Physical therapy interventions, other than general physical exercise interventions, in children and adolescents before, during and following treatment for cancer
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
Primary objective
To evaluate the efficacy of physical therapy intervention on the quality of life (QoL) outcomes of children and adolescents who have been diagnosed with cancer. Participants must be between the ages of 0 and 19 years at the time of the physical therapy intervention study. The intervention may occur prior to, during or following cancer treatment, or in a range of times of delivery. The intervention must be compared to a control group of children receiving standard care, no physical therapy intervention or a comparison intervention. We will exclude general physical exercise studies where the primary aim is to improve physical fitness through aerobic, anaerobic, resistance exercise, or combined physical exercise training regimens (i.e. combined aerobic and resistance exercise regimens). We will also record any adverse effects resulting from physical therapy interventions.
Secondary objectives
To evaluate the efficacy of physical therapy interventions on fatigue, pain, peripheral neuropathy, balance and gait, as well as the range of motion and strength of a specific joint or impaired body region.
Background
Description of the condition
It is estimated that globally over 250,000 children and adolescents between the ages 0 to 19 years will be diagnosed with cancer each year (Kids Cancer Care 2016; WHO 2016); and 175,000 (70%) of them will be children under the age of 15 years (Ward 2014). Progress in cancer treatments has resulted in improved survival rates of children and adolescents with cancer, now approaching or exceeding 80% for 5‐year post‐diagnosis survival (O'Leary 2008; Robison 2009; Skinner 2012); thus, there has been increased awareness of the need for survivorship care plans including medical follow‐up and surveillance for long‐term effects of cancer treatment (Buckner 2014; CCS 2015; Robison 2009).
Two‐thirds of children who have been diagnosed with cancer will also develop at least one chronic or long‐term side effect after the cancer treatment (Skinner 2012). Long‐term and late effects are expected health complications resulting from the cancer or cancer therapy (chemotherapy, radiation therapy, surgery and stem cell transplant), that never resolve or emerge months or years following treatment completion, and impact overall health and quality of life (Green 2012). These effects include impairments such as pain, fatigue, and weakness (Van Cleve 2012), peripheral neuropathy, limitations in range of motion, and deficits in balance and gait (Robison 2009; Skinner 2012; Baggott 2009); all of which may negatively affect the child’s overall function, quality of life and ability to participate in age‐appropriate activities including play (Moody 2006; Pruitt 2009).
Cancer treatments can negatively impact the major body systems including musculoskeletal, cardiorespiratory and neurological systems (Pruitt 2009). The risk of long‐term side effects are dependent on the tumour type and tumour‐related factors (e.g. location within the body, extent of the cancer), the type of cancer treatment administered (e.g. type of surgery, chemotherapy type and dosage, radiation therapy type, location, dosage), as well as patient‐related factors (e.g. the child’s gender, age, overall health pre‐cancer diagnosis, and developmental stage at time of diagnosis) (Pruitt 2009; NCI 2016). The focus of this review will be on the musculoskeletal and neurological effects of cancer and cancer treatment.
Musculoskeletal System
Specific long‐term effects from cancer treatment on the musculoskeletal system include effects on muscle and soft tissues (myopathies including proximal muscle weakness, soft tissue contracture and radiation fibrosis syndrome), as well as effects on bone resulting in scoliosis or kyphosis, limb length discrepancies, and osteoporosis (NCI 2016; Pruitt 2009). The impact of surgery such as amputation and limb‐salvage intervention may result in chronic pain, gait and balance dysfunction, and impact overall activity. Effects involving the musculoskeletal system are more likely to occur in cancers such as acute lymphoblastic leukaemia, osteosarcoma, and brain and spinal cord tumours; and in those children who have undergone a stem cell transplant (NCI 2016; Pruitt 2009).
Neurological System
Specific long‐term effects involving the neurological system include motor and sensory deficits (loss of fine motor skills, impairments in coordination and balance, movement disorders, and peripheral nerve damage in the hands and feet) (NCI 2016; Pruitt 2009). A long‐term effect seen in adult survivors of childhood cancer includes chronic peripheral neuropathy, a condition that may result from use of a neurotoxic agent such as vincristine and cisplatin (NCI 2016; Pruitt 2009).
Description of the intervention
Focused physical therapy intervention may help children with the late and long‐term physical effects resulting from cancer treatment, particularly those effects associated with prolonged cancer treatments (Stubblefield 2013). Physical therapy is a health‐care profession that aims to restore and optimise function, mobility and quality of life of individuals of all ages (Punzalan 2009). In oncology rehabilitation, physical therapists work with clients to manage musculoskeletal and neuromuscular impairments (Punzalan 2009). Rehabilitation needs of cancer patients include treatments to address acute, late and long‐term effects as well as those associated with palliative care (Punzalan 2009).
The physical therapist will perform an assessment to determine physical function, joint mobility, and muscle strength and flexibility. Findings of the assessment are used to inform an appropriate tailored intervention for the child (Punzalan 2009). Physical therapy can help children with cancer regain function through interventions that aim to reduce pain in soft tissues (muscles, tendons and ligaments), build muscle strength, improve soft tissue and joint flexibility, range of motion, and function as well as overall mobility. Treatment services can be delivered before (prehabilitation), during and after treatment completion (rehabilitation) (Krivitzky 2015). Prehabilitation services include interventions that are administered between the time of diagnosis and cancer treatment initiation. Prehabilitation intervention may be prescribed to enhance a child’s physical functioning and general health status to enable improved tolerance to cancer treatments, overall outcomes and recovery from the upcoming cancer treatment. Rehabilitation services delivered during or following cancer treatment, are defined as services that help a child to recover function or relearn skills after a diagnosis of cancer. Importantly, focused and timely physical therapy intervention may help to prevent the development of late effects and attenuate the severity of long‐term effects (Krivitzky 2015).
The interventions considered in this review will include physical therapy techniques such as manual therapy, therapeutic range of motion and strengthening exercises for a joint or muscle region, balance retraining, gait re‐education, and electrophysical modalities that are provided with the aim of addressing impairments related to cancer treatment. The physical therapy may be delivered as prehabilitation or rehabilitation intervention; however, the children and adolescents participating in the study must be between 0 and 19 years old at the time of the study physical therapy intervention.
Why it is important to do this review
To date, the majority of research trials in cancer rehabilitation have been performed with adult cancer survivors. Positive results from physical therapy interventions, primarily in the area of breast cancer, have been reported (Cho 2016; De Groef 2015; McNeely 2010; Nilsen 2015; Pergolotti 2015).
Impairment‐based cancer rehabilitation for children and adolescents with cancer is a growing area of research and clinical practice. Studies with childhood cancer patients and survivors including physical therapy have been performed; however, factors such as small sample sizes, varying intervention protocols and differences in cancer types among trials make it difficult to draw conclusions on overall efficacy.
A recent Cochrane Review examined the effects of general exercise training interventions for children and adolescents with cancer (Braam 2016). The review included five studies involving 131 participants, all of whom were being treated for Acute Lymphoblastic Leukaemia. Preliminary findings support benefit from general physical exercise training for body composition, flexibility and cardiorespiratory fitness. To date, however, no systematic reviews have been performed examining the benefits of physical therapy interventions for specific impairments related to cancer treatment. Thus, the main distinctions between this review and that of Braam 2016 will be (1) the type of intervention (physical therapy vs general physical exercise) and (2) the focus of the intervention (impairment‐driven vs physical fitness).
Objectives
Primary objective
To evaluate the efficacy of physical therapy intervention on the quality of life (QoL) outcomes of children and adolescents who have been diagnosed with cancer. Participants must be between the ages of 0 and 19 years at the time of the physical therapy intervention study. The intervention may occur prior to, during or following cancer treatment, or in a range of times of delivery. The intervention must be compared to a control group of children receiving standard care, no physical therapy intervention or a comparison intervention. We will exclude general physical exercise studies where the primary aim is to improve physical fitness through aerobic, anaerobic, resistance exercise, or combined physical exercise training regimens (i.e. combined aerobic and resistance exercise regimens). We will also record any adverse effects resulting from physical therapy interventions.
Secondary objectives
To evaluate the efficacy of physical therapy interventions on fatigue, pain, peripheral neuropathy, balance and gait, as well as the range of motion and strength of a specific joint or impaired body region.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials (RCTs), cross‐over trials (if data is available prior to the cross‐over), and controlled clinical trials (CCTs) comparing the effects of physical therapy interventions for children and adolescents who are between the ages of 0 and 19 years.
Types of participants
Children and adolescents who are aged 0 to 19 years at the time of the physical therapy intervention. All childhood cancer types will be eligible for inclusion in the review. We will include studies involving adults (20 years old or more) with cancer only if the results of the subgroup of children with cancer (0 to 19 years of age) are available or reported separately.
Types of interventions
We will include studies comparing physical therapy interventions (such as manual therapy techniques, therapeutic range of motion and strengthening for a specific joint or impaired body region, balance and gait retraining), and electrophysical modalities to address a specific symptom (e.g. pain), impairment (e.g. gait dysfunction) or body region (e.g. shoulder). The intervention may be delivered before (prehabilitation), during or following cancer treatment, or in a range of times of delivery. The intervention will be compared to a control group receiving standard care, no intervention or a comparison intervention (assuming the effect of the physical therapy intervention can be isolated).
The physical therapy intervention must be delivered or supervised by a physical therapist or healthcare professional (e.g. nurse, occupational therapist). The programme may be offered as an individualised treatment or a group intervention and can be performed in any setting or location (e.g. hospital, outpatient hospital or physical therapy clinic, home, or elsewhere). The duration of the physical therapy intervention period must be at least four weeks. The time spent per physical therapy session must be reported or sufficiently described such that delivery of the intervention would take at least 15 minutes.
Exclusion criteria
1. Studies where the primary focus is aerobic capacity or general physical fitness alone.
2. Studies where the prescription is consistent with a general exercise or physical activity prescription that is described in terms of frequency, intensity, type and time.
Types of outcome measures
Primary and secondary outcomes listed below will not be used as criteria for including studies, but rather as a list of outcomes of interest within the included studies.
Primary outcomes
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The primary outcomes of this review will be quality of life and adverse events.
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Quality of life will be measured by scales such as the Pediatric Quality of Life Inventory (PedsQL), Pediatric Quality of Life (PedsQL Core), Child Health Questionnaire (CHQ), and DISABKIDS or other validated questionnaire.
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Adverse events related to the physical therapy intervention such as falls, fractures, soft tissue injuries, or any worsening of impairments (e.g. pain) requiring withdrawal from the study.
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Secondary outcomes
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Secondary outcomes of the review are as follows.
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Fatigue will be assessed by a validated scale such as the PedsQL Multidimensional Fatigue Scale, Childhood Cancer Fatigue Scale (CCFS), or the Fatigue Scale for a child (FS‐C), the same scale for adolescents (FS‐A), and for parents (FS‐P), or equivalent valid instrument.
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Pain will be measured by Visual Analog Scale (VAS), or other valid instrument.
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Peripheral neuropathy will be measured by a validated scale such as the Pediatric Modified Total Peripheral Neuropathy Score (ped‐mTNS), Total Neuropathy Score‐Pediatric Vincristine (TNS‐PV), Total Neuropathy Score (TNS).
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Balance will be assessed by a validated scale such as the Bruininks Osteretsky Test of Motor Proficiency (BOTMP) Balance Subtest, Bruininks Osteretsky Test of Motor Proficiency Second Edition (BOT‐2) Balance Subtest, Berg Balance Scale (BBS), Alberta Infant Motor Scale (AIMS), Romberg test, Pediatric Balance Scale (PBS), Movement Assessment Battery for Children (Movement ABC‐2), The Flamingo Balance Test or equivalent.
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Gait will be assessed descriptively or by use of a computerised/electronic gait analysis.
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Range of motion will be measured by goniometry, or another valid instrument.
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Strength will be assessed with a hand‐held dynamometer, use of a Biodex/Cybex, spring scale, lateral step‐up test, sit‐to‐stand test, up‐and‐down stairs test, minimum chair height test, incremental shuttle walking test, or another valid instrument.
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Search methods for identification of studies
Cochrane Childhood Cancer will run the searches in CENTRAL, MEDLINE and Embase; all other searches (CINAHL, PEDro, ongoing trial registries and conference proceedings) will be run by the review authors. We will not apply any language restrictions.
Electronic searches
We will search the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library — we will use the latest issue; MEDLINE Ovid (from 1946 to present); Embase Ovid (from 1947 to present); CINAHL/EBSCO (1937 to present); and Physiotherapy Evidence Database (PEDro; from 1929 to present) (www.pedro.org.au). We have modified electronic searches from the recommended Cochrane Childhood Cancer methods used in reviews (Module CCG).
The search strategies for the different electronic databases (using a combination of controlled vocabulary and text words) are shown in the appendices (Appendix 1; Appendix 2; Appendix 3; Appendix 4; Appendix 5).
Searching other resources
Bibliographic searching
We will search trials not registered in CENTRAL, MEDLINE, Embase, CINAHL, and PEDro, either published or unpublished, by searching the reference lists of relevant articles and review articles. We will search the five latest editions of conference proceedings of the International Society for Paediatric Oncology (SIOP), the American Society of Clinical Oncology (ASCO), the American Society of Pediatric Hematology/Oncology (ASPHO), and the Multinational Association for Supportive Care in Cancer (MASCC). We will scan the ISRCTN Registry (www.isrctn.com), the National Institutes of Health (NIH) Register (www.clinicaltrials.gov), and the World Health Organization portal (http://apps.who.int./trialsearch) for ongoing trials.
The search strategies for other resources are shown in the appendices (Appendix 6; Appendix 7).
Personal communication
We will contact oncology rehabilitation researchers working in the paediatric area to verify details of any outstanding clinical trials and any relevant unpublished material.
Data collection and analysis
Selection of studies
After performing the search, two authors will independently identify studies meeting the inclusion criteria. We will resolve discrepancies by consensus between authors. In cases where consensus cannot be reached, a third author will act as arbiter. We will obtain a full copy of the publication for any study potentially meeting inclusion criteria based on information provided in the title or abstract. We will provide reasons for exclusion of screened studies. We will note duplicate publications of the same study, but will count the study only once.
We will provide a flow diagram for the selection of studies in our review.
Data extraction and management
At least two review authors will extract the characteristics for each trial using a data extraction form. We will compare the results, resolve disagreements by discussion and consensus, and create a composite table. In the case of disagreements, a third author will be used for final resolution. We will extract information on the trial design (RCT, cross‐over or CCT), data on characteristics of participants, sample size, number of participants in each study arm, type of intervention(s), control intervention, duration of intervention in weeks, randomization and blinding, type and duration of cancer treatment, stage of cancer treatment (e.g. during or after treatment), recruitment method and location where study took place, country of study, outcome assessed, inclusion/exclusion criteria, outcomes, follow‐up times, adverse events, dropouts and withdrawals, conflicts of interests of primary investigations, funding source, and study findings.
In cases where there is more than one publication for a study, we will use the primary publication and reference the other publications if used for supplementary information.
Assessment of risk of bias in included studies
Two review authors will independently assess risk of bias in the RCTs, cross‐over trials and CCTs; rating each risk‐of‐bias item as 'low', 'unclear' or 'high' risk of bias. We will use the 'risk of bias' criteria as mentioned in the module of Cochrane Childhood Cancer (Module CCG); these are based on recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). 'Risk of bias' assessment will be done with the following criteria: random sequence generation (selection bias); allocation concealment (selection bias); blinding of participants (performance bias); blinding of personnel (performance bias); blinding of outcome assessment (detection bias) for each outcome separately; incomplete outcome for each outcome separately (attrition bias); selective reporting (reporting bias); and other sources of bias (other bias). We will resolve disagreements by discussion; but if we cannot reach consensus, a third author will be invited to arbitrate.
Statistical methods to identify selective outcome reporting are not well developed yet. However, the Cochrane Handbook for Systematic Reviews of Interventions suggests different ways to assess selective reporting (Higgins 2011). If the protocol is available, we will compare the outcomes in the protocol with the published report. If the protocol is not available, we will compare the outcomes mentioned in the Methods section with the reported results. If non‐significant results are mentioned but reported inadequately, we will gather information directly from the authors of the study.
In addition to the pre‐specified 'Risk of bias' items, we will add 'Treatment Adherence' as a further potential source of bias. We consider adherence to physical therapy treatment to be a vital component to successful treatment. For the purposes of evaluating risk, adherence is defined as the percentage of sessions attended/completed by the participant with 'low risk of bias' (i.e. adherence 70% or greater), 'unclear' (not reported) or 'high risk of bias' (i.e. adherence < 70%).
Measures of treatment effect
We will analyze continuous data (QoL, adverse events, fatigue, pain, gait, peripheral neuropathy, balance, range of motion, strength) as mean differences either weighted or standardised using a random‐effects model. We will use difference in means (MD) for continuous variables when data are provided using the same units, measurement methods or outcome measure. We will use the standardised mean difference (SMD) for continuous variables when trials report results using different measurement units, measurement methods or outcome measures. We will analyze dichotomous outcomes (e.g. adverse event rates, outcomes reported as dichotomous variables) using risk ratio (RR). All results will be presented with corresponding 95% confidence intervals (CIs).
Unit of analysis issues
The only unit of analysis issue we anticipate is with cross‐over designs, in which we will use only first‐cycle data (prior to cross‐over).
Dealing with missing data
When information relevant to study selection, data extraction or assessment of risk of bias is missing, we will attempt to contact the authors to obtain the missing data. When applicable, we will extract data by allocated intervention, irrespective of compliance with the allocated intervention, to allow an intention‐to‐treat analysis. We will state if this is not possible and will perform an 'as treated' analysis.
Assessment of heterogeneity
We will assess heterogeneity by visual inspection of the forest plots and by the use of the statistical test for heterogeneity I² statistic (Higgins 2011). I² values ranging from 0% (homogeneity) to 100% (heterogeneity) will be calculated to quantify variability in study effect. An I² value greater than 50% will be considered the cutpoint for significant heterogeneity (Higgins 2011). Where possible, subgroup analyses will be performed to explore and explain heterogeneity among studies.
Assessment of reporting biases
In addition to the evaluation of reporting bias as described in the Assessment of risk of bias in included studies section, we plan to assess reporting bias by constructing a funnel plot if there are a sufficient number of included studies (at least 10 studies included in a meta‐analysis), otherwise the power of the tests is too low to distinguish chance from real asymmetry (Higgins 2011).
To minimise the effect of publication bias, we will search the grey literature and contact authors of trials.
Data synthesis
We will enter data of the included studies into Review Manager 5 software (Review Manager 2014) and undertake analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
We will pool the results of studies, (1) if there are at least three studies with the same outcome measure (or measurement) for the given primary or secondary outcome; and (2) if appropriate, after consideration of heterogeneity between the trials. We will pool outcomes when sufficient data are available in the papers or from the trialists' data sets using the random‐effects model. We will describe outcomes that we cannot pool in narrative form in the Results section. We will create a 'Summary of findings' table, including post‐intervention results as well as short‐term follow‐up results (3 to 6 months after the intervention completion) and long‐term follow‐up results (1 year or more after the intervention completion).
In a multi‐arm study we will include the intervention groups as separate comparisons if each arm meets the criteria for inclusion, and will split the 'shared' control/comparison group for analyses. We will note all the intervention groups in the table of 'Characteristics of the included studies'. However, we will only describe and analyse the intervention groups relevant to the review (Higgins 2011).
For each comparison we will prepare a 'Summary of findings' table using the GRADE profiler software (Guyatt 2008), in which we will present the following outcomes: QoL, fatigue, pain, balance, range of motion, strength, adverse events. For each outcome two review authors will independently assess the quality of the evidence by using the five GRADE considerations, i.e. study limitations, inconsistency, indirectness, imprecision and publication bias, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Subgroup analysis and investigation of heterogeneity
A priori subgroup analyses include examining the pooled effect estimate by the type of physical therapy intervention, the timing of the intervention (i.e. prior to, during, or following cancer treatment), and cancer type.
Where possible, we will perform subgroup analyses to assess if the observed effect of an intervention is consistent across participants based on subgroups of (1) age of the participant (continuous co‐variate) and (2) the location of the physical therapy intervention (inpatient hospital, outpatient clinic or home), and (3) by study design (RCT, CCT, cross‐over).
Sensitivity analysis
For any outcomes for which pooling is possible we will perform sensitivity analyses for 'Risk of bias' criteria separately. We will exclude studies with a high risk of bias and unclear risk of bias in the sensitivity analyses, and compare the results of studies with a low risk of bias with the results of all available studies. Sensitivity analyses will only be done when there remain at least two studies with a low risk of bias in the analyses.
