Interventions for the management of fatigue in adults with a primary brain tumour
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effective management of pharmacological and non‐pharmacological interventions for reducing fatigue in patients with a primary brain tumour (PBT).
Background
Description of the condition
Cancer‐related fatigue is 'a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning' (NCCN 2014). Cancer‐related fatigue is a common side effect of cancer and its treatment (Roscoe 2002), occurring across various cancer types (Stone 2000) and in disease‐free survivors (Servaes 2007). As the scientific knowledge about cancer‐related fatigue expands, the importance of its effective management is increasingly recognised by oncologists (Goedendorp 2009).
Prevalence of fatigue in primary brain tumours
Within the entire cancer population, fatigue is often particularly experienced by patients with a primary brain tumour (PBT). Fatigue in PBT has been studied both as a primary outcome (Armstrong 2010; Lovely 1999) and as a secondary outcome to related symptoms such as anxiety and depression (Rooney 2011), quality of life (Kvale 2009) and sleep‐wake disturbances (Miaskowski 2011). Prevalence estimates range from 25% to over 90%. At the highest, 96% of high‐grade glioma patients reported moderate or severe fatigue in one study (Fox 2007). Studies with mixed high‐grade and low‐grade tumour populations estimate 42% of PBT patients suffer from fatigue (Pelletier 2002). Additionally, although many studies focus on the initial phases of diagnosis and treatment, fatigue remains troublesome throughout the course of survivorship. For example, fatigue can be prevalent across the 12 months following PBT diagnosis (Molassiotis 2010), with fatigue reported in 39% of low‐grade glioma patients sampled more than eight years after diagnosis (Struik 2009).
Associated clinical variables
The clinical variable most frequently associated with fatigue in PBT is cranial radiation therapy, with an estimated report of fatigue in 80% of patients undertaking radiation therapy (Lovely 1999). One mechanism by which radiation therapy may exacerbate fatigue is via endocrine dysfunction, when the irradiated area includes the hypothalamus, or pituitary gland, or both. The hypothalamic‐pituitary‐adrenal axis feedback system is responsible for controlling the secretion of many hormones that regulate many body processes, including sleep (Arlt 1997; Taphoorn 1995). Fatigue is also a recognised side effect of many of the medications taken by PBT patients, including anticonvulsant drugs (Lu 2009; Maschio 2008; Struik 2009), and corticosteroids (Drappatz 2007; Hinds 2007).
Fatigue is further associated with sleep disturbance, cognitive complaints, depression, and anxiety (Armstrong 2010; Fox 2007; Pelletier 2002), and this cluster of symptoms may significantly influence patients' quality of life (Fox 2007). Symptom clustering can make the presence of fatigue hard to distinguish from other symptoms, like anxiety or depression (Rooney 2011). Therefore, fatigue is perhaps best investigated as a multifactorial symptom, alongside other related reported issues (Armstrong 2010).
The influence of tumour grade on fatigue remains unclear. Some authors find fatigue to be more common in high‐grade than in low‐grade tumours (Salo 2002), while others do not (Armstrong 2010; Pelletier 2002).
Methods of measuring fatigue
Many tools have been developed to measure fatigue in patients with cancer (Jean‐Pierre 2007). The Brief Fatigue Inventory detailed in Mendoza 1999, has been used in several studies including brain tumour correlational studies (Kim 2012), and clinical trials (Gehring 2012). Other measurement tools validated for use in cancer include the Functional Assessment of Cancer Therapy‐Fatigue (Yellen 1997), the Cancer‐Related Fatigue Distress Scale (Holley 2000), the Fatigue Assessment Questionnaire (Glaus 1998), the Revised Piper Fatigue Scale (Piper 1998), and the Multidimensional Fatigue Symptom Inventory (Stein 2004). Several general and brain tumour‐specific quality of life measures also assess fatigue, such as the Functional Assessment of Cancer Therapy‐Brain (FACT‐Br) (Cella 1993), the MD Anderson Symptom Inventory Brain Tumour Module (MDASI‐BT) (Armstrong 2006), and the World Health Organization Quality of Life assessment (WHOQOL) (WHOQOL Group 1995). The large number of different tools available, and the fact that each instrument relies on subjective patient reporting of one or several fatigue domains, highlights the need for both a systematic review, and caution when combining study data to summarise findings.
Description of the intervention
The review will include all interventions for fatigue in PBT patients. These may include pharmacological and non‐pharmacological interventions, and general strategies for the specific management of fatigue. We define pharmacological interventions as a drug, given by any route, at any therapeutic dose, with the primary intention of treating fatigue in persons with a PBT. Such drugs may include psychostimulants and antidepressants. Non‐pharmacological interventions will be defined as any psychological or behavioural treatment, given with the primary aim of improving fatigue in PBT, including physical activity, physically‐based therapies, and psychosocial interventions.
How the intervention might work
Recent studies have started to explore interventions aimed at improving and alleviating symptoms of fatigue, by targeting pharmacological or non‐pharmacological pathways.
Pharmacological Interventions
Pharmacological treatments might reduce fatigue by acting on critical neurotransmitter pathways. For example, the central nervous system stimulant, methylphenidate, is suggested to enhance neural signal processing by increasing concentrations of dopamine and norepinephrine (Volkow 2002). Similarly, the central nervous system stimulant, modafinil, has been associated with enhancing the effect of dopamine, associated with improved wakefulness and motivation (Young 2010).
Non‐Pharmacological Interventions
Psychological interventions may improve fatigue by introducing and reinforcing coping strategies, activity planning, and fatigue education (Armstrong 2012). This approach has been shown to be effective through the use of cognitive behavioural therapy, an approach that identifies the negative or maladaptive thoughts/beliefs of patients about fatigue, challenging and replacing them with more helpful and realistic alternatives (Beck 1979).
These strategies can be used alongside the promotion of behavioural changes such as exercise. Exercise may improve fatigue in PBT patients by increasing mental and physical stamina. Winningham's Psychobiological‐Entropy model proposes, for example, that a reduction in fatigue can be achieved through a balance between activity and rest (Winningham 1992). Previously, rest was recommended for cancer patients with fatigue, however, rest could promote muscle wasting and decreasing cardiorespiratory fitness further, adding to the perception of fatigue (Dimeo 2001). By increasing functional capacity, exercise could improve the patient's perception of fatigue (NCCN 2014). Additionally, exercise can also relieve the emotional and mental components of fatigue by alleviating anxiety and improving mood (Dimeo 2001).
Why it is important to do this review
There is a pressing need for a high quality review of studies for interventions for managing fatigue in patients with PBT, as fatigue is consistently the single most frequently reported symptom in studies of patients with PBT. With survival times for low‐grade PBT typically measured in years, and survival times for certain subgroups of high‐grade PBT patients gradually increasing, there is great potential benefit in establishing which interventions are effective for fatigue. Effective interventions could improve quality of life, yet the multifactorial nature of fatigue (potentially including genetic, neuroendocrine, immune and psychosocial causes) makes it a symptom that can be particularly difficult to treat (Bowe 2012).
A clear synthesis of the evidence for the effectiveness of managing fatigue in PBT is currently lacking. This review will answer a clinically useful research question: what are the effective interventions for managing fatigue in adults with a primary brain tumour?
Objectives
To assess the effective management of pharmacological and non‐pharmacological interventions for reducing fatigue in patients with a primary brain tumour (PBT).
Methods
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials (RCTs) of any intervention (pharmacological or non‐pharmacological) for the management of fatigue in adults with PBT, where fatigue is (one of) the primary or secondary therapeutic outcome(s). Due to the prediction that there may currently be few RCTs that satisfy the inclusion criteria, we will include a narrative description of relevant non‐RCTs in the 'Excluded studies' section. This will provide valuable information about interventions that may warrant further investigation. Consequently, we will not include an ‘RCT‐only’ filter in the initial search, but will only include RCTs in the meta‐analysis.
Types of participants
We will include studies that evaluate the effect of interventions for adults (aged 16 years or older) who have self reported fatigue (via a questionnaire, validated measure, or presence/absence report), and have a histological diagnosis of PBT at any stage in their illness, regardless of sex, tumour stage, tumour type and cancer treatment received. We will exclude studies evaluating the treatment of fatigue in children, and studies that include non‐fatigued participants in the treatment group.
Types of interventions
Pharmacological interventions
For pharmacological interventions, we will investigate the efficacy and effectiveness of any drug, given by any route, and at any therapeutic dose, with the intention of treating fatigue in PBT. Such drugs are likely to include psychostimulants, and may include antidepressants. For ethical reasons, RCTs of psychoactive drugs may not automatically include a placebo arm. In order to increase the relevance of the review we will include studies without a placebo arm, provided that participants have been randomised to a control group of some kind (e.g. treatment as usual, another active drug, or allocation to a waiting list).
Non‐pharmacological interventions
For psychological interventions, we will study any cognitive treatment given with the aim of improving fatigue in PBT. For behavioural interventions, we will investigate the efficacy of any behavioural or social treatment given for the improvement of fatigue in PBT; this may include exercise and energy management techniques. We will include RCTs where the control group is allocated to treatment as usual, or to a waiting list.
Types of outcome measures
Primary outcomes
The primary outcome will be fatigue at primary study endpoint. Due to potential differences in efficacy endpoints between the different interventions we will analyse both short‐term and long‐term effects of these interventions, when the data are available.
Fatigue may be summarised categorically as ‘present’ or ‘absent’ (e.g. in response to a clinical interview), or else quantified ordinally on a rating scale assessing fatigue. Such rating scales can be specific to fatigue, or may assess fatigue as part of a wider symptom screen (e.g. as part of quality of life). We will include studies where fatigue is self reported, using any validated method. Due to the subjective nature of fatigue, we will not include studies using clinician‐reported or relative‐or carer‐reported measures, as these may not be a true reflection of the patients' symptoms.
Where fatigue is measured by a rating scale, we will quantify its improvement with respect to the recommended scale threshold for ‘caseness’. Where possible, we will also record total number of patients reaching 'non‐fatigued' status.
Secondary outcomes
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General functioning, including quality of life measurements, and depression and cognitive outcomes according to validated measures.
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Adverse events, as reported by studies (e.g. insomnia).
Where possible and appropriate, we will combine these outcomes in a meta‐analysis. The secondary outcomes are not criteria for eligibility for this review, but are outcomes that will be noted and reviewed if recorded.
Search methods for identification of studies
Electronic searches
We will search the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, current issue), MEDLINE (1950 to present), EMBASE (1980 to present), PsycINFO (1974 to present), and CINAHL (1982 to present). The MEDLINE search strategy is listed in Appendix 1. For databases other than MEDLINE, we will adapt the search strategy accordingly. We will not apply any language restrictions in any of the searches.
Searching other resources
Unpublished and grey literature
We will search online databases of registered clinical trials to identify ongoing trials. We will also approach the major co‐operative trial groups active in this area.
Handsearching
We will handsearch the reference lists of included studies and previous systematic reviews. We will handsearch journal and conference materials over the past year from the following sources.
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Annual Meeting of the European Society of Medical Oncology (ESMO)
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Annual meeting of the European Association of Neuro‐Oncology (EANO)
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Annual meeting of the World Federation of Neuro‐Oncology (WFNO)
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Annual Meeting of the American Society of Clinical Oncology (ASCO)
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Annual Meeting of the Society for Neuro‐Oncology (SNO)
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Annual Meeting of the Society for Behavioral Medicine (SBM)
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Annual Meeting of the American Psychosocial Oncology Society (APOS)
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Annual Meeting of the International Psycho‐Oncology Society (IPOS)
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Annual Meeting of the Multinational Association of Supportive Care in Cancer (MASCC)
Data collection and analysis
Selection of studies
We will download all titles and abstracts retrieved by electronic searching to the reference management database EndNote. We will remove duplicates and three review authors (JD, SYK, DC) will independently examine the remaining references. The review authors will not be blinded to the authors or affiliations of the studies. We will exclude those studies that clearly do not meet the inclusion criteria, and we will obtain copies of the full text of potentially relevant references. Three review authors (JD, SYK, DC) will independently assess the eligibility of retrieved papers. We will resolve disagreements by discussion and document reasons for exclusion.
Data extraction and management
Data Extraction
For included trials, we will extract data as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Three review authors (JD, SYK, DC) will independently extract data onto a data extraction form specially designed for the review.
We will extract data on the following.
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Article details (author, year of publication, journal citation, country and language).
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Intervention (characteristics and duration).
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Study design and methodology (including inclusion and exclusion criteria, assignment process, timing of measurements, concealment).
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Population demographics and total number involved.
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Details of participants' health status (including tumour pathology and treatment details).
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Dichotomous and continuous outcome measures (fatigue, cognitive functioning, quality of life, depression, overall survival, progression‐free survival, and adverse events).
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Risk of bias.
Where possible, we will extract all data relevant to an intention‐to‐treat analysis, in which participants are analysed in groups to which they are assigned.
Data Management
We will collate and enter data into Review Manager 5 (RevMan 2014). For continuous outcomes (e.g. fatigue and quality of life measures), we will extract the final value and standard deviation of the outcome of interest, and the number of patients assessed at endpoint in each treatment arm at the end of follow‐up, in order to estimate the mean difference between treatment arms and its standard error. We will note the time points at which outcomes were collected and reported.
Assessment of risk of bias in included studies
We will assess the risk of bias in included studies using the Cochrane Collaboration's tool (Higgins 2011). This will include assessment of:
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selection bias: random sequence generation and allocation concealment;
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performance bias: blinding of participants and personnel (patients and treatment providers);
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detection bias: blinding of outcome assessment;
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performance bias: similar care to patient out with the intervention they received;
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attrition bias: incomplete outcome data;
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reporting bias: selective reporting of outcomes; and
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other possible sources of bias.
Three review authors (JD, SYK, DC) will apply the 'Risk of bias' tool independently and differences will be resolved by discussion. We will summarise results in both a 'Risk of bias' graph and a 'Risk of bias' summary. We will interpret the results of the meta‐analyses in light of the findings with respect to risk of bias (see Appendix 2 for the 'Risk of bias' assessment tool. We will judge and report all bias criteria in terms of 'low', 'high' or 'unclear' risk of bias. We will classify criteria as having an unclear risk of bias when insufficient information is provided, or when there is uncertainty over the potential for bias.
Measures of treatment effect
Continuous data
For continuous outcomes (e.g. fatigue scales, cognitive tests and measures, depression measures, quality of life measures), we will express the treatment effect as a mean difference (MD) with 95% confidence interval (CI), if trials measure these outcomes on the same scale. We will extract post intervention data to calculate MD, the final value and standard deviation (SD) of the outcome of interest, and the number of participants assessed in each treatment arm at the end of follow‐up. If trials measure outcomes on different scales, we will express treatment effect as standardised mean differences (SMDs) between treatment arms, with 95% CIs.
Dichotomous data
For dichotomous outcomes (e.g. fatigue) we will extract the number of patients in each treatment arm who experienced the outcome of interest, at baseline and at study endpoint. We will dichotomise fatigue using validated thresholds.
Unit of analysis issues
Unit of analysis issues will be reviewed by three review authors (JD, SYK, DC) according to The Cochrane Handbook for Systematic Reviews of Interventions, and differences will be resolved by discussion (Higgins 2011). These may include reports where:
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groups of individuals are randomised together to the same intervention (i.e. cluster‐randomised trials);
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there are multiple observations for the same outcome (e.g. repeated measurements, recurring events).
Dealing with missing data
We will not impute missing outcome data for the primary outcome. For the primary outcome, if data are missing, or only imputed data were reported, we will contact trial authors to request data on the outcomes among participants who were assessed. We will include details of missing data in the narrative summary and 'Risk of bias' table, alongside an assessment of the extent to which the missing data could have altered the results of the review.
Assessment of heterogeneity
We will assess heterogeneity between studies by visual inspection of forest plots (including the presence of outliers and a poor overlap of confidence intervals), and by a formal statistical test of the significance of the heterogeneity (Deeks 2001). We will investigate and report heterogeneity according to Higgins 2011.
Assessment of reporting biases
Three review authors (JD, SYK, DC) will review and record reporting biases. If suitable (when more than 10 trials are included in a meta‐analysis), we will examine funnel plots to assess the potential for small study effects, such as publication bias.
Data synthesis
We will pool data for meta‐analysis using Review Manager 5if studies are comparable with respect to participants, interventions and outcomes (RevMan 2014). We will aim to combine studies at the level of the intervention itself (e.g. psychostimulant, cognitive behavioural therapy, exercise) rather than broad categories (e.g. pharmacological, psychological, behavioural). The meta‐analysis will be carried out as follows.
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We will pool the MDs between the treatment arms at the end of follow‐up if all trials measure the outcome on the same scale and at the same primary study endpoint, otherwise we will pool SMDs.
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For dichotomous data, we will use risk ratios (RRs) and 95% CIs.
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We will use random‐effects models with inverse variance weighting for all meta‐analyses, with a 95% CI (DerSimonian 1986).
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For dichotomous data for adverse events, we will pool RRs.
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We will note the time points at which outcomes were collected and reported.
Subgroup analysis and investigation of heterogeneity
We will also conduct subgroup analyses comparing changes in scale score studies using identical scales, where appropriate. Where data permit, we will perform subgroup analyses according to World Health Organization (WHO) tumour grade (low‐grade/high‐grade) and interventions delivered only during treatment/only during follow‐up.
Sensitivity analysis
All review authors will be involved in determining whether sensitivity analysis will be required, under the guidance of Higgins 2011.
We will consider the following factors as possible sources of heterogeneity across studies.
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Differing study quality (high or low levels of risk of bias).
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Different classes of agents.
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Dosage or scheduling differences.
We may identify additional possible types of sensitivity analyses during the conduct of the review.
