Review Article …downloads.hindawi.com/journals/ijpedi/2011/461512.pdfProgress in treatments for childhood cancer have greatly improved cure rates, with 5-year survival now approaching

Hindawi Publishing CorporationInternational Journal of PediatricsVolume 2011, Article ID 461512, 11 pagesdoi:10.1155/2011/461512

Review Article

Exercise Interventions in Children with Cancer: A Review

Tseng-Tien Huang and Kirsten K. Ness

Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA

Correspondence should be addressed to Kirsten K. Ness, [email protected]

Received 8 July 2011; Revised 3 September 2011; Accepted 3 September 2011

Academic Editor: Julie Blatt

Copyright © 2011 T.-T. Huang and K. K. Ness. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

The purpose of this review is to summarize literature that describes the impact of exercise on health and physical functionamong children during and after treatment for cancer. Relevant studies were identified by entering the following search terms intoPubmed: aerobic training; resistance training; stretching; pediatric; children; AND cancer. Reference lists in retrieved manuscriptswere also reviewed to identify additional trials. We include fifteen intervention trials published between 1993 and 2011 thatincluded children younger than age 21 years with cancer diagnoses. Nine included children with an acute lymphoblastic leukemia(ALL) diagnosis, and six children with mixed cancer diagnoses. Generally, interventions tested were either in-hospital supervisedexercise training or home based programs designed to promote physical activity. Early evidence from small studies indicates thatthe effects of exercise include increased cardiopulmonary fitness, improved muscle strength and flexibility, reduced fatigue andimproved physical function. Generalizations to the entire childhood cancer and childhood cancer survivor populations are difficultas most of the work has been done in children during treatment for and among survivors of ALL. Additional randomized studiesare needed to confirm these benefits in larger populations of children with ALL, and in populations with cancer diagnoses otherthan ALL.

1. Introduction

Progress in treatments for childhood cancer have greatlyimproved cure rates, with 5-year survival now approaching80% [1]. This has resulted in a growing population ofchildhood cancer survivors. In 2006, there were more than11 million cancer survivors in the United States; three timesthe number of survivors in 1971 [2]. It is estimated that1 in 810 individuals under the age of 20 is a survivor ofchildhood cancer and that 1 in 640 individuals between theages of 20 and 39 years has successfully survived childhoodcancer [3]. Improving survival rates, however, does not comewithout consequences. Treatment of childhood cancer isassociated with a spectrum of late effects, including impairedgrowth and development, cognitive dysfunction, dimin-ished neurological function, cardiopulmonary compromise,musculoskeletal sequelae, and secondary malignancy [4–6].Oeffinger et al. [6] reported that one-third of childhoodcancer survivors have severe or life-threatening medicalcomplications 30 years after diagnosis. Therefore, attention

today is focused not only on survival but also on the qualityof survival.

Impaired physical fitness has been reported during andafter childhood cancer treatment [7–12]. Impaired physicalfitness typically includes reduced cardiopulmonary function,decreased muscle strength, fatigue, and altered physicalfunction. Treatments for childhood cancer, including radio-therapy, chemotherapy, and surgery, can result in acuteand long-term injury to the heart, lungs, and skeletalmuscles, systems necessary for optimal physical fitness [8,13–19]. Additionally, reduced levels of physical activityboth during and after treatment for childhood cancer cancontribute to cardiac deconditioning and skeletal muscleatrophy, ultimately limiting opportunities for participationin recreational activities and life roles that are dependenton adequate physical fitness. Exercise intervention has thepotential to improve cardiopulmonary and musculoskeletalfunction, perhaps preventing long-term deficits in physicalfitness if incorporated during or soon after treatment inchildren with cancer diagnoses [20–24].

2 International Journal of Pediatrics

Another factor that may be associated with impairedphysical fitness among childhood cancer survivors is cancer-related fatigue. Fatigue during and after treatment has thepotential to have a negative impact on physical activityand on psychosocial well-being. A recent study reportedthat the prevalence of cancer-related fatigue was over threetimes higher in long-term survivors of childhood cancerwhen compared to the general population (OR: 3.29; 95%CI: 1.9–5.70) [25]. In another investigation that evaluatedassociations between demographic and medical factors andhealth-related quality of life (HRQOL) among pediatriccancer survivors, Meeske et al. [26] found that fatigue was themost powerful predictor of functional status and HRQOL.Given that there is evidence that exercise and physical activityprograms can reduce fatigue, and enhance psychosocialhealth in survivors of adult cancer, such interventions mayhave a similar effect in the pediatric population [27].

This review of the literature indicates that there isgrowing evidence for the positive effects of physical trainingon organ system function, fatigue and physical well-beingin children during and after treatment for cancer [20,28]. However, the optimal intervention modality and theintensity, timing, and duration of the intervention aredifficult to determine. In the published literature, very fewexercise interventions undertaken in the pediatric cancer orpediatric cancer survivor populations have been randomizedclinical trials, and, across studies, the components of aerobictraining, resistance, and flexibility exercises are implementedwith differing intensity, timing, and duration. In addition,the sample sizes are small, limited primarily to studypopulations with acute leukemia diagnoses, and includewidely varied outcome measures, making it difficult to drawfirm conclusions or compare results between trials. We sum-marize here the literature that describes the effects of exerciseintervention on immune system function, cardiopulmonaryhealth, skeletal muscle strength, fatigue, and overall physicalwell-being among children during and after treatment forcancer.

2. Methods and Search Results

This paper summarizes exercise intervention studies amongchildren with cancer and is limited to studies that tested ordescribed exercise intervention in children diagnosed witha primary pediatric cancer when younger than 21 yearsof age, and, includes only manuscripts available as full-text in the English language. Studies were identified bysearching the PUBMED database with the terms exercise;aerobic training; resistance training; stretching; pediatric;children; cancer. Reference lists of retrieved studies werealso assessed to identify additional trials. The search of thePubmed database initially resulted in a total of 48 citations.Of these, we excluded 31 citations (3 review only, 5 notavailable in English, 17 no exercise intervention, and 6 adult-cancer survivors only). We include 17 published manuscriptsdocumenting 15 studies published by June of 2011. A reviewof the reference lists from the retrieved manuscripts did notidentify any additional papers. When reporting the outcomes

of each study, if numerical results were available, effectsizes were converted to Cohen’s d, representing standarddeviations of change or differences in standard deviationsbetween groups [29], to allow for easier comparison of themagnitude of the exercise intervention responses amongstudies.

2.1. Exercise Intervention Studies among Pediatric Survivors.A summary of the 15 published studies included in thisreview examining exercise intervention for children withcancer is shown in Tables 1 and 2. A total of 302 childrenwith cancer, survivors of childhood cancer, or normalcontrols participated in the 15 trials; 46 were young adults[30] and 256 were children or adolescents [21–23, 31–43]. Of these 15 exercise interventions during or afterpediatric cancer treatment, seven included a control groupor control intervention, nine employed supervised trainingwith aerobic, resistance, and/or flexibility training with orwithout home-based exercises [21–23, 31–40, 43], five testedenhanced physical activity (EPA) interventions [30, 34, 36,39, 42], and one used an individualized home-based exerciseprogram [41]. We differentiate between nonrandomized(Table 1) and randomized trials (Table 2) to highlight theneed for additional experimental evidence to evaluate theeffects of exercise intervention for children with cancer.Only 121 children with cancer diagnoses have participatedin four randomized controlled trials; 41 were children andadolescents with ALL during maintenance chemotherapy[21, 36] and 70 were the survivors of childhood cancerwith mixed diagnoses [33, 42]. We also differentiate betweenexercise and EPA by noting that exercise implies a specifictraining regimen with established frequency, intensity, andduration and that EPA includes dynamic activities completedduring the performance of everyday tasks [44]. The majorityof the interventions included only patients with acutelymphoblastic leukemia (ALL) diagnoses; only six studieswere done in study populations with mixed diagnoses [30,31, 34, 38, 39, 42]. One study was completed in children withALL during the first six months of medical treatment [32],and six were completed among children with ALL duringthe maintenance or continuation phase of medical treatment[21, 23, 35–37, 43]. Outcome measures described included(1) immunological function [31, 35], (2) cardiovascularfitness [21–23, 35, 36, 38, 40], (3) muscle strength andflexibility [21–23, 33, 34, 36, 40, 43], (4) fatigue or sleepefficacy [30, 34, 40–42], (5) general physical function [9, 21,32, 33, 36, 40], and (6) quality of life [9, 21, 32, 34, 39].

2.2. Effect of Exercise on Immune Suppression and GrowthFactors. Chemotherapy treatment for pediatric cancer sup-presses the immune system and may interfere with normalgrowth, increasing susceptibility to infection and stuntingor delaying musculoskeletal development during treatment[45–47]. Concern about the effects of exercise on immunefunction and growth factors includes the possibility thatexercise may tax an already compromised immune orendocrine system and either delay recovery or further impactnormal skeletal growth [48]. A pilot study by Ladha et al.

International Journal of Pediatrics 3

Ta

ble

1:D

escr

ipti

onof

non

-ran

dom

ized

exer

cise

tria

lsin

child

ren

wit

hca

nce

r.

Firs

tau

thor

and

year

Des

ign

Dem

ogra

phic

sE

xerc

ise

inte

rven

tion

(typ

eof

trai

nin

g,fr

equ

ency

,an

ddu

rati

on)

∗ Mai

nou

tcom

es

Shar

key,

1993

[38]

.P

rete

st/p

ostt

est

tria

l

N=

10.

Mix

edca

nce

rty

pes

.5

mal

es.M

ean

age

atth

eti

me

ofth

est

udy

:19±

3yr

s.

Inte

rven

tion

:aer

obic

trai

nin

gw

ith

hom

eex

erci

setw

ice

per

wee

k(w

eek

1-2

star

ted

wit

h15

min

ute

sof

war

m-u

p,15

min

ute

sof

exer

cise

at60

%of

HR

max

and

15m

inu

tes

ofco

ol-d

own

,wee

k3–

630

min

ute

sof

exer

cise

at70

–80%

HR

max

,an

dw

eek

7–12

30m

inu

tes

ofae

robi

cex

erci

seat

70–8

0%H

Rm

axpl

us

hom

eex

erci

seon

cep

erw

eek)

.D

ura

tion

:12

wee

ksof

out-

pati

ent

card

iac

reh

abili

tati

on.

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yfa

t(−

),sp

irom

etry

(−),

pea

kh

eart

rate

(−),

pea

kox

ygen

upt

ake

(−),

anae

robi

cth

resh

old

(−),

peak

card

iac

inde

x(−

),p

eak

stro

kevo

lum

ein

dex

(−),

orva

scu

lar

resi

stan

ce(−

).E

xerc

ise

tim

e(+

13%

).

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a,20

06[3

5].

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ran

dom

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safe

tyas

sess

men

tw

ith

both

aca

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ran

da

hea

lthy

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trol

popu

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ther

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ean

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min

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m-u

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nd

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alk

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age-

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lthy

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ects

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the

sam

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enti

on.

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rati

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0m

inu

tes

ofac

ute

bou

tofe

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An

acu

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dn

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any

sign

ifica

nt

neg

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ects

onn

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ilco

un

t.

San

Juan

,200

7[4

3]Sa

nJu

an,2

007

[23]

Ru

iz,2

010

[37]

Pre

test

/pos

ttes

ttr

ial

N=

7.C

hild

ren

rece

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gm

ain

ten

ance

ther

apy

for

ALL

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ys.M

ean

age

atth

eti

me

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est

udy

:5.

1±

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yrs.

Inte

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:th

ree

wee

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sess

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s(9

0–12

0m

inu

tes)

ofsu

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ised

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stan

cetr

ain

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(ben

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pres

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gex

ten

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ull-

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etit

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s)an

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robi

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se(s

tart

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ith

10m

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ofex

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ses

at50

%of

age-

pred

icte

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Rm

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ogre

ssed

to30

min

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sof

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tin

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sex

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0%H

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axby

the

end

ofth

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from

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fact

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(−),

and

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grow

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ng

prot

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s(−

).

4 International Journal of PediatricsT

abl

e1:

Con

tin

ued

.

Firs

tau

thor

and

year

Des

ign

Dem

ogra

phic

sE

xerc

ise

inte

rven

tion

(typ

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trai

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equ

ency

,an

ddu

rati

on)

∗ Mai

nou

tcom

es

Kea

tsan

dC

ulo

s-R

eed,

2008

[34]

.P

rete

st/p

ostt

est

tria

l.N=

10.A

dole

scen

tsw

ith

can

cer.

2m

ales

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nag

eat

the

tim

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the

stu

dy:1

6.2±

1.6

(ran

ge14

–18)

yrs

Inte

rven

tion

:phy

sica

lact

ivit

yan

ded

uca

tion

alin

terv

enti

on(3

0m

inu

tes

ofed

uca

tion

alse

ssio

n,4

5m

inu

tes

ofae

robi

ctr

ain

ing,

and

15m

inu

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ofco

rest

ren

gth

and

flex

ibili

tytr

ain

ing

inth

efi

rst

8w

eeks

;ava

riet

yof

non

com

peti

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phys

ical

acti

viti

esin

the

fin

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wee

ks)

Du

rati

on:1

6w

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oup-

base

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tyin

terv

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on.

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enda

nce

rate

:81.

5%ov

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-wee

kin

terv

enti

on.

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erbo

dyst

ren

gth

(+),

flex

ibili

ty(+

),to

talP

A(+

),Q

OL

(+),

and

gen

eral

fati

gue

(+).

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icip

ants

faile

dto

mai

nta

inth

eir

post

inte

rven

tion

PAle

vels

atbo

th3-

and

12-m

onth

follo

w-u

pti

me

poi

nts

.

San

Juan

,200

8[2

2].

Pre

test

/pos

ttes

ttr

ial.

N=

8.C

hild

ren

afte

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for

leu

kem

ia.4

boys

.M

ean

age

atth

eti

me

ofth

est

udy

:10.

9±

2.8

yrs.

Inte

rven

tion

:th

ree

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s(9

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late

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peti

tion

s)an

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cex

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se(s

tart

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ith

10m

inu

tes

ofex

erci

ses

at50

%of

age-

pred

icte

dH

Rm

axan

dpr

ogre

ssed

to30

min

ute

sof

con

tin

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sex

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seat≥7

0%H

Rm

axby

the

end

ofth

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rati

on:8

wee

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t

Mu

scle

stre

ngt

h(+

),V

O2

pea

k(+

),fu

nct

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alm

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)(T

UD

s,3-

and

10-m

eter

TU

G)

and

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-rep

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s(+

).B

MI

(−),

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vean

dpa

ssiv

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),V

T(−

),or

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ax(−

).

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en,2

009

[40]

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ostt

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hild

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wit

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LL.M

ean

age

atth

eti

me

ofth

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:9.3±

3.2

(ran

ge6–

14)

yrs

Inte

rven

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:tw

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ns

(45

min

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s)of

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ond

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exer

cise

(66–

77%

ofH

Rm

axin

firs

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ks,

77–9

0%H

Rm

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follo

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ks,

and≥9

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axin

the

last

4w

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)an

da

hom

e-ba

sed

exer

cise

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ram

(str

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h,

flex

ibili

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nd

aero

bic

fitn

ess)

.D

ura

tion

:12

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omm

un

ity-

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dex

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m

Seve

nty

per

cen

tof

trai

ner

sw

ere

sati

sfied

wit

hth

epr

ogra

m.B

MI

(−),

mu

scle

stre

ngt

h(−

),ex

erci

seca

paci

ty(−

),fu

nct

ion

alm

obili

ty(−

),or

fati

gue

leve

ls(−

).

Bla

auw

broe

k,20

09[3

0].

Pre

test

/pos

ttes

ttr

ial.

N=

38.A

dult

surv

ivor

sof

child

hoo

dca

nce

r(m

ixed

can

cer

type

s).1

4m

ales

.Age

atdi

agn

osis

8.1±

6.7

year

s;ti

me

sin

cedi

agn

osis

21.8±

7.1

year

s.M

ean

age

atth

eti

me

ofth

est

udy

:29.

8±

8.6

yrs

Inte

rven

tion

:en

han

ced

phys

ical

acti

vity

(su

chas

wal

kin

g,cy

clin

g,h

ouse

keep

ing,

and

gard

enin

g)co

un

selin

g.T

he

cou

nse

lor

enco

ura

ged

the

surv

ivor

sto

chan

geth

eir

lifes

tyle

and

enh

ance

daily

phys

ical

acti

vity

tom

eet

publ

ish

edex

erci

segu

idel

ines

(i.e

.,at

leas

t15

0m

inu

tes

ofm

oder

ate-

to-v

igor

ous

exer

cise

/wee

k)an

dph

oned

the

surv

ivor

sat

thre

ew

eeks

,six

wee

ks,a

nd

nic

ew

eeks

toch

eck

goal

s.Fe

edba

ckfr

oma

ped

omet

er.

Du

rati

on:1

0w

eeks

ofco

un

selin

g.

Sign

ifica

nt

impr

ovem

ents

infa

tigu

ean

dda

ilyst

eps

afte

rin

terv

enti

on.T

her

ew

asa

low

corr

elat

ion

(0.1

2)be

twee

nin

crea

sein

daily

step

san

dth

ede

crea

sein

fati

gue.

International Journal of Pediatrics 5T

abl

e1:

Con

tin

ued

.

Firs

tau

thor

and

year

Des

ign

Dem

ogra

phic

sE

xerc

ise

inte

rven

tion

(typ

eof

trai

nin

g,fr

equ

ency

,an

ddu

rati

on)

∗ Mai

nou

tcom

es

Spey

er,2

010

[39]

.C

ross

-ove

r,si

ngl

est

udy

desi

gn.

N=

30.C

hild

ren

wit

hca

nce

r(h

emat

olog

icm

alig

nan

cy:1

5,so

lidtu

mor

s:12

,un

know

n:3

).18

mal

es.M

ean

age

atth

eti

me

ofth

est

udy

:13.

6±

2.9

yrs.

Inte

rven

tion

:th

ree

wee

kly

sess

ion

s(3

0m

inu

tes)

ofad

apte

dph

ysic

alac

tivi

ty(b

all

gam

es,c

ircu

sar

ts,t

hro

win

gga

mes

,sh

ooti

ng

gam

es,r

acke

tsp

orts

,vid

eoga

mes

,an

dbo

dybu

ildin

g).

Con

trol

:sta

nda

rdca

rew

ith

out

adap

ted

phys

ical

acti

vity

.D

ura

tion

:fou

rp

erio

dsof

enh

ance

dph

ysic

alac

tivi

ty(c

ross

-ove

r).

QO

Lsc

ores

inph

ysic

alan

dps

ych

olog

ical

dim

ensi

ons

wer

eh

igh

erfo

rth

ech

ildre

nw

ho

prac

tice

dth

anfo

rth

ose

wh

odi

dn

otpr

acti

cead

apte

dph

ysic

alac

tivi

tydu

rin

gh

ospi

taliz

atio

n.

Ch

amor

ro-V

ina,

2010

[31]

.N

onra

ndo

miz

edco

ntr

olle

dtr

ial.

Inte

rven

tion

grou

p:N=

7.C

hild

ren

wh

oh

adu

nde

rgon

eH

CT.

5bo

ys.M

ean

age

atth

eti

me

ofth

est

udy

:8±

4yr

s.C

ontr

olgr

oup:N=

13.9

boys

.Mea

nag

eat

the

tim

eof

the

stu

dy:7±

3yr

s.

Inte

rven

tion

:Fiv

ew

eekl

yse

ssio

ns

( ∼50

min

ute

s)of

supe

rvis

edre

sist

ance

trai

nin

g(a

rmcu

rl,e

lbow

exte

nsi

on,b

ench

pres

s,lo

gex

ten

sion

,hal

fsqu

at,a

bdom

inal

cru

nch

,su

pin

ebr

idge

,an

dro

win

g;12

–15

repe

titi

ons)

(str

etch

ing

exer

cise

invo

lvin

gal

lmaj

orm

usc

legr

oups

)an

dae

robi

cex

erci

se(1

0–40

min

ute

sof

cycl

eer

gom

etry

at50

%to

70%

ofH

Rm

ax).

Con

trol

:sta

nda

rdca

re.

Du

rati

on:3

wee

ks,d

uri

ng

trea

tmen

t.

Fitn

ess

leve

ls(+

)(h

alf

squ

at)

orbo

dym

ass

(+).

Exe

rcis

ein

terv

enti

ondu

rin

gin

pati

ent

stay

for

HC

Tdi

dn

otaff

ect

imm

un

ece

llre

cove

ryin

you

ng

child

ren

wit

hh

igh

-ris

kca

nce

r.

Yeh

,201

1[4

1].

Non

ran

dom

ized

con

trol

led

tria

l.

Inte

rven

tion

grou

p:N=

12.C

hild

ren

and

adol

esce

nts

wit

hA

LL.6

boys

.Mea

nag

eat

the

tim

eof

the

stu

dy:1

1±

4yr

s.C

ontr

olgr

oup:

N=

10.6

boys

.Mea

nag

eat

the

tim

eof

the

stu

dy:

12.5±

4yr

s.

Inte

rven

tion

:th

ree

wee

kly

sess

ion

s(3

0m

inu

tes)

ofin

divi

dual

ized

hom

e-ba

sed

aero

bic

exer

cise

prog

ram

(exe

rcis

ein

ten

sity

:40

%–6

0%of

HR

R)

Con

trol

:sta

nda

rdca

reD

ura

tion

:6w

eeks

,du

rin

gtr

eatm

ent

Gen

eral

fati

gue

(+).

Slee

p/re

stan

dco

gnit

ive

fati

gue

scor

es(−

).

Goh

ar,2

011

[32]

.P

rete

st/p

ostt

est

tria

l.N=

9.C

hild

ren

wit

hA

LL.3

mal

es.M

edia

nag

eat

tim

eof

the

stu

dy:4

(ran

ge2–

14)

yrs

Inte

rven

tion

:in

divi

dual

ized

hom

e-ba

sed

exer

cise

prog

ram

(str

etch

ing

exer

cise

:an

kle

dors

iflex

ion

;5da

ys/w

eek,

stre

ngt

hen

ing

exer

cise

:low

er-

and

upp

er-e

xtre

mit

yex

erci

se;

10re

peti

tion

s5

days

/wee

k,an

dae

robi

cex

erci

se:w

alki

ng,

bike

ridi

ng,

and

dan

cin

g10

–30

min

ute

s;5

days

/wee

k).

Du

rati

on:6

-7m

onth

s,du

rin

gtr

eatm

ent.

Gro

ssm

otor

fun

ctio

n(+

)an

dQ

OL

mea

sure

s(+

)th

rou

ghou

tth

est

udy

(at

diag

nos

is,i

ndu

ctio

n,

con

solid

atio

n,i

nte

rim

mai

nte

nan

ce,a

nd

dela

yed

inte

nsi

fica

tion

).H

owev

er,

QO

Lsc

ores

decr

ease

dfr

omin

teri

mm

ain

ten

ance

tode

laye

din

ten

sifi

cati

on.T

he

pare

nts

repo

rted

bein

gsa

tisfi

edw

ith

the

PT

prog

ram

.∗

(+)

toin

dica

tea

sign

ifica

nt

effec

t;(−

)to

indi

cate

no

sign

ifica

nt

effec

t/ch

ange

.A

LL:

acu

tely

mph

obla

stic

leu

kem

ia;

AM

L:ac

ute

mye

loid

leu

kem

ia;

BM

D:

bon

em

iner

alde

nsi

ty;

BM

I:bo

dym

ass

inde

x;C

NS:

cen

tral

ner

vou

ssy

stem

;H

RR

:h

eart

rate

rese

rve;

HC

T:

hem

atop

oiet

icst

emce

lltr

ansp

lan

t;PA

:phy

sica

lact

ivit

y;P

T:p

hysi

calt

her

apy;

QO

L:qu

alit

yof

life;

VO

2pe

ak:p

eak

aero

bic

fitn

ess;

HR

max

:max

imu

mof

hea

rtra

te;T

UD

s:ti

me

up

and

dow

nst

air

test

;TU

G:t

imed

up

and

gote

st;V

T:

ven

tila

tory

thre

shol

d.


Ta

ble

2:D

escr

ipti

onof

the

ran

dom

ized

exer

cise

tria

lsin

child

ren

wit

hca

nce

r.

Firs

tau

thor

and

year

Dem

ogra

phic

sE

xerc

ise

inte

rven

tion

(typ

eof

trai

nin

g,fr

equ

ency

,an

ddu

rati

on)∗ M

ain

outc

omes

Mar

ches

e,20

04[2

1].

Inte

rven

tion

grou

p:N=

13.

ALL

rece

ivin

gm

ain

ten

ance

ther

apy.

8m

ales

.M

ean

age

atth

eti

me

ofth

est

udy

:7.6

(ran

ge,

4.3–

10.6

)yr

s.C

ontr

olgr

oup:N=

15.

12m

ales

.M

ean

age

atth

eti

me

ofth

est

udy

:8.6

(ran

ge5.

1–15

.8)

yrs

Inte

rven

tion

:five

sess

ion

s(2

0to

60m

inu

tes

imm

edia

tely

afte

rin

itia

ltes

tin

g,an

d2,

4,8,

and

12w

eeks

late

r)of

PT

(str

etch

ing

and

stre

ngt

hen

ing

exer

cise

s,su

perv

ised

)an

dan

indi

vidu

aliz

edh

ome-

base

dex

erci

sepr

ogra

m(b

ilate

rala

nkl

edo

rsifl

exio

nst

retc

hin

gfo

r30

sec

5da

ysp

erw

eek,

bila

tera

llow

erex

trem

ity

stre

ngt

hen

ing

3se

ts,3

days

per

wee

k,an

dae

robi

cex

erci

ses)

.C

ontr

ol:n

oin

stru

ctio

ns

rela

ted

toph

ysic

alfi

tnes

san

dn

oP

Tin

terv

enti

on.

Du

rati

on:1

6w

eeks

,du

rin

gtr

eatm

ent.

Hem

oglo

bin

leve

l(−)

,an

kle

dors

iflex

ion

stre

ngt

h(−

),T

UD

s(−

),9-

min

ute

wal

k-ru

n(−

),an

dQ

OL

(−).

An

kle

dors

iflex

ion

ran

geof

mot

ion

(act

ive)

and

knee

exte

nsi

onst

ren

gth

incr

ease

din

inte

rven

tion

grou

pfr

ombe

fore

toaf

ter

test

.

Hin

ds,2

007

[42]

.

Inte

rven

tion

grou

p:N=

14.C

hild

ren

and

adol

esce

nts

wit

hca

nce

r.9

mal

es.M

ean

age

atth

eti

me

ofth

est

udy

:13.

0(r

ange

8.5–

17.4

)yr

sC

ontr

olgr

oup:N=

15.3

mal

es.M

ean

age

atth

eti

me

ofth

est

udy

:11.

9(r

ange

7.4–

18.1

)yr

s

Inte

rven

tion

:en

han

ced

phys

ical

acti

vity

(ped

alin

ga

stat

ion

ary

bike

-sty

leex

erci

ser,

30m

inu

tes,

twic

eda

ilydu

rin

gbr

ief

hos

pita

lizat

ion

).C

ontr

ol:s

tan

dard

care

.D

ura

tion

:2–4

days

,du

rin

gtr

eatm

ent.

Slee

peffi

cien

cy(+

).

Moy

er-M

ileu

r,20

09[3

6].

Inte

rven

tion

grou

p:N=

6.C

hild

ren

rece

ivin

gm

ain

ten

ance

ther

apy

for

ALL

.3m

ales

.Mea

nag

eat

the

tim

eof

the

stu

dy:7

.2±

0.7

yrs.

Con

trol

grou

p:N=

7.4

mal

es.M

ean

age

atth

eti

me

ofth

est

udy

:5.9±

0.7

yrs.

Inte

rven

tion

:an

indi

vidu

aliz

edex

erci

sepr

ogra

m(t

hre

e15

–20-

min

ute

sess

ion

sof

mod

erat

e-to

-vig

orou

sac

tivi

typ

erw

eek)

and

nu

trit

ion

aled

uca

tion

.C

ontr

ol:r

ecei

ved

stan

dard

diet

reco

mm

enda

tion

and

perf

orm

edac

tivi

tyas

tole

rate

d.D

ura

tion

:12

mon

ths,

enh

ance

dph

ysic

alac

tivi

typr

ogra

m

Nu

trie

nt

inta

ke(−

),h

eigh

t(−

),w

eigh

t(−

),or

BM

I(−

)be

twee

nin

terv

enti

onan

dco

ntr

olgr

oups

.No

inte

rven

tion

effec

tfo

ru

pper

body

stre

ngt

h(p

ush

-up

com

plet

ed)

orfl

exib

ility

(sit

and

reac

hdi

stan

ce).

Self

-rep

orte

dPA

(+)

and

aca

rdio

vasc

ula

rfi

tnes

s(+

).

Har

tman

,200

9[3

3].

Inte

rven

tion

grou

p:N=

25.

Ch

ildre

nw

ith

ALL

.14

boys

.Med

ian

age

atth

eti

me

ofth

est

udy

:5.3

(ran

ge1.

3–15

.6)

yrs.

Con

trol

grou

p:N=

26.1

6bo

ys.M

edia

nag

eat

the

tim

eof

the

stu

dy:6

.2(r

ange

1.7–

17.1

)yr

s.

Inte

rven

tion

:pre

ven

tive

PT

prog

ram

(wee

kly

stre

ngt

hen

ing

and

stre

tch

ing

exer

cise

and

shor

t-bu

rst

hig

h-i

nte

nsi

tyex

erci

sein

BM

Dtw

ice

per

wee

k).

Con

trol

:sta

nda

rdca

re.

Du

rati

on:2

year

s,du

rin

gtr

eatm

ent.

Perc

enta

geof

body

fat

(−)

orle

ssbo

dym

ass

(−).

BM

Dde

crea

sed

sign

ifica

ntl

yin

both

grou

psbe

twee

nth

est

art

and

end

oftr

eatm

ent.

Mot

orp

erfo

rman

ce(−

)or

ankl

edo

rsifl

exio

nra

nge

ofm

otio

n(−

)be

twee

ngr

oups

.∗

(+)

toin

dica

tea

sign

ifica

nt

effec

t;(−

)to

indi

cate

no

sign

ifica

nt

effec

t/ch

ange

.A

LL:a

cute

lym

phob

last

icle

uke

mia

;BM

D:b

one

min

eral

den

sity

;BM

I:bo

dym

ass

inde

x;PA

:phy

sica

lact

ivit

y;P

T:p

hysi

calt

her

apy;

QO

L:qu

alit

yof

life;

TU

Ds:

tim

eu

pan

ddo

wn

stai

rte

st.


[35] investigated the effects of an acute bout (30 minutes) ofexercise (heart rate 70–85% of peak oxygen uptake capacity(VO2 peak)) on neutrophil counts and immune functionin children undergoing maintenance therapy for ALL (n =4; mean age 11.3 ± 5.3 years). They found no deleteriouseffects of this intervention on immune function. Their workis supported by Chamorro-Vina et al. who demonstratedthat a daily 3-week in-hospital moderate intensity exercisetraining regimen, including both supervised resistance andaerobic components, did not affect immune cell recoveryin 7 children who had undergone hematopoietic stemcell transplantation [31]. This same group of authors alsoreport no significant impact of a 3 times per week 16-week aerobic and resistance training intervention on levelsof growth hormone, insulin-like growth factors, and insulin-like growth binding proteins levels (IGFBP-2 and -3) [37]in children with ALL. In this study, protein levels of IGFBPsremained stable even after 20 weeks of detraining.

2.3. Effect of Exercise on the Cardiopulmonary System. Cardi-opulmonary fitness is impaired in children during treatmentand among survivors of childhood cancer [9, 10]. Reports ofthe effects of exercise intervention on the cardiopulmonarysystem during treatment are mixed. Marchese et al. [21]examined effects of exercise on cardiovascular response inchildren (aged 4–15 years) receiving maintenance therapyfor ALL. Participants were randomly assigned into a physicaltherapy (PT) intervention group with home-based aerobictraining two times per week (n = 13) or a control (non-PT intervention) group (n = 15). Following a four-monthintervention, these authors reported no cardiopulmonaryresponse to training as assessed by a nine minute run-walk test. Additionally, more than 50% of the childrenscored below the 25th percentile for cardiopulmonary fitnesswhen compared to the normative sample in the AmericanAlliance of Health, Physical Education, Recreation andDance Association Guidelines at both the pre- and posttestassessments. Similarly, Takken et al. [40] implemented a12-week community-based exercise program in 9 childrenwith ALL (aged 6–14 years) and found no cardiopulmonaryresponse to training as assessed by standardized cardiopul-monary exercise testing. Of note, some children in thisstudy complained that the training program was boring,too intense, and hard to combine with their other activitieswhich may have limited compliance. Moyer-Mileur et al.[36], who provided a home-based intervention to childrenwith ALL during the maintenance phase of chemotherapy,report slightly more promising results. In a much longerduration intervention, with a perhaps more palatable inten-sity of training, they assigned thirteen 4–10-year-old childrento either 15–20 minutes of moderate to vigorous physicalactivity 3 times per week (n = 6) or to no intervention(n = 7). After 12 months, regular physical activity andcardiopulmonary fitness were assessed with a pedometer anda Progressive Aerobic Cardiovascular Endurance Run test(PACER) [49], respectively. The authors reported that theexercise group recorded more steps on the pedometer (P =0.06, Cohen’s d = 1.12) and performed slightly better on the

PACER (P = 0.05, Cohen’s d = 1.22) than the control groupat the end of the intervention.

It appears that hospital type supervised exercise inter-ventions have better cardiopulmonary outcomes than dothose that are home or community based. San Juan et al. [9]reported positive results after implementation of a 16-weeksupervised (in-person) exercise program among 7 childrenwith ALL, 4–7 years of age, also during the maintenancephase of chemotherapy. Their study population achieveda significant increase in both ventilatory threshold (beforetraining 15.8 ± 3.3; after training 20.7 ± 2.9 milliliters perkilogram per minute (mL/kg/min), P < 0.05, Cohen’s d =1.58) and peak oxygen uptake (before training 24.3 ± 5.9;after training 30.2 ± 6.2 mL/kg/min, P < 0.05, Cohen’sd = 0.97). A subsequent study by San Juan et al. [9] showedsimilar benefits for an 8-week supervised exercise trainingprogram among 8 children after HCT.

Supervised exercise training also appears to have promisefor childhood cancer survivors with long-term cardiopul-monary compromise. A study by Sharkey et al. [38] exam-ined the effects of a 12-week aerobic training programamong childhood cancer survivors who had been treatedwith anthracycline chemotherapy (cumulative dosage 349 ±69 milligrams per meter squared (mg/m2)). Among the 10patients who completed the twice weekly program (mean age19 ± 3 years; mean time since diagnosis 8 ± 4 years), therewas an average increase in exercise time on cardiopulmonaryexercise testing (CPET) of 13 percent (%) from before toafter test (P < 0.05, Cohen’s d = 0.47). They also reporteda trend toward improvement in peak oxygen uptake (P =NS, Cohen’s d = 0.36) and anaerobic threshold (P = NS,Cohen’s d = 0.58), but no significant changes in bodyfat, spirometer parameters, cardiac index, or stroke volumeindex. Unfortunately, although these 10 participants showedsome improvement in exercise tolerance, their exercisecapacity remained substantially lower than those of normalsubjects.

2.4. Effect of Exercise on the Musculoskeletal System. Cancertherapy in children also impacts the musculoskeletal system.Limited range of motion, loss of muscle mass, and reducedmuscle strength are common among children with cancerand among survivors [33, 50–52]. Fortunately, the earlyintervention research targeting these impairments is verypromising. Improved muscle strength and flexibility isreported following training among children during mainte-nance therapy for ALL [9, 21] and in groups of children withmixed cancer diagnoses [34]. In their 12-week home-basedPT intervention for children during maintenance therapy forALL (n = 13 intervention group, n = 15 control group),Marchese et al. [21] reported that stretching and resistancetraining improved ankle range of motion (P < 0.01, Cohen’sd = 0.62) and knee extension strength (P < 0.01, Cohen’sd = 0.35). In another intervention during ALL maintenancetherapy among 7 children 4–7 years of age, San Juan et al. [9]implemented resistance training for the major muscle groupsand reported muscle strength gains (P < 0.05, Cohen’s d =0.85 to 1.48) after just eight weeks of training [9]. These gains


were maintained after a 20-week detraining period [9]. In alonger intervention program (2 years) designed to preventbone loss in children during treatment for ALL (interventiongroup n = 25, control group n = 26) Hartman et al. [33]reported that stretching and twice daily short-burst high-intensity exercise resulted in improved dorsiflexion range ofmotion (P = 0.001, Cohen’s d = 0.94), but not in improvedbone health. In a group-based physical activity interventionwith a group of adolescent cancer survivors with mixeddiagnoses (n = 10), Keats and Culos-Reed [34] reportedimproved upper body strength (P < 0.05, Cohen’s d = 0.64)after 16 weeks of participation.

2.5. Effect of Exercise on Fatigue. Fatigue is a commonsymptom in children during and following cancer treatment[53, 54]. Both exercise and EPA type interventions showsome efficacy in the management of fatigue during andafter cancer chemotherapy in children [30, 34]. However,it appears that fatigue reduction also requires a trainingresponse. In three studies, where the response to training waspositive, fatigue reduction was evident and even persisted,whereas in one study, where the exercise response was null,so was the fatigue reduction response. Yeh et al. [41] reportedreduced levels of fatigue (P = 0.03, Cohen’s d = 0.54)among children with ALL (n = 12) who completed a six-week home-based aerobic exercise program when comparedto a control group who did not (n = 10), and Blaauwbroeket al. [30] reported reduced levels of fatigue (P < 0.005,Cohen’s d = −0.92) and increased levels of physical activity(P < 0.005, Cohen’s d = 0.94) after 10 weeks of a home-based physical activity counseling intervention in childhoodcancer survivors. The Blaauwbroek study was implementedin survivors (n = 38) who were on average 30 yearsof age and 22 years from their original cancer diagnosis.Importantly, fatigue reduction was maintained in their studypopulation at a three-year follow-up time point. The resultsof a study by Keats and Culos-Reed [34] also demonstrateda reduction in fatigue (P = 0.01, Cohen’s d = 0.69)after a 16-week group-based physical activity intervention insurvivors of pediatric cancer (n = 10). In contrast, a 12-weekcommunity-based exercise training program where there wasno exercise response, perhaps because of noncompliance,also demonstrated no fatigue reduction response (P = NS,Cohen’s d = −0.26) [40].

2.6. Effect of Exercise on General Physical Functioning. Sup-pressed immune system function, poor cardiopulmonaryfitness, reduced muscle strength, and fatigue may decreasethe ability of a child with cancer or a childhood cancer sur-vivor to participate comfortably in regular physical activity.Implementation of a program of exercise or EPA, on theother hand, may improve their strength and fitness and, if italleviates fatigue, may increase ease of movement and enableactivities that have a physical component. The evidence forefficacy of exercise and EPA programs to improve overallphysical functioning and mobility in survivors of pediatriccancer is mixed. Among children with ALL, four differentexercise intervention studies have documented the beneficial

effects of a supervised training program or home-basedexercise [9, 32] on general physical functioning, whereasthree other studies have failed to find a positive effectof exercise on physical functioning [21, 33, 40]. Like theimpact of exercise on fatigue, the impact of exercise onphysical functioning appears to require that the interventionhave a training effect. San Juan et al. in their series ofthree manuscripts (n = 7) demonstrated that a supervisedtraining program among young children with ALL or inchildren following HCT, consisting of both resistance andaerobic exercises, improved not only muscle strength andcardiopulmonary fitness but also functional mobility asassessed by performance on three and ten meter timedup and go (TUG) tests (Cohen’s d −0.63 to −1.53, P <0.05) [9]. Gohar et al. [32] reported improved gross motorfunction in nine children after implementing individualizedhome-based exercise programs during the early phases oftreatment for ALL in nine children. However, the twelve-week supervised community-based intervention by Takkenet al. [40] among 9 children during the maintenance phaseof ALL treatment that had no training effect also had noimpact on functional mobility. Additionally, Marchese et al.[21], who demonstrated improvements in ankle range ofmotion and knee extension strength, but no improvementsin cardiopulmonary fitness (P = 0.25, Cohen’s d = 0.57)after implementation of a 16-week home program duringmaintenance therapy for children (intervention group n =13, control group n = 15) with ALL, also reported noimprovements in performance on the TUG test (P = 0.17,Cohen’s d = −0.55).

2.7. Effect of Exercise on Health-Related Quality of Life. Sixof the studies we reviewed reported a health-related qualityof life outcome (HRQOL) in response to exercise trainingor EPA [9, 21, 32, 34, 39]. Four reported a positive effectand two no effect. Positive effects were found in threestudies with no control population, making it difficult toattribute the outcomes to the intervention rather than todevelopmental maturation or disease recovery. Gohar et al.[32] and Speyer et al. [39] both report overall improvementin HRQOL in response (P < 0.001, Cohen’s d = 1.43 to 2.32)to an individualized home-based exercise intervention [32]or to an in-hospital adapted physical activity intervention[39] among children during acute phases of treatment.Interestingly, the study by Gohar et al. [32] reported an initialreduction in HRQOL when chemotherapy was intensifiedduring treatment among 9 children with ALL. San Juan etal. [9] also reported improved HRQOL (P < 0.05, Cohen’sd = 1.1) in response to their 8-week long supervised exerciseintervention among 8 children following HCT, and Keatsand Culos-Reed [34], in a group of 10 adolescent cancersurvivors with mixed diagnoses, reported improved HRQOL(P = 0.01, Cohen’s d = 0.34) after a sixteen-week physicalactivity and educational intervention. These results in theadolescent survivors of mixed diagnoses persisted for at leastone year following the end of the intervention. In contrast tothe results of their study among children following HCT, SanJuan et al. reported no effect of exercise training on HRQOL


(P = NS, Cohen’s d = 0.31 to 0.58) among 7 children whoreceived 16-week supervised exercise intervention duringmaintenance therapy for ALL [9]. This finding is similar tothat of Marchese et al., who also reported no differencesbetween the intervention (n = 13) and control (n = 15)groups on HRQOL in their study of the effects of a 16-week home-based PT intervention among children duringmaintenance therapy for childhood ALL [21].

3. Conclusion

It appears that exercise training can be safely undertakenduring treatment for ALL and HCT with no major effects onthe immune system and that exercise does not have a dele-terious effect on growth factors during treatment for ALL.The published evidence is positive for the impact of exerciseon muscle strength and flexibility and mixed for the impactof exercise intervention on cardiopulmonary fitness amongchildren with ALL during maintenance therapy, amongchildren following HCT, and among survivors exposed tocardiotoxic agents. Fatigue and general physical function areenhanced if the intervention generates a cardiopulmonarytraining effect. The evidence for the effects of exercisetraining on HRQOL in the childhood cancer population ismixed and difficult to disentangle from the effects of diseaserecovery and normal maturation. The early evidence suggeststhat supervised hospital training is effective, likely becausecompliance and training intensity are assured. Home- orcommunity-based programs appear to be less effective.Unfortunately, supervised training is expensive and oftenunrealistic for families who may have to travel long distancesto a center that specializes in cancer care.

Even though early results are promising, specific limi-tations in the existing literature do not allow us to yet beable to state with confidence that exercise interventions offerclear benefits during or after treatment for childhood cancer.There have only been four randomized trials, sample sizeshave been small, and diagnosis groups included in the trialshave been very limited (mostly ALL). Intent to treat typeof analysis has not always been completed, and mechanismsto characterize the effects of participant dropout have notbeen employed. In addition, inconsistencies in exercisetype, duration, and frequency, and outcome measurementprohibit conclusions that might guide how an individualclinician might prescribe exercise in practice.

Further research is needed. Studies designed to identifyand characterize the type and intensity of exercise necessaryto achieve clinically meaningful positive cardiopulmonary,musculoskeletal, symptom limiting, physical function, andquality of life outcomes in children with a variety of diag-noses are necessary. These interventions must be not onlysafe but also realistic and portable so that children, families,and long-term survivors can adopt and incorporate exerciseand physical activity into their everyday lives when they arenot near the specialized center that provides care for childrenwith cancer. Additionally, larger well-designed randomizedstudies that employ strong statistical methodology and thatevaluate the effects of participant dropout on the outcomes

are important to see if the early results from these multiplesmall, mostly observational trials remain positive in largerpopulations of children with varied cancer diagnoses.

References

[1] M. A. Smith, N. L. Seibel, S. F. Altekruse et al., “Outcomesfor children and adolescents with cancer: challenges for thetwenty-first century,” Journal of Clinical Oncology, vol. 28, no.15, pp. 2625–2634, 2010.

[2] T. Hampton, “Cancer survivors need better care: new reportmakes recommendations,” Journal of the American MedicalAssociation, vol. 294, no. 23, pp. 2959–2960, 2005.

[3] S. B. J. Bhatia and A. T. Meadows, “Late effects of childhoodcancer and its treatment,” in Principles and Practice of PediatricOncology, P. D. Pizzo Pa, Ed., pp. 1490–1514, LippincottWilliams & Wilkins, Philadelphia, Pa, USA, 2006.

[4] M. M. Hudson, A. C. Mertens, Y. Yasui et al., “Health status ofadult long-term survivors of childhood cancer: a report fromthe childhood cancer survivor study,” Journal of the AmericanMedical Association, vol. 290, no. 12, pp. 1583–1592, 2003.

[5] A. C. Mertens, Y. Yasui, J. P. Neglia et al., “Late mortalityexperience in five-year survivors of childhood and adolescentcancer: the childhood cancer survivor study,” Journal ofClinical Oncology, vol. 19, no. 13, pp. 3163–3172, 2001.

[6] K. C. Oeffinger, A. C. Mertens, C. A. Sklar et al., “Chronichealth conditions in adult survivors of childhood cancer,” NewEngland Journal of Medicine, vol. 355, no. 15, pp. 1572–1582,2006.

[7] S. Aznar, A. L. Webster, A. F. San Juan et al., “Physical activityduring treatment in children with leukemia: a pilot study,”Applied Physiology, Nutrition and Metabolism, vol. 31, no. 4,pp. 407–413, 2006.

[8] M. E. M. Jenney, E. B. Faragher, P. H. M. Jones, and A.Woodcock, “Lung function and exercise capacity in survivorsof childhood leukaemia,” Medical and Pediatric Oncology, vol.24, no. 4, pp. 222–230, 1995.

[9] A. F. San Juan, C. Chamorro-Vina, J. L. Mate-Munoz et al.,“Functional capacity of children with leukemia,” InternationalJournal of Sports Medicine, vol. 29, no. 2, pp. 163–167, 2008.

[10] M. van Brussel, T. Takken, A. Lucia, J. van der Net, and P.J. M. Helders, “Is physical fitness decreased in survivors ofchildhood leukemia? A systematic review,” Leukemia, vol. 19,no. 1, pp. 13–17, 2005.

[11] M. van Brussel, T. Takken, J. Van Der Net et al., “Physicalfunction and fitness in long-term survivors of childhoodleukaemia,” Pediatric Rehabilitation, no. 3, pp. 267–274, 2006.

[12] J. T. Warner, W. Bell, D. K. H. Webb, and J. W. Gregory,“Daily energy expenditure and physical activity in survivors ofchildhood malignancy,” Pediatric Research, vol. 43, no. 5, pp.607–613, 1998.

[13] M. J. Adams, P. H. Hardenbergh, L. S. Constine, and S.E. Lipshultz, “Radiation-associated cardiovascular disease,”Critical Reviews in Oncology/Hematology, vol. 45, no. 1, pp.55–75, 2003.

[14] J. M. Argiles, F. J. Lopez-Soriano, and S. Busquets, “Mecha-nisms to explain wasting of muscle and fat in cancer cachexia,”Current Opinion in Supportive and Palliative Care, vol. 1, no. 4,pp. 293–298, 2007.

[15] K. S. Courneya, “Exercise in cancer survivors: an overview ofresearch,” Medicine and Science in Sports and Exercise, vol. 35,no. 11, pp. 1846–1852, 2003.


[16] C. Duggan, L. Bechard, K. Donovan et al., “Changes in restingenergy expenditure among children undergoing allogeneicstem cell transplantation,” American Journal of Clinical Nutri-tion, vol. 78, no. 1, pp. 104–109, 2003.

[17] L. C. M. Kremer, E. C. Van Dalen, M. Offringa, J. Ottenkamp,and P. A. Voute, “Anthracycline-induced clinical heart failurein a cohort of 607 children: long-term follow-up study,”Journal of Clinical Oncology, vol. 19, no. 1, pp. 191–196, 2001.

[18] S. E. Lipshultz, “Exposure to anthracyclines during childhoodcauses cardiac injury,” Seminars in Oncology, vol. 33, no. 3,supplement 8, pp. S8–S14, 2006.

[19] S. E. Lipshultz, S. R. Lipsitz, S. E. Sallan et al., “Chronicprogressive cardiac dysfunction years after doxorubicin ther-apy for childhood acute lymphoblastic leukemia,” Journal ofClinical Oncology, vol. 23, no. 12, pp. 2629–2636, 2005.

[20] R. D. K. S. Liu, M. J. M. Chinapaw, P. C. Huijgens, and W. V.Mechelen, “Physical exercise interventions in haematologicalcancer patients, feasible to conduct but effectiveness to beestablished: a systematic literature review,” Cancer TreatmentReviews, vol. 35, no. 2, pp. 185–192, 2009.

[21] V. G. Marchese, L. A. Chiarello, and B. J. Lange, “Effects ofphysical therapy intervention for children with acute lym-phoblastic leukemia,” Pediatric Blood and Cancer, vol. 42, no.2, pp. 127–133, 2004.

[22] A. F. San Juan, C. Chamorro-Vina, S. Moral et al., “Benefitsof intrahospital exercise training after pediatric bone marrowtransplantation,” International Journal of Sports Medicine, vol.29, no. 5, pp. 439–446, 2008.

[23] A. F. San Juan, S. J. Fleck, C. Chamorro-Vina et al., “Effectsof an intrahospital exercise program intervention for childrenwith leukemia,” Medicine and Science in Sports and Exercise,vol. 39, no. 1, pp. 13–21, 2007.

[24] A. F. S. Juan, K. Wolin, and A. Lucıa, “Physical activityand pediatric cancer survivorship,” Recent Results in CancerResearch, vol. 186, pp. 319–347, 2011.

[25] I. M. Johannsdottir, M. J. Hjermstad, T. Moum et al.,“Increased prevalence of chronic fatigue among survivors ofchildhood cancers: A population-based study,” Pediatric Bloodand Cancer. In press.

[26] K. A. Meeske, S. K. Patel, S. N. Palmer, M. B. Nelson, and A.M. Parow, “Factors associated with health-related quality oflife in pediatric cancer survivors,” Pediatric Blood and Cancer,vol. 49, no. 3, pp. 298–305, 2007.

[27] C. L. Cox, M. Montgomery, K. C. Oeffinger et al., “Promotingphysical activity in childhood cancer survivors,” Cancer, vol.115, no. 3, pp. 642–654, 2009.

[28] K. Y. Wolin, J. R. Ruiz, H. Tuchman, and A. Lucia, “Exercisein adult and pediatric hematological cancer survivors: anintervention review,” Leukemia, vol. 24, no. 6, pp. 1113–1120,2010.

[29] J. Cohen, Statistical Power Analysis for the Behavioral Sciences,Lawrence Erlbaum Associates, Hillsdale, NJ, USA, 1988.

[30] R. Blaauwbroek, M. J. Bouma, W. Tuinier et al., “The effectof exercise counselling with feedback from a pedometer onfatigue in adult survivors of childhood cancer: a pilot study,”Supportive Care in Cancer, pp. 1–8, 2008.

[31] C. Chamorro-Vina, J. R. Ruiz, E. Santana-Sosa et al., “Exerciseduring hematopoietic stem cell transplant hospitalization inchildren,” Medicine and Science in Sports and Exercise, vol. 42,no. 6, pp. 1045–1053, 2010.

[32] S. F. Gohar, M. Comito, J. Price, and V. Marchese, “Feasibilityand parent satisfaction of a physical therapy interventionprogram for children with acute lymphoblastic leukemia in

the first 6 months of medical treatment,” Pediatric Blood andCancer, vol. 56, no. 5, pp. 799–804, 2011.

[33] A. Hartman, M. L. Te Winkel, R. D. Van Beek et al., “Arandomized trial investigating an exercise program to pre-vent reduction of bone mineral density and impairment ofmotor performance during treatment for childhood acutelymphoblastic leukemia,” Pediatric Blood and Cancer, vol. 53,no. 1, pp. 64–71, 2009.

[34] M. R. Keats and S. N. Culos-Reed, “A community-basedphysical activity program for adolescents with cancer (projectTREK): program feasibility and preliminary findings,” Journalof Pediatric Hematology/Oncology, vol. 30, no. 4, pp. 272–280,2008.

[35] A. B. Ladha, K. S. Courneya, G. J. Bell, C. J. Field, and P.Grundy, “Effects of acute exercise on neutrophils in pediatricacute lymphoblastic leukemia survivors: a pilot study,” Journalof Pediatric Hematology/Oncology, vol. 28, no. 10, pp. 671–677,2006.

[36] L. J. Moyer-Mileur, L. Ransdell, and C. S. Bruggers, “Fitnessof children with standard-risk acute lymphoblastic leukemiaduring maintenance therapy: response to a home-basedexercise and nutrition program,” Journal of Pediatric Hema-tology/Oncology, vol. 31, no. 4, pp. 259–266, 2009.

[37] J. R. Ruiz, S. J. Fleck, J. L. Vingren et al., “Preliminary findingsof a 4-month intrahospital exercise training intervention onIGFs and IGFBPs in children with leukemia,” Journal ofStrength and Conditioning Research, vol. 24, no. 5, pp. 1292–1297, 2010.

[38] A. M. Sharkey, A. B. Carey, C. T. Heise, and G. Barber,“Cardiac rehabilitation after cancer therapy in children andyoung adults,” American Journal of Cardiology, vol. 71, no. 16,pp. 1488–1490, 1993.

[39] E. Speyer, A. Herbinet, A. Vuillemin, S. Briancon, and P.Chastagner, “Effect of adapted physical activity sessions inthe hospital on health-related quality of life for children withcancer: a cross-over randomized trial,” Pediatric Blood andCancer, vol. 55, no. 6, pp. 1160–1166, 2010.

[40] T. Takken, P. van der Torre, M. Zwerink et al., “Development,feasibility and efficacy of a community-based exercise trainingprogram in pediatric cancer survivors,” Psycho-Oncology, vol.18, no. 4, pp. 440–448, 2009.

[41] C. H. Yeh, J. P. Man Wai, U. S. Lin, and Y. C. Chiang, “A pilotstudy to examine the feasibility and effects of a home-basedaerobic program on reducing fatigue in children with acutelymphoblastic leukemia,” Cancer Nursing, vol. 34, no. 1, pp.3–12, 2011.

[42] P. S. Hinds, M. Hockenberry, S. N. Rai et al., “Clinical FieldTesting of an Enhanced-Activity Intervention in HospitalizedChildren with Cancer,” Journal of Pain and Symptom Manage-ment, vol. 33, no. 6, pp. 686–697, 2007.

[43] A. F. San Juan, S. J. Fleck, C. Chamorro-Vina et al., “Early-phase adaptations to intrahospital training in strength andfunctional mobility of children with leukemia,” Journal ofStrength and Conditioning Research, vol. 21, no. 1, pp. 173–177,2007.

[44] American College of Sports Medicine, ACSM’s Guidelinesfor Exercise Testing and Prescription, Williams & Wilkins,Philadelphia, Pa, USA, 2000.

[45] E. Golden, B. Beach, and C. Hastings, “The pediatrician andmedical care of the child with cancer,” Pediatric Clinics of NorthAmerica, vol. 49, no. 6, pp. 1319–1338, 2002.

[46] C. S. M. Oude Nijhuis, S. M. G. J. Daenen, E. Vellenga et al.,“Fever and neutropenia in cancer patients: the diagnostic role


of cytokines in risk assessment strategies,” Critical Reviews inOncology/Hematology, vol. 44, no. 2, pp. 163–174, 2002.

[47] J. Skinner, J. L. Finlay, P. M. Sondel, and M. E. Trigg,“Infectious complications in pediatric patients undergoingtransplantation with T lymphocyte-depleted bone marrow,”Pediatric Infectious Disease, vol. 5, no. 3, pp. 319–324, 1986.

[48] A. S. Fairey, K. S. Courneya, C. J. Field, and J. R. Mackey,“Physical exercise and immune system function in cancersurvivors: a comprehensive review and future directions,”Cancer, vol. 94, no. 2, pp. 539–551, 2002.

[49] D. M. Chun, C. B. Corbin, and R. P. Pangrazi, “Validation ofcriterion-referenced standards for the mile run and progres-sive aerobic cardiovascular endurance tests,” Research Quar-terly for Exercise and Sport, vol. 71, no. 2, pp. 125–134, 2000.

[50] L. H. Gerber, K. Hoffman, U. Chaudhry et al., “Functionaloutcomes and life satisfaction in long-term survivors ofpediatric sarcomas,” Archives of Physical Medicine and Reha-bilitation, vol. 87, no. 12, pp. 1611–1617, 2006.

[51] V. G. Marchese, L. A. Chiarello, and B. J. Lange, “Strengthand functional mobility in children with Acute LymphoblasticLeukemia,” Medical and Pediatric Oncology, vol. 40, no. 4, pp.230–232, 2003.

[52] K. K. Ness, E. B. Morris, V. G. Nolan et al., “Physical perfor-mance limitations among adult survivors of childhood braintumors,” Cancer, vol. 116, no. 12, pp. 3034–3044, 2010.

[53] N. R. Clanton, J. L. Klosky, C. Li et al., “Fatigue, vitality,sleep, and neurocognitive functioning in adult survivors ofchildhood cancer: a report from the childhood cancer survivorstudy,” Cancer, vol. 117, no. 11, pp. 2559–2568, 2011.

[54] M. J. Hockenberry, M. C. Hooke, M. Gregurich, K. McCarthy,G. Sambuco, and K. Krull, “Symptom clusters in children andadolescents receiving cisplatin, doxorubicin, or ifosfamide,”Oncology Nursing Forum, vol. 37, no. 1, pp. E16–27, 2010.

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Review Article …downloads.hindawi.com/journals/ijpedi/2011/461512.pdfProgress in treatments for childhood cancer have greatly improved cure rates, with 5-year survival now approaching