Physical function and fitness in long-term survivors of childhood leukaemia

Abstract

To evaluate the physical function and fitness in survivors of childhood leukaemia 5-6 years after cessation of chemotherapy.
Thirteen children (six boys and seven girls; mean age 15.5 years) who were treated for leukaemia were studied 5-6 years after cessation of therapy. Physical function and fitness were determined by anthropometry, motor performance, muscle strength, anaerobic and aerobic exercise capacity.
On motor performance, seven of the 13 patients showed significant problems in the hand-eye co-ordination domain. Muscle strength only showed a significantly lower value in the mean strength of the knee extensors. The aerobic and the anaerobic capacity were both significantly reduced compared to reference values.
Even 5-6 years after cessation of childhood leukaemia treatment, there are still clear late effects on motor performance and physical fitness. Chemotherapy-induced neuropathy and muscle atrophies are probably the prominent cause for these reduced test results. Physical training might be indicated for patients surviving leukaemia to improve fitness levels and muscle strength.

Full text

Pediatric Rehabilitation, July 2006; 9(3): 267–274
Physical function and fitness in long-term survivors of
childhood leukaemia
MARCO VAN BRUSSEL
1
, TIM TAKKEN
1
, JANJAAP VAN DER NET
1
,
RAOUL H. H. ENGELBERT
1
, MARC BIERINGS
2
, MARJA A. G. C. SCHOENMAKERS
1
,
& PAUL J. M. HELDERS
1
1
Department of Paediatric Physical Therapy & Exercise Physiology and
2
Department of Paediatric Haematology,
University Hospital for Children and Youth ‘Wilhelmina Kinderziekenhuis’, University Medical Center Utrecht,
Utrecht, The Netherlands
(Received 6 May 2005; accepted 14 October 2005)
Abstract
Objective: To evaluate the physical function and fitness in survivors of childhood leukaemia 5–6 years after cessation of
chemotherapy.
Materials and methods: Thirteen children (six boys and seven girls; mean age 15.5 years) who were treated for leukaemia
were studied 5–6 years after cessation of therapy. Physical function and fitness were determined by anthropometry, motor
performance, muscle strength, anaerobic and aerobic exercise capacity.
Results: On motor performance, seven of the 13 patients showed significant problems in the hand-eye co-ordination domain.
Muscle strength only showed a significantly lower value in the mean strength of the knee extensors. The aerobic and the
anaerobic capacity were both significantly reduced compared to reference values.
Conclusion: Even 5–6 years after cessation of childhood leukaemia treatment, there are still clear late effects on motor
performance and physical fitness. Chemotherapy-induced neuropathy and muscle atrophies are probably the prominent
cause for these reduced test results. Physical training might be indicated for patients surviving leukaemia to improve fitness
levels and muscle strength.
Keywords: Fitness,exercise,aerobic,anaerobic,quality of life,cancer
Objetivo: Evaluar la capacidad y la funcio
´nfı
´sica de sobrevivientes de leucemia, 5 a 6 an
˜os despue
´s de suspender la
quimioterapia.
Material y me
´todos: trece nin
˜os (6 nin
˜os y 7 nin
˜as, con edades promedio de 15.5 an
˜os) que fueron tratados por leucemia
fueron estudiados 5 a 6 an
˜os despue
´s de suspender la terapia. La capacidad y la funcio
´nfı
´sica fueron determinadas por
medio de la antropometrı
´a, la actividad motora, la fuerza muscular, la capacidad de realizar ejercicio aero
´bico y anaero
´bico.
Resultados: En la actividad motora 7 de los 13 pacientes mostraron problemas significativos en la coordinacio
´n ojo-mano. La
potencia muscular mostro
´solamente un valor significativamente bajo en el promedio de la fuerza de los extensores de la
rodilla. Tanto la capacidad aero
´bica como la anaero
´bica estuvieron reducidas en comparacio
´n a los valores de referencia.
Conclusio
´n:5a6an
˜os despue
´s de haber suspendido el tratamiento de la leucemia en la infancia, au
´n hay efectos tardı
´os
claros que repercuten en la actividad motora y la capacidad fı
´sica. La neuropatı
´a inducida por la quimioterpia y las atrofias
musculares, son probablemente las causas mas prominentes de la disminucio
´n de los resultados en estas pruebas.
Introduction
Childhood leukaemia has an increasing number
of survivors; therefore more emphasis is focused
on the long-term effects of disease and treatment.
The success rate is attributed to the usage of more
intensive systemic therapy. The chemotherapeutic
treatment for children with leukaemia has short- and
long-term effects on the neuromuscular and cardio-
vascular systems. VincristineÕ-induced peripheral
neuropathy is a well-defined complication of treat-
ment for ALL [1]. Children with leukaemia show
decreased muscle strength early in treatment [2,3].
The magnitude of this decreased muscle strength
and its impact on function and physical fitness are
currently not well understood [2].
Correspondence: Tim Takken, Msc, PhD, Department of Paediatric Physical Therapy & Exercise Physiology, University Hospital for Children and Youth
‘Wilhelmina Kinderziekenhuis’, University Medical Centre Utrecht, Room KB.02.056. PO Box 85090, 3508 AB Utrecht, The Netherlands.
Tel: þ31302504030. Fax: þ31302505333. E-mail: t.takken@umcutrecht.nl
ISSN 1363–8491 print/ISSN 1464–5270 online/06/030267–274 ß2006 Informa UK Ltd.
DOI: 10.1080/13638490500523150

In children with leukaemia several scientific stud-
ies have been conducted investigating physical
fitness [4–7]. In these studies, the main focus was
on cardiac and pulmonary function. There is
increasing evidence indicating that there are factors
other than cardio-pulmonary factors, which limit the
physical fitness of leukaemia patients [7,8].
Obesity is an often occurring phenomenon after
childhood leukaemia treatment [9–11]. Warner et al.
[7] found in leukaemia patients a strong negative
relationship between exercise capacity, including
sub-maximal oxygen consumption and adiposity.
According to Warner et al. this could be caused by a
reduction in quantity and quality of mitochondria in
the muscles of leukaemia patients [7]. This leads to a
reduced oxygen uptake during sub-maximal exercise
as well as the reduced capacity in leukaemia patients
to oxidize fats as a fuel. This reduced oxidation of
fats could lead to a form of adiposity [7].
In the literature there are several publications on
exercise capacity in leukaemia patients after being
treated medically [5,12,13]. However, no studies
investigated the anaerobic exercise capacity of
these patients, although it has been shown that the
anaerobic exercise capacity might be very important
in the performance of daily childhood activities with
chronic conditions [14]. Also a decreased anaerobic
performance in survivors of solid tumour cancers
was previously reported [15].
The objective of this study is to determine
whether physical function and fitness is reduced in
survivors of leukaemia 5–6 years after their final
treatment, compared to reference values of healthy
children and adolescents. (Physical function refers
to the capacity to perform activities of daily living.
Physical fitness refers to the exercise capacity as
measured under laboratory conditions (i.e. muscular
strength, cardiopulmonary fitness).)
Material and methods
Patients
Thirteen patients being treated for acute lym-
phoblastic leukaemia (six boys, seven girls) at
the Wilhelmina Children’s hospital, Utrecht,
The Netherlands, participated in this study. Their
characteristics can be appreciated from Table I.
Children who started chemotherapy in 1996
were treated according to the Dutch Childhood
Leukaemia Study Group (DCLSG) protocol ALL-8
[16] and children who started chemotherapy in 1997
were treated according to the DCLSG protocol
ALL-9 [17]. One patient with T-cell non-Hodgkin
Lymphoma (T-NHL) was also treated according
to protocol ALL-8 and was included in this study.
Excluded were children with High-Risk ALL,
receiving more intensive chemotherapy and children
who were mentally disabled. Six of 13 were treated
according to DCLSG protocol ALL-8 and seven
of 13 according to Dutch Childhood Leukaemia
Study Group protocol ALL-9. Children treated with
protocol ALL-8 received 8 1.5 mg m
2
Vincristine
over two periods of 4 weeks. Children treated
with protocol ALL-9 received 34 2.5 mg/dose
Vincristine during the whole treatment period of
2 years (Table II). In protocol 8, both dexametha-
sone and prednisone were used as corticosteroid-
therapy, in protocol 9 dexamethasone alone was
used, the equivalent doses of steroids was 5–6 times
higher in protocol 9 compared to protocol 8.
On the other hand, the latter protocol contained
more cytostatic agents (daunorubicine, ara-C,
6-thioguanine). Neither protocols included cranial
irradiation. The eligible patients were participants in
a previous study (n¼18) from the group [3].
Thirteen patients of the original cohort participated
in this study. Five did not participate: three for
personal reasons, one for coming to the hospital too
often and one left the country. The characteristics
(age, gender and type of ALL) of these five patients
did not differ from the other 13 patients. Informed
consent was obtained from the parents and/or from
the children if they were older than 12 years of age.
Skin-fold and muscle strength measurements were
performed by the second author (TT) who is an
experienced exercise physiologist and has significant
familiarity with these measurements. All other
measurements were performed by the first author
(MvB). The medical-ethics committee of the Uni-
versity Medical Centre Utrecht approved all study
procedures.
Anthropometry
The participants’ body mass and height were
determined using respectively an electronic scale
and a stadiometer; subcutaneous adiposity was
determined from skin-fold measurements using
Table I. Anthropometric parameters and time of treatment
of the 13 ALL survivors.
Variables MSD Range
Age (years) 15.5 5.8 8.6–23.7
Weight (kg) 54.24 19.5 25.1–80.7 NS
Height (m) 1.54 0.2 1.26–1.8 NS
BMI (kgm
2
) 20.75 3.8 15.1–26.1 NS
7SF (mm) 96.3 46.6 49–182 NS
Time off treatment
(months)
61.9 6.8 46–73
NS: not significantly different from reference values; BMI: body
mass index; 7SF: sum of the seven skin-folds.
268 M. van Brussel et al.

Harpenden skin-fold callipers (Holtain, Crymych,
UK). The measurements were taken at seven sites
(at the right side of the body); triceps, biceps,
subscapular, suprailiac, mid-abdominal, medial calf
and thigh in accordance with the American College
of Sports Medicine guidelines [18]. No percentage
of body fat was calculated because there are no
validated prediction formulae for leukaemia patients
[11]. Therefore, the sum of the seven skin-folds
was used as an index for body fat after Pollack et al.
[19]. Body Mass Index was calculated as body mass/
height
2
. The BMI of the included patients were
compared and to international cut-off points for
body mass index for overweight and obesity [20].
Motor performance
The movement assessment battery for children
(Movement ABC test) tested the motor performance
of the patients [21, 22]. The Movement ABC screens
motor performance of children between 4–12 years.
The Movement ABC consist of test items for four age
groups: 4–6 years, 7–8 years, 9–10 years and 11–12
þ
years. As described in the manual, the instrument can
be used for children above this age as well [22]. In the
Dutch version of the Movement ABC the upper age
band is therefore listed as 11–12
þ
. Children above
12 years of age were compared with the normative
percentile scores of the age band 11–12
þ
[22].
The test can be divided into two parts: a checklist
and a motor performance test. The motor test
measures three different aspects of motor perfor-
mance, i.e. manual dexterity, ball skills, dynamic
and static balance. Percentile scores of the child’s
motor abilities were compared with a normative
age-matched sample of children [21]. A score below
the 5th percentile indicates that the child has
significant movement difficulties. In scores between
the 5th and 15th percentile, the child is at risk for
these difficulties. The motor performance is ade-
quate in scores above the 15th percentile [21].
Children were evaluated using the score forms for
their appropriate age group.
Strength measurement
Muscle strength was measured with a hand-held
dynamometer (Citec dynamometer CT 3001, C.I.T.
Technics, Groningen, the Netherlands) in six dif-
ferent muscle groups (shoulder abductors, knee
extensors, foot dorsal flexors, wrist extensors, hip
flexors and grip strength). Maximum muscle
strength was tested using the ‘break’ method, in
which the examiner gradually overcomes the muscle
strength of the patient and stops at the moment the
extremity gives way. Grip strength was measured
using the ‘make’ method. With the subjects sitting
and the arms held 90flexion at their sides, the
dynamometer was gripped as hard as possible for 3
seconds without pressing the instrument against the
body and without touching the elbow to the body.
During the test, the examiner manually stabilized
the body parts proximal to the tested limb segment.
Each person was tested once and in this session
every muscle group was measured three times and
the highest score was recorded. The highest value
was used for comparison. Reference values for
muscle strength (mean and SD for age and gender)
were obtained from Beenakker et al. [23] and van
der Ploeg et al. [24] and grip-strength from
Engelbert et al. [25] and used for analyses.
Exercise capacity
Wingate anaerobic exercise test. The Wingate
Anaerobic test (WAnT) as described by Bar-Or [26]
was performed on a calibrated electromagnetic
braked cycle ergometer (Lode Examiner, Lode BV,
Groningen, the Netherlands). The ergometer was
upgraded and calibrated by the manufacturer to
a maximal resistance of 800 W instead of the standard
400 W. External resistance was controlled and the
power output was measured using the Lode Wingate
Table II. Patient characteristics and outline of treatment according to protocol ALL-8 and ALL-9.
Treated with protocol ALL-8 Treated with protocol ALL-9
Number 6 7
Male-to-female ratio 3 : 3 3 : 4
Age (years) 17.9 13.5
Medication
Induction VCR/Pred/DNR/L-ASPþMTX/Ara-c/Pred i.th VCR/Pred/L-ASP þMTX/Ara-C/Pred i.th.
Intensification MD-MTX/6MP þMTX/Ara-c/Pred i.th MD-MTX/6MP þMTX/Ara-c/Pred i.th.
Reinduction VCR/Dexa/Adria/L-Asp/6MP, Ara-C,
6TG þMTX/Ara-c/Pred i.th.
none
Maintenance 6 MP/MTX 6 MP/MTX þQ
5 weeks: VCR/Dexa
VCR: vincristine; Pred: prednisone; DNR: daunorubicine; L-Asp: L-asparaginase; Ara-C: cytosine-arabinoside; MTX: methotrexate;
Adria: doxorubicine; 6TG: 6-thioguanine; 6MP: 6-mercaptopurine; Dexa: dexamethasone; i.th: intrathecal.
Physical function and fitness in long-term survivors of childhood leukaemia 269

software package. The seat height was adjusted to
the patients’ leg length (comfortable cycling height).
The external load (torque; in Nm) was determined,
dependent of bodyweight (at 0.53 bodyweight and
0.55 bodyweight for girls and boys under 14 years
of age and 0.67 bodyweight and 0.7 bodyweight
for older girls and boys, respectively) according
to the user manual. The patients’ feet were placed
in the Velcro toe-straps and the exercise protocol was
explained. The patients were instructed to exercise
for 1 minute at the cycle ergometer with an external
load of 15 W at 50–60 rpm. Thereafter, the sprint
protocol started. The patients were instructed to cycle
all-out for 30 seconds. Power output during the
WAnT was corrected for the inertia of the mass
of the flywheel (23.11 kg m
2
). Measured variables
were mean power and peak power. Mean power
represents the average power output over the 30
seconds sprint. Peak power is the highest recorded
power output achieved during the 30 seconds sprint.
Cardio-pulmonary exercise test (CPET). Patients
performed a cardio-pulmonary exercise test using
an electronically braked cycle ergometer (Lode
Examiner). The test started with 1 minute of
unloaded cycling, preceded to the application of
resistance to the ergometer. After this minute,
workload was increased with a constant increment
of 10 or 20 W every minute. The protocol was
selected to elicit a maximal exercise response within
6–12 minutes [27]. This protocol continued until
the patient stopped because of exhaustion,
despite verbal encouragement of the test-leader.
The highest achieved workload (W
max
) was
recorded. During the cardio-pulmonary exercise
test, subjects breathed through a facemask (Hans
Rudolph Inc, USA) connected to a calibrated
metabolic cart (Oxycon Champion, Jaeger, Viasys,
Bilthoven, the Netherlands). Expired gas was passed
through a flow meter (Triple V volume transducer),
an oxygen (O
2
) analyser and a carbon dioxide
(CO
2
) analyser. The flow meter and gas analysers
were connected to a computer, which calculated
breath-by-breath minute ventilation (VE), oxygen
uptake (VO
2
), carbon dioxide output (VCO
2
)
and the respiratory exchange ratio (RER ¼
VCO
2
/VO
2
) from conventional equations. Heart
rate (HR) was measured continuously during the
maximal exercise test through a bipolar electrocar-
diogram. Maximal effort occurred when one of the
two criteria were met: HR > 180 beats per minute
or RER > 1.0. Peak oxygen consumption (VO
2peak
)
was taken as the average value over the last 30
seconds during the maximal exercise test. Relative
VO
2peak
was calculated as absolute VO
2peak
divided
by body mass. For both the anaerobic exercise test
as well as the cardio-pulmonary exercise test,
the patients were compared to recently obtained
reference values from the laboratory using the same
experimental procedures [28].
Statistics
All data were entered and analysed in SPSS 12.0
for Windows. Due to the small number of patients
and the individual variability in response, there were
no statistically significant differences between the
patients in the two treatment protocols with respect
to any of the variables. Therefore, the data of
both groups were pooled and used together in the
statistical analysis. Independent samples T-tests
were used to test differences between patients and
reference values. Alpha level was set at p< 0.05 for
all analyses.
Results
The anthropometrical parameters of the patients
indicated that none of 13 patients were obese and
three patients were overweight, although mean
scores did not differ from reference values. The
results of the Movement ABC are shown in Table III
and indicate that 7/13 of the patients had a score
below the 15th percentile score in the ‘ball skills’
domain compared to healthy children. All patients
scored above the 15th percentile in the manual
dexterity domain. One patient scored between the
5th and 15th percentile on dynamic balance.
The strength measurement data (Table IV) indi-
cated that only knee extension strength was signif-
icantly reduced from normal values. All other muscle
tests were within normal ranges.
The measurements of the anaerobic capacity
indicate that all values were significantly lower
in the survivors of ALL compared to the control
group (Table V). Table V also shows the data of the
cardiopulmonary exercise test. VO
2peak
,VO
2peak
/kg,
W
max
and VE
max
were significantly lower in the
survivors of leukaemia compared to reference values.
Table III. Frequencies of percentile scores of the Movement
ABC test.
Manual dexterity
(number of patients)
Ball skills
(number of
patients)
Static and
dynamic balance
(number of patients)
p>15 13 6 12
p¼5–15* 0 3 1
p5040
Total 13 13 13
*Scores between the 5th and the 15th percentile indicate that the
child is at risk for motor delay.
270 M. van Brussel et al.

Discussion
This study found that long-term survivors of
childhood leukaemia had a lower level of physical
function and fitness compared to healthy children.
Although the disease in the present patient group is
in remission, they may experience late effects from
the anti-leukaemia therapy (chemotherapy) affecting
multiple organ systems. Chemotherapeutic agents
have known toxicities on different organ systems and
can affect the function of lung, heart and muscle
[29–31]. Corticosteroid therapy, in particular proto-
cols with dexamethasone, are associated with obesity
or overweight as an early and late side effect [32].
Movement ABC
The Movement ABC showed that there were a
number of patients with problems in hand-eye
co-ordination. The outcome values of the movement
ABC are quite remarkable compared to earlier
described values. Reinders-Messelink et al. [33]
studied motor performance in 17 children during
and after chemotherapy. They found balance prob-
lems to be most severe during treatment. The manual
dexterity skills showed an opposite pattern. The
percentage of patients with manual dexterity prob-
lems was higher after treatment compared at the
start. In the study of Schoenmakers et al. [3] the
percentage of patients with manual dexterity prob-
lems (11%) was somewhat lower compared to the
percentage of patients reported by Reinders-
Messelink et al. [33] (33.3%). The percentage of
patients with manual dexterity problems in the study
(7.7%) was also lower than the number of patients
reported by Reinders-Messelink et al. [33]. The
patients in the study of Schoenmakers et al. [3] were
the same patients (13 of the 18) tested in the current
study. The outcome might be due to the small sample
size in all these studies. Just like the study of
Schoenmakers et al., gross motor disturbance was
found more frequently occurring than fine motor
problems [3]. Unlike the study of Reinders-
Messeling et al. there were no balance problems
with the patients of the present study. The greatest
problems were seen with the ball skills (hand-eye
co-ordination). A relationship between the motor
problems and vincristine-induced neurotoxicity
seemed plausible, but the effect of other neuro-
toxic drugs, like methotrexate and steroids, could
not be ruled out [33–35].
Strength measurement
The findings of the present study indicates that 5–6
years after treatment muscle strength of the knee
extensors was still reduced compared to reference
values, other muscle groups were within the normal
range, however. This might be explained by the effect
of chemotherapy on muscle fibres (especially type II
fibres) and the neural drive. Harila-Saari et al. [1]
Table V. Anaerobic and aerobic exercise performance of the 13 ALL survivors.
Variables MSD Range Mpredicted SD p-value
Wingate Anaerobic test
Mean power (W) 376.1 (171.9) 163–587 492.9 (276.9) 0.000
Peak power (W) 538.6 (289.6) 218–1094 867.32 (508.2) 0.000
Cardio-pulmonary exercise test
VO
2peak
(L min
1
) 1.99 (0.99) 0.93–3.398 2.69 (1.15) 0.001
VO
2peak/kg
(ml kg
1
min
1
) 36.64 (18.3) 17.15–62.65 49.58 (21.22) 0.001
W
max
(W) 155 (82.41) 60–280 222.98 (97) 0.000
VE
max
(L min
1
) 64.69 (36.1) 27.60–146.5 94.9 (37.9) 0.001
VO
2peak
: peak oxygen uptake; VO
2peak/kg
: peak oxygen uptake related to body mass, W
max
: maximal work load; VE
max
: maximal ventilation.
Table IV. Muscle strength measurement values of six different muscle groups (mean, standard deviations
(SD) and range, z-scores and p-values).
Patients Controls
MSD (range) MSD (range) Z-score p-value
Grip strength 117.4 75.20 (36.0–290.0) 120.5 57.0 (57.4–192.0) 0.32 0.35
Shoulder abductor 161.8 64.17 (75.0–298.0) 144.7 46.2 (93.7–226.3) 0.58 0.1
Knee extensor 252.1 81.13 (129.0–350.0) 299.7 98.9 (166.0–396.0) 0.67 0.001
Foot dorsal flexor 206.6 81.77 (78.0–346.0) 185.7 50.9 (127.5–248.9) 0.41 0.25
Wrist extensor 142.3 68.46 (64.0–280.0) 153.2 66.0 (75.0–237.0) 0.14 0.8
Hip flexor 212.0 78.31 (112.0–336.0) 206.6 65.6 (129.4–291.4) 0.14 0.6
Control values obtained from references [23–25].
Physical function and fitness in long-term survivors of childhood leukaemia 271

showed in their study both demyelination and a loss
of descending motor fibres or loss of muscle fibres in a
population after treatment from childhood ALL,
indicating impairment within both the central and
peripheral motor nervous system. Atrophy of type II
fibres of the proximal muscle, especially those in
the lower limbs, are manifestations of corticosteroid-
related myopathies [36]. Decreased muscle strength
has been identified in young adults surviving ALL in
their childhood [37]. Lehtinen et al. [38] found a
decreased motor nerve conduction in the peripheral
nerves even 5 years after treatment, while 33% of their
population still had clinical neurological findings
[38].
The reason why only a reduced strength in the
knee extensors was used might be explained by the
fact that lower extremity strength appears more
affected than upper extremity strength in decondi-
tioning studies [39]. Especially weight-bearing mus-
cles in the lower extremities are the most affected
muscles during periods of under loading [39].
Anaerobic exercise capacity
The anaerobic exercise capacity of the patients in the
present study was significantly reduced compared to
the control group. This finding is in accordance with
the findings of McKenzie et al. [15] in childhood
and adolescent survivors of solid tumour cancers.
During short-term high intensity exercise such as the
WAnT Type IIa and Type IIx muscle fibres are
heavily recruited [26]. It is well known that during
catabolic periods such as cachexia and corticosteroid
treatment the major amount of muscle atrophy
occurs in type II muscle fibres [36]. Presumably
type I fibres are more resistant to atrophy in these
conditions. Moreover, recent studies suggest that
WAnT performance is also related to intra- and
inter-muscular co-ordination [40]. Thus, the
reduced anaerobic capacity might be a result of
both an impaired motor co-ordination and a reduced
active muscle mass during exercise. In these patients,
deviant scores were also found on the Movement
ABC which could confirm the hypothesis of
impaired motor co-ordination.
CPET
The various parameters of the cardiopulmonary
exercise test indicate a significant decrease of the
aerobic exercise capacity. The VO
2peak
,W
max
and
VE
max
were significantly reduced compared to refer-
ence values, in concordance with other studies [5].
The significantly lower VO
2peak
indicates that the
physical fitness of ALL survivors is reduced com-
pared to healthy children. VO
2peak
is the product of
cardiac output and the arterio-mixed venous oxygen
difference (the Fick equation). Abnormalities in
cardiac output may indicate reduced cardiac func-
tion. The patients had a maximal heart rate between
169–201 beats per min. at maximal exercise with,
respectively, a respiratory exchange ratio between
0.95–1.41. This indicates that ALL survivors can
achieve high heart rates in combination with a
metabolic acidosis, as is usually found in healthy
children. The fact that there was no decrease of the
blood saturation indicates that there was no major
impairment in pulmonary function. The significant
lower aerobic exercise capacity could be due to a
combination of metabolic and neuromuscular
impairments.
There is some evidence that exercise training can
improve physical fitness and health-related quality
of life of leukaemia patients [41, 42]. This improve-
ment makes it a relevant issue in the care for
survivors of ALL. Exercise physiologists and other
professionals could assist in designing appropriate
exercise training programmes for attenuating cancer-
related fatigue and improving physical fitness [36]
in order to help increase physical fitness in children
surviving cancer [43, 44].
Because of the small patient group with a hetero-
geneous age range from a single centre it is difficult
to determine the generalizability of the current
findings. Moreover, the cross-sectional design of
the study does not show the rate of recovery
after the treatment phase. Longitudinal multi-
centre studies should be initiated to study the effects
of the disease, treatment and rehabilitation in this
patient group.
Conclusion
In conclusion, it was found that even 5–6 years after
cessation of therapy there still are clear late effects
of chemotherapy in patients treated for child-
hood leukaemia. Aerobic and anaerobic physical
fitness and motor performance were consider-
ably lower compared to healthy children.
Chemotherapy-induced muscle atrophy, myopathy
and neuropathy might be the cause of the signifi-
cantly reduced test scores. The results indicate that
prescription of exercise in general by health-care
professionals would be advisable so that these
children are encouraged to be just as active as they
were before treatment. If children are already active,
but still have a reduced exercise capacity, a tailored
exercise programme should be initiated.
Acknowledgements
We are grateful to Harrie
¨t Wittink MSc PhD PT
for the revision and correction of the final
272 M. van Brussel et al.

manuscript. This study was funded by the ‘Stichting
Nationaal Fonds tegen Kanker, Amsterdam, the
Netherlands’.
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