tumors undergoing
press (P = 0.014). Similar interaction effect results were neoadjuvant treatment. To our knowledge, this is the first
obtained after controlling for the covariables (baseline values of trial in pediatric solid tumor patients investigating whether,
the study variables, length of treatment, type of tumor, and during neoadjuvant treatment, an exercise program can af-
total days of in-room isolation). fect muscle strength, cardiorespiratory fitness, functional
Secondary endpoints. No significant group–time in- capacity, PA levels, body mass and BMI, or QoL. We be-
teraction effect was found for any of the secondary endpoints lieve that our study represents an important addition to the
(Table 3). A trend was found toward a training-induced im- current body of knowledge because data on the safety of
provement in the ventilatory threshold, that is, P = 0.040 for exercise interventions in very debilitated and immunocom-
the group–time interaction effect, yet this value was above the promised children like the ones studied here is still scarce,
significance threshold of P = 0.005. Similar interaction effect especially in pediatric solid tumors (2).
results were obtained after controlling for the covariables There is a particular need for early targeted exercise pro-
(baseline values of the study variables, length of treatment, grams in pediatric cancer not only because long-term im-
type of tumor, and total days of in-room isolation). pairment of muscle strength has been detected in a considerable
No significant group–time interaction effect was found ei- number of childhood cancer survivors (22) but also because
ther when performing subgroup analyses separately by sex, this may be especially problematic in children since muscle
age (first decade or second decade of life), adherence to strength is essential for health and growth (20) as well as for
training (G or Q 65%, respectively), main type of tumor (sarcoma leisure and play time with peers, and such activities are im-
or nonsarcoma) or intensity of treatment (intermediate portant for individual and social development. Moreover,
TABLE 3. Results of secondary endpoints by group.
Endpoint Group n with Data Baseline Posttreatment Detraining Group (P) Time (P) Interaction (P)
Aerobic capacity
V̇O2peak (mLIminj1)
All subjects Control n = 25 1066 T 113 1035 T 114 1176 T 119 0.994 0.016 0.435
Exercise n = 24 1075 T 136 1073 T 97 1124 T 123
Arm ergometer only Control n = 11 780 T 91 766 T 83 878 T 101 0.351 0.232 0.333
Exercise n=9 922 T 113 943 T 90 943 T 117
Treadmill tests only Control n = 14 1291 T 167 1247 T 175 1409 T 176 0.590 0.067 0.755
Exercise n = 15 1167 T 206 1150 T 145 1234 T 181
j1
VT (mLImin )
All subjects Control n = 25 610 T 74 640 T 85 690 T 89 0.050 0.040 0.040
Exercise n = 24 854 T 89 911 T 91 826 T 92
Arm ergometer only Control n = 11 550 T 82 598 T 101 658 T 102 0.011 0.577 0.512
Exercise n=9 984 T 133 983 T 98 966 T 147
Treadmill tests only Control n = 14 652 T 113 677 T 134 717 T 143 0.435 0040 0.027
Exercise n = 15 781 T 115 877 T 126 751 T 116
Functional capacity in ADL
TUDS (s) Control n = 15 7.5 T 0.4 7.4 T 0.4 7.1 T 0.4 0.198 0.222 0.376
Exercise n = 17 9.9 T 1.6 8.2 T 1.3 8.7 T 1.3
TUG3 (s) Control n = 16 3.8 T 0.2 3.9 T 0.2 3.9 T 0.1 0.491 0.284 0.104
Exercise n = 17 4.2 T 0.3 3.8 T 0.1 4.2 T 0.3
Anthropometric variables
Body mass (kg) Control n = 25 45.4 T 3.9 46.4 T 4.2 47.5 T 4.2 0.591 0.001 0.941
Exercise n = 24 42.6 T 4.1 43.3 T 4.0 44.2 T 4.2
BMI (kgImj2) Control n = 25 18.8 T 1.0 19.0 T 1.0 19.3 T 1.0 0.591 0.018 0.853
Exercise n = 24 19.2 T 1.0 19.6 T 1.0 19.7 T 1.1
j1
PA levels (minId )
Time inactive Control n = 18 589 T 41 559 T 25 562 T 27 0.159 0.303 0.973
Exercise n = 20 536 T 20 510 T 27 518 T 28
MVPA Control n = 18 19 T4 33 T6 31 T 6 0.766 0.001 0.600
Exercise n = 20 19 T3 31 T5 28 T 6
QoL
Patients Control n = 25 1733 T 73.2 1922 T 362 — 0.570 0.005 0.709
Exercise n = 24 1175 T 89.0 1847 T 392 —
Guardians/parents Control n = 25 1779 T 72.5 1783 T 68.6 — 0.983 0.282 0.318
Exercise n = 24 1728 T 79.2 1829 T 90.6 —
Data are mean T SEM. Significant P values are in bold (threshold P value was set at 0.005, i.e., 0.05 divided by number of primary outcomes (i.e., 0.05/10 = 0.005).
MVPA, moderate-vigorous physical activity; TUDS, Timed Up and Down Stairs test; TUG3, 3 m Timed Get Up and Go test; V̇O2peak, peak oxygen uptake; VT, ventilatory threshold.

228 Official Journal of the American College of Sports Medicine http://www.acsm-msse.org

Copyright © 2017 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
solid tumors usually demand high-intensity treatments, which
seem to have a higher negative impact on muscle mass (22),
and this damage can persist into adulthood (13). For instance,
childhood cancer survivors are 8.5 times more likely than their
siblings to report musculoskeletal problems and 1.8 times more
likely to report limitations in physical performance (14). Ex-
ercise interventions can improve muscle strength of pediatric
patients with blood malignancies (28). Our results on pediatric
cancer patients with solid tumors undergoing neoadjuvant
treatment are in line with the results of previous research on
children with hematological cancer (15,16,28), showing an
increase in upper and lower muscle strength. This is the first
report demonstrating that an exercise program can increase
muscle strength in pediatric cancer patients with solid tumors
despite the aggressive nature of the disease and its treatment.
The causes of cancer-related muscle dysfunction, a prevalent
phenomenon in oncology, are multifactorial and involve tu-
mors, treatments, lifestyle, and clinical setting (17). Exercise
can be a powerful intervention to halt or even reverse muscle
atrophy and dysfunction, as demonstrated in our present study.
Another important finding was that detraining values of muscle
strength still tended to be higher compared with baseline in the
exercise group. This partial maintenance of muscle strength
after detraining is in line with previous research from our
group on children with ALL (16), and reflects the fact that, in
general, human muscular strength suffers a relatively limited
decrease after relatively short periods of detraining, which is
due, at least partly, to some aspects of neuromuscular perfor-
mance (i.e., motor unit recruitment) being maintained during
periods of detraining (12).
In the present work, although the exercise program did
not significantly improve secondary outcomes, which are
also important, such as cardiorespiratory fitness, functional
capacity, PA levels, or QoL, it did not induce any decline
and, in fact, QoL showed a trend for improvement after the
exercise intervention. Neoadjuvant chemotherapy refers to
the administration of systemic therapy before local treatment
of the primary tumor. Most pediatric solid malignancies are
sensitive to intensive neoadjuvant chemotherapy, but these
protocols induce prolonged and profound immunosuppres-
sion (decline in immune cell number and impairment in
immune cell function), causing an increased frequency of
health problems such as upper respiratory tract infections,
which have been suggested as a contributing factor to im-
paired exercise capacity (7). Indeed, during the intervention
period, some of our patients were affected by pneumonia,
making it difficult for them to participate in the exercise
sessions and to achieve the attainment of the goals set. Also,
previous research has shown that children with ALL who
had received anthracyclines as part of their chemotherapy
treatment show reduced exercise duration and V̇O2peak dur-
ing exercise testing (5). Moreover, survivors of childhood
sarcoma have difficulties with physical functioning and have
limited PA levels related to both local and global effects of
sarcoma therapy (9). In our study, we found no differences
in cardiorespiratory capacity between groups, probably as a
EXERCISE AND PEDIATRIC SOLID TUMORS
Copyright © 2017 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
result of the deleterious effects of the chemotherapy that
affected all participants in a similar manner. Further research
might determine if benefits can be obtained in this variable
CLINICAL SCIENCES
in the longer term. Fatigue is one of the most frequent and
taxing side effects of chemotherapy. Due to their physical
limitations, study participants probably felt less confident
regarding their capacity to perform ADL and, as a result,
their QoL may not have improved significantly. Finally, our
study included patients diagnosed with malignant bone tu-
mors, that is, osteosarcoma and Ewing_s sarcoma. Previous
studies have shown that physical functional levels are con-
siderably reduced during and after the acute stages of bone
tumor treatment, particularly in patients with lower extrem-
ity sarcomas (19,23,25–27). In the same way, our bone tumor
patients suffered from motor function disability resulting in
insufficient activity, or weakness, restricting the patients_
ability to participate fully in ADL.
Strengths and limitations. Our analysis has several
strengths: RCT design, individually supervised training in-
tervention, reasonable adherence to intervention, and eval-
uation after a detraining period. Potential limitations should
also be considered: interventions had different durations
according to the neoadjuvant period, and results were attained
from pediatric cancer patients with solid tumors and may not
be directly generalizable to other populations. In addition,
muscle strength was assessed with the same equipment used
for training performed in the gymnasium. Although use of the
same equipment for testing and training is a common practice,
it could result in neural adaptations that increased performance
measures in the exercise compared to the control group inde-
pendent from actual strength training adaptations. However,
the three familiarization sessions before baseline testing
should have minimized the potential bias of greater neural
adaptations in the exercise compared with the control group.
In addition, because some children had an amputated lower
limb or a malignant bone tumor increasing fracture risk, they
could not perform leg press tests or their aerobic capacity had
to be evaluated with a different type of ergometer (arm crank)
compared with the rest of participants. In this regard, although
the use of different protocols to assess the same endpoint is
another study limitation, it could be also viewed as a strength, at
least from an ethical point of view, because we wanted to assess
and train all the children regardless of their specific type of
functional limitation. Studying the effects of in-hospital ex-
ercise interventions in pediatric cancer patients is tremen-
dously challenging. Pediatric cancer is relatively unusual and
normally involves debilitating therapies; together, these fac-
tors cause enormous recruitment difficulties. Therefore, stud-
ies assessing the effects of regular exercise training in pediatric
cancer patients are comparatively scarce and further research
to determine the effects and optimal dosage of exercise pro-
grams in this particular population is warranted.
CONCLUSION
In sum, our results suggest that an in-hospital exercise pro-
gram in pediatric cancer patients with solid tumors undergoing
Medicine & Science in Sports & Exercised 229
 neoadjuvant treatment can be safely applied to increase upper
and lower-body muscle strength.
CLINICAL SCIENCES
Alejandro Lucia and Steven J. Fleck are supported by a grant from
the National and Strength Conditioning Association (NSCA). A Lucı́a
is also supported by a grant from Cátedra Real Madrid-Universidad
Europea (2015/UEM07) and Fondo de Investigaciones Sanitarias
and Fondos Feder (FIS, grant PI12/00914 and PI15/00558). Luisa
Soares-Miranda is supported by grant SFRH/BPD/76947/2011
funded by FCT (QREN-POPH-Type 4.1—Advanced training, subsi-
dized by the European Social Fund and national funds of MEC),
PTDC/DES/099018/2008 - FCT/FCOMP-01- 0124-FEDER-009573,
and The Research Centre in Physical Activity Health and Leisure is
supported by FCT: UID/DTP/00617/2013. Carmen Fiuza-Luces is
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supported by a research contract ‘ Sara Borrell’’ (ISCIII-MINECO-
Spain/FEDER-EU, CD14/00005). Antonio Pérez-Martı́nez is supported
in part by National Health Service of Spain grant FIS (ISCIII-MINECO-
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Antonio Pérez-Martı́nez and Alejandro Lucia share senior
authorship.
The authors declare they have no financial competing interests.
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