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Table of contents
1. Effects of Exercise Intervention for Children with Acute Lymphoblastic Leukemia: A Systematic Review..

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Document 1 of 1

Effects of Exercise Intervention for Children with Acute Lymphoblastic Leukemia: A Systematic
Review
Author: Wong, Jeremy, DPT, PCS; Fetters, Linda, PhD, PT, FAPTA
ProQuest document link
Abstract: Background: The purpose of this systematic review is to examine the research literature on the effects
of therapeutic exercise on strength, function, and endurance, when implemented during and immediately
following chemotherapy, in children with acute lymphoblastic leukemia (ALL). This review of the literature, which
includes children with ALL and the effects of therapeutic exercise across the levels of the International
Classification of Function (ICF), has not been previously undertaken. Five-year survivability of ALL has
significantly increased and a review to address the long-term effects of ALL and its treatment is merited.
Procedure: We searched 3 electronic databases and reviewed reference lists in relevant articles and online
sources published between 1999 and 2012. Thirteen intervention studies were appraised that included 345
participants. Results: Across all studies, therapeutic exercise was a safe intervention for patients with ALL, with
each study noting positive outcomes. However, the validity of the studies overall was low, with a preponderance
of studies lacking sufficient design rigor, a variety of exercise parameters, poor tracking of adherence to
intervention, and incomplete statistical analyses. Conclusions: Additional randomized controlled trials with
greater statistical rigor, which examine practical exercise parameters, address participant compliance, and
relate outcomes across levels of the International Classification of Function are needed to better determine the
potential benefits of therapeutic exercise for children with acute lymphoblastic leukemia.
Full text: Headnote
ABSTRACT
Background: The purpose of this systematic review is to examine the research literature on the effects of
therapeutic exercise on strength, function, and endurance, when implemented during and immediately following
chemotherapy, in children with acute lymphoblastic leukemia (ALL). This review of the literature, which includes
children with ALL and the effects of therapeutic exercise across the levels of the International Classification of
Function (ICF), has not been previously undertaken. Five-year survivability of ALL has significantly increased
and a review to address the long-term effects of ALL and its treatment is merited. Procedure: We searched 3
electronic databases and reviewed reference lists in relevant articles and online sources published between
1999 and 2012. Thirteen intervention studies were appraised that included 345 participants. Results: Across all
studies, therapeutic exercise was a safe intervention for patients with ALL, with each study noting positive
outcomes. However, the validity of the studies overall was low, with a preponderance of studies lacking
sufficient design rigor, a variety of exercise parameters, poor tracking of adherence to intervention, and
incomplete statistical analyses. Conclusions: Additional randomized controlled trials with greater statistical rigor,
which examine practical exercise parameters, address participant compliance, and relate outcomes across
levels of the International Classification of Function are needed to better determine the potential benefits of
therapeutic exercise for children with acute lymphoblastic leukemia.
Key Words: acute lymphoblastic leukemia, strength, function, endurance
INTRODUCTION
Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer, accounting for one third of
all diagnosed cancers in children, in the United States.' Acute lymphoblastic leukemia is the malignant
proliferation of lymphoblasts, which may affect several of the body's systems and organs, resulting in anemia,
thrombocytopenia, and neutropenia. Due to current medical treatments and participation in clinical trials, the 5year relative survival rate has improved from 58% for children diagnosed between 1975 and 1977 to 91% for
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those diagnosed between 2001 and 2007.' With significantly improved ALL survivability, the burden of care has
shifted to the mitigation of late adverse effects of ALL and to the effects of treatment, including chemotherapy.
Deficits in muscle strength, functional capacity, and cardiovascular endurance have been reported during and
after completion of current treatment for ALL.2-7
Many factors contribute to concurrent and late adverse effects of ALL along the continuum of care. Weakness,
fatigue, and decreased physical function are commonly reported at diagnosis of new onset ALL, related to
pathologic progression of abnormal blood counts.8'10 Standard treatment for ALL, chemotherapy, is linked to
peripheral neuropathy, myopathy, cancerrelated fatigue, and deficits affecting the nervous, respiratory, skeletal,
muscular, and circulatory systems."'14 Furthermore, already existing impaired cardiac, respiratory, and muscle
function may further worsen, as decreased levels of physical activity are reported during and after treatment of
ALL'5'16 which may last from months to years depending on severity. As ALL typically occurs at a young age, it
is also important to consider the effects on a child's development into adulthood as long-term survivors of ALL
report increased risk for obesity, osteopenia, cardiorespiratory complication, and decreased psychosocial
health.'7'28
Recent studies have demonstrated the use of therapeutic exercise to improve the strength, function, and
endurance of children, during and after treatment for ALL.29'41 These studies have investigated the use of
therapeutic exercise delivered through a variety of intervention models with varying frequency, duration, and
intensity as well as variations in settings (hospital, clinic, community, home), modalities (strength training,
functional activities, pedometers), health professionals, and timing related to chemotherapy. Timing of the
intervention may prove significant as exercise may prevent several long-term adverse effects of ALL treatment.
As research emerges in response to the increasing survivability of children with ALL, it is crucial to review the
current literature, to evaluate, and then summarize the preliminary findings. To date, there is no systematic
review that has examined the effects of exercise on children with ALL.
The purpose of this paper is to report a systematic review of the research literature to address the question,
"For children with acute lymphoblastic leukemia, what are the effects of therapeutic exercise on strength,
function, and endurance when implemented during and immediately following chemotherapy?"
METHODS
We used both the Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The (PRISMA)
Statement42 and the American Academy for Cerebral Palsy and Developmental Medicine (AACPDM)
Methodology to Develop Systematic Reviews of Treatment Interventions43 for development of our systematic
review.
Types of Studies
Inclusion criteria
Studies of intervention including randomized control trials, cohort studies, and case series, were included. Fulltext studies published in English were included.
Exclusion criteria
Dissertations and reports published outside of scientific journals were excluded.
Types of Participants
Inclusion criteria
Studies that included male and female children from birth to age 21 years, who had been diagnosed with ALL,
were included.
Exclusion criteria
Studies conducted primarily with adults greater than age 21 years, or on other types of cancer were excluded.
Types of Interventions
Inclusion criteria
Studies were included with an exercise intervention aimed at prevention of long-term adverse effects of ALL
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treatment, such as chemotherapy. Exercise was defined as physical activity that is planned or structured and
may be done to improve or maintain one or more components of physical fitness.44 Interventions were aimed at
prevention or treatment of at least one of the following: muscle strength, cardiovascular endurance, joint range
of motion (ROM), balance, or function. The types of exercises were not limited and included physical activities,
gross motor play, home exercise programs (HEP), and strength, power, and endurance training. Interventions
that were implemented during or following chemotherapy were included. Studies included interventions in all
settings such as a hospital, research facility, home, or community setting. The interventions were implemented
by a variety of professionals including physical therapists, exercise physiologists, physicians, and research staff.
Exclusion criteria
Studies using an exercise intervention that was combined with other interventions other than ALL-related
chemotherapy were excluded. These other interventions included psychotherapy or specific medication trials.
Types of outcome measures
Studies that reported on outcome measures assessing muscle strength, physical function, duration of physical
activity, or cardiovascular endurance were included.
Search Methods
We electronically searched MEDLINE, CINAHL, and SPORTDiscus from their respective inceptions to October
2012. A University of Southern California research information specialist was consulted to develop a thorough
and accurate search of the literature. For each database, search strategies included the following key terms and
database specific subject headings for (1) acute lymphoblastic leukemia, (2) physical therapy, rehabilitation, and
exercise, and (3) outcomes on strength, function, and endurance. Individual searches were performed for each
key term, and then combined within each of these 3 subgroups. A final search was performed combining each
subgroup. The reference lists of relevant systematic reviews and randomized control trials, as well as online
resources such as Google Scholar, were cross-referenced for additional studies.
Citations were collected and sorted using reference management software EndNote X6. Titles and available
abstracts were compiled and screened by both authors, after duplicates were removed. Studies were screened
based on above inclusion and exclusion criteria. Disagreements were resolved by referencing inclusion and
exclusion criteria until 100% consensus was achieved. Commonly, studies were excluded because they were a
medical drug trial or psychological intervention, were not an intervention study, or did not primarily study
children with ALL. Resultant articles were assessed for full-text eligibility. After articles were excluded with
reasons, the remaining full-text articles that met inclusion criteria were appraised by both authors. Figure 1 is a
flow diagram of the article selection process that was modeled after the PRISMA flowchart.
Article Appraisal
Levels of Evidence
Articles were appraised using the AACPDM levels of evidence43 that ranks various research designs. Higher
levels of evidence demonstrate reduced bias and support that the intervention was responsible for the observed
outcomes. The AACPDM levels of evidence provide a hierarchy in which greater confidence is placed in studies
identified with increased study rigor and controlled research designs.
Validity Appraisal
To further determine each intervention study's internal validity, studies were scored according to an Intervention
Appraisal Form.45 The 11 criteria were each scored 1 point if the criterion was present, or 0 points if it was
absent. The criteria were: (1) random participant assignment to treatment, (2) groups similarity at baseline, (3)
reduced biased sampling procedure, (4) all participants allocated and accounted for, (5) intention-to-treat
analysis included, (6) subject/therapist blinding optimization, (7) groups treated equally, other than intervention,
(8) reliable and valid outcome measures, (9) descriptive and inferential statistics applied to results, (10) clinically
relevant statistics applied to results, and (11) confidence intervals reported. A higher score indicates a study
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and its results have better validity. Discrepancies were resolved by discussion and referencing the original text,
until 100% scoring consensus was achieved.
Data Extraction
The included articles were read in full by both authors. We recorded the level of evidence, validity score,
research design, patient demographics and timing of chemotherapy, control, and intervention group parameters
including exercise frequency and duration, outcome measures, and statistical results. Outcome measures were
categorized according to the International Classification of Function, Disability and Health (ICF) model.46 The
ICF model provides a framework for measuring health and disability with respect to patient function, roles in
society, and contextual and environmental factors. Range of motion outcomes were defined as measurements
of joint motion, typically measured in degrees of osteokinematic movement. Strength outcomes were defined as
measurements of muscle produced concentric force, typically performed for short periods of time, with high
intensity, and sufficient recovery between measurements. Functional outcomes were defined as measurements
of gross motor ability to access one's environment or perform activities of daily living. These outcomes typically
included the ability to safely stand up from the floor, walk, and go up and down stairs. Endurance outcomes
were defined as measurements of cardiorespiratory fitness, typically performed for extended periods of time at a
consistent intensity, such as walking.
Data Analysis
Systematic reviews include a meta-analysis if the effect sizes have been computed in the study or the data is
available to compute the effect sizes (ie, means and standard deviations). The majority of the literature included
in our systematic review did not report the effect sizes nor the necessary data for computation. A meta-analysis
of this subset of the literature would not have been representative of the group of studies. Thus, we completed a
qualitative systematic review of the literature and quantified trends in the study characteristics and results as
possible.
Studies were grouped and analyzed according to 6 criteria: (1) level of evidence, (2) site of intervention, (3) time
of intervention in relation to chemotherapy, (4) involvement of a physical therapist, (5) compliance of the
participants, and (6) ICF model classification of outcomes.
Outcome measures were grouped and analyzed according to 3 criteria: (1) direction of effect of intervention, (2)
statistical significance with p-value, (3) value of confidence interval (Cl).
RESULTS
Study Selection and Quality
A total of 13 studies were identified for inclusion in the review from a possible 263 identified through the search
(Figure 1). A total of 345 subjects participated across the 13 studies.
Table 1 includes the validity characteristics of the 13 studies. Eight of the 13 studies were cohort designs (Level
IV) with only 3 RCTs (Level II; 92 total participants). There was one case series (Level IV) and one case-control
study (Level IV). Validity scores had a range of 2-9 points (out of 11). Thus, there was a preponderance of
studies with low levels of evidence. One common and serious design flaw limiting the validity score was the
failure to include a comparison or control group, which was reflected in the low number of RCT designed
studies. Furthermore, p-values and Cl values were not reported consistently across the studies. Therefore,
higher statistical rigor and validity were indicated for outcomes with reported p-values <0.05 and Cl that did not
cross zero, compared to outcomes with reported p-values <0.05 and Cl that did cross zero or did not report CL
Intervention Characteristics
Across all studies, there was a preponderance of exercises directed at improving ROM, strength, and
endurance. Table 2 includes a summary of the characteristics of the interventions. Each study reported no
harm, injury, or adverse effects to the subjects as a result of the interventions. Interventions were offered during
various phases of chemotherapy treatment including during chemotherapy (n = 5), during the maintenance
phase of chemotherapy (n = 5), or after chemotherapy (n = 3). This may likely have affected the tolerance to
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exercise and subsequent results of the intervention. It is difficult and perhaps unrealistic to compare the effects
of exercise during active chemotherapy treatment with the results of even the same exercise program after
chemotherapy has been completed. For the 5 studies during chemotherapy, there were 10 positive results out
of 13 outcome measures, with no results statistically significant, and no results with 95% Cl that did not cross
zero. For the 3 studies during the maintenance phase of chemotherapy, there were 32 positive results out of 43,
with 23 results statistically significant, and 5 results with 95% Cl that did not cross zero. For the 3 studies after
chemotherapy, there were 16 positive results out of 26, with 9 results statistically significant, and 9 results with
95% Cl that did not cross zero. Outcomes measured during maintenance chemotherapy and after
chemotherapy demonstrated similar percentages of positive (>69%) outcomes, and higher statistically
significant results (>46%) with 95% Cl that did not cross zero (>20%), compared to outcomes during
chemotherapy (>76%, 0%, and 0% respectively).
Duration of treatment varied from 20 to 120 minutes, with 10 studies reporting treatments from 30 to 60 minutes.
For studies that included a supervised treatment in a research facility, treatment durations were 60 minutes or
greater in 5 of 8 studies that reported this information. In studies reporting an HEP treatment, all 6 of 6 studies
reported treatment durations with a range between 20 and 60 minutes. The total duration of the study
intervention varied from 6 weeks to 3 years. Two of 3 studies with intervention duration greater than one year
did not report treatment duration per session, and are therefore difficult to compare to the studies of shorter
overall duration of intervention. Frequency of treatment varied from 2 and 7 times per week for all studies
except one study with frequency of once per week initially and then as needed.
Only 5 of the 13 studies included physical therapists as the professional providing the interventions. Research
assistants, physicians, dieticians, exercise physiologists, and fitness instructors were the other personnel
delivering interventions with one study using only an instructional video to communicate HEP instructions.
Home programs were an important component in 10 of the 13 studies with one study relying completely on a
home program for the intervention. However, only 5 studies reported measuring adherence to the programs and
of those studies that did report this outcome, only 3 studies reported adherence greater than or equal to 67%.
The other 2 studies had an adherence rate of 11% and 25%.
Table 3 includes the studies' results. There was a wide variety of tests and measures used as outcomes.
Strength outcomes were most commonly reported, though the methods varied, including strength measured by
dynamometer, functional testing, or repetition max. A variety of measures were used to capture outcomes
relating to function, endurance, and quality of life (QOL), with few studies sharing common outcomes. Most of
the study outcomes were at the ICF Body Structure and Function (BSF) Level and Activity Level, with only 7
studies including the Participation Level. No study related changes in BSF to Participation. There were 58
positive results of the 82 outcome measures collected across the 13 studies with 32 of the results statistically
significant, and 14 of the results with 95% Cl that did not cross zero. Range of motion and strength outcomes
were categorized in the ICF BSF Level. For ROM outcome measures, there were 4 positive results out of 7, with
one result statistically significant, and no results with 95% Cl that did not cross zero. For strength outcome
measures, there were 22 positive results out of 28, with 16 results statistically significant, and 7 results with 95%
Cl that did not cross zero. Function and endurance outcomes were categorized in the ICF Activity Level. For
function outcome measures, there were 12 positive results out of 15, with 8 results statistically significant, and 4
results with 95% Cl that did not cross zero. For endurance outcome measures, there were 11 positive results
out of 15, with 6 results statistically significant, and 3 results with 95% Cl that did not cross zero. Quality of life
outcomes were categorized in the ICF Participation Level. For QOL outcome measures, there were 9 positive
results out of 17, with one result statistically significant, and no results with 95% Cl that did not cross zero.
Outcomes for strength, function, and endurance demonstrated higher percentages of positive (>77%) and
statistically significant results (>51%) with 95% Cl that did not cross zero (>24%), compared to outcomes for
ROM and QOL (<55%, <9%, and 0% respectively).
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DISCUSSION
Across all the studies in this review, it appears that therapeutic exercise can be a safe intervention for patients
with ALL, as studies reported no harmful effects or physical injuries. Though this intervention is preliminarily
supported, further research is required. The 13 studies include only 3 RCTs with a total of 92 participants, with
inconsistent timing of intervention during chemotherapy, a variety of exercise parameters, poor tracking of
adherence to intervention, and incomplete report of statistical analysis of results including statistical
significance, 95% CIs, and effect sizes. These qualities have limited our ability to statistically analyze the results
of the collected studies, and produce a strong statement on the effectiveness of therapeutic exercise in children
with ALL. However, the initial results are encouraging. All studies have demonstrated positive outcomes, with
increased support for interventions during the maintenance phase of chemotherapy and after chemotherapy,
compared to during the course of chemotherapy. It will be important to further investigate the timing of
intervention as the former group of studies (maintenance, and after chemotherapy) tended toward a highintensity episodic treatment model compared to the latter group (during chemotherapy) which provided longer
term intervention and regular follow up. Determining such precise temporal factors will have an impact on
variables such as frequency of physical therapy referrals, allocation of financial resources, and dosage of
exercise intervention. The current evidence supports the positive effect of therapeutic exercise for children with
ALL to improve strength and function, with less support to improve ROM and QOL. Further research is required
to determine a possible relationship between ICF levels of BSF, activity, and participation. Due to the lifelong
and widespread effect of ALL, it is especially critical to address and treat the whole patient across all levels of
the ICF, and particularly improvement of function and participation. Since a direct relationship has not been
established between BSF and Activity Levels of the ICF, studies focused on improving function may have
greater relevance for return to typical childhood activities and roles. It appears that supervised treatment in a
research facility is more effective than unsupervised HEP. This is likely due to longer treatment duration per
session, improved intervention adherence, and proper administration of the exercise protocol of the supervised
treatment compared to the unsupervised. Nevertheless, further strides in the area of improving compliance for
HEP intervention are essential to enhance clinical feasibility and potential for greater cost effectiveness.
Therefore, additional higher level randomized controlled trials with greater statistical rigor that examine practical
exercise parameters, address participant compliance, and relate outcomes across levels of the ICF are needed
to better determine the potential benefits of therapeutic exercise for children with ALL with regards to timing,
setting, and dosing of intervention.
CONCLUSIONS
Across all studies, therapeutic exercise was a safe intervention for patients with ALL during and after
chemotherapy, with each study reporting positive outcomes. However, the validity of the studies overall was
low, with a preponderance of studies lacking sufficient design rigor, a variety of exercise parameters, poor
tracking of adherence to intervention, and incomplete statistical analyses. Additional randomized controlled
trials that address these challenges are needed to better determine the potential benefits of therapeutic exercise
for children with ALL.
ACKNOWLEDGEMENTS
The authors claim no conflict of interest or relevant affiliations.
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AuthorAffiliation
Jeremy Wong, DPT, PCS'iLinda Fetters, PhD, PT, FAPTA2
1 Division of Pediatric Rehabilitation Medicine, Physical Therapy, Children's Hospital, Los Angeles, CA;
Adjunct Instructor of Clinical Physical Therapy, Division of Biokinesiology &Physical Therapy,
Ostrow School of Denistry, University of Southern California, Los Angeles, CA
2 Division of Biokinesiology and Physical Therapy, Ostrow School of Denistry &Department of Pediatrics,
Keck School of Medicine, University of Southern California, Los Angeles, CA
AuthorAffiliation
Address correspondence to: Jeremy Wong, DPT, PCS, Division of Pediatric Rehabilitation Medicine, Children's
Hospital, Los Angeles, 4650 Sunset Blvd, Los Angeles, CA 90027 (jeremywong79@yahoo.com).
Subject: Studies; Children & youth; Older people; Leukemia; Hospitals; Chemotherapy; Clinical trials;
Publication title: Rehabilitation Oncology
Volume: 32
Issue: 3
Pages: 40-51
Number of pages: 12
Publication year: 2014
Publication date: 2014
Year: 2014
Publisher: Rehabilitation Oncology
Place of publication: Richmond
Country of publication: United States
Publication subject: Medical Sciences--Oncology
Source type: Scholarly Journals
Language of publication: English
Document type: Feature
Document feature: Charts Tables References

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ProQuest document ID: 1551410390

Document URL: http://search.proquest.com/docview/1551410390?accountid=48290
Copyright: Copyright Rehabilitation Oncology 2014
Last updated: 2014-08-06
Database: ProQuest Nursing & Allied Health Source

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