Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) with a parallel, single-stage or cross-over design, including studies with a quasi-randomised allocation in cases where allocation concealment is described.
Types of participants
Study participants will be adults (≥18 years of age) with a histological or clinical diagnosis of cancer, meeting international criteria for cancer cachexia of any stage (Fearon 2011). Stages of cachexia will include:
pre-cachexia, defined as weight loss ≤ 5% with anorexia and metabolic changes;
cachexia, defined as weight loss > 5% in the past 6 months or Body Mass Index (BMI) < 20 kg/m2 and ongoing weight loss > 2% or sarcopenia, anorexia or systemic inflammation; and
refractory cachexia, defined as active catabolism, ongoing weight loss, not responsive to treatment and life expectancy of < 3 months (Fearon 2011).
Where baseline demographic data are insufficient to assess participants against these criteria we will contact the study authors to seek additional data.
We will aim to include studies which are relevant to the review objectives, but which were not performed specifically to address cancer cachexia; e.g. studies in groups with advanced cancer. As such, studies will be included where at least half of the study population falls within the definitions outlined above. Participants may be studied in any hospital or community setting. Studies relating to participants during or following treatment with curative intent, or with no evidence of current disease, will not be included.
Types of interventions
We will include studies examining any programme of exercise offered as a sole intervention or in combination with another intervention. Programmes using aerobic/endurance training, resistance training or a combination of both will be considered. Programmes are expected to vary in terms of session length (minutes) and frequency (sessions/week), intensity of training (low, moderate, high) and overall duration (weeks). There will be no restriction on these or other programme characteristics including the setting in which the programme is offered (hospital/centre/home) and level of supervision (none, minimal, close). Interventions will be compared to either no treatment, usual care, or an active control group, e.g. a nutritional or drug intervention.
Types of outcome measures
The primary outcome will be lean body mass assessed immediately following a programme of exercise.
Secondary outcomes include adherence to prescribed programmes, occurrence of adverse events and, subject to availability of data, muscle strength and endurance, maximal and submaximal exercise capacity, fatigue, and health-related quality of life.
Search methods for identification of studies
An electronic search strategy using a combination of terms based on the target population, intervention, comparator and outcomes has been developed. The version that will be run on MEDLINE can be found in Appendix 1. It will be adapted where necessary for the other databases listed below. We will search the following electronic databases from their start date:
CENTRAL, DARE and HTA - Health Technology Assessments (onThe Cochrane Library);
ISI Web of Science;
LILACS (Latin American and Caribbean Health Sciences);
PEDro (the Physiotherapy Evidence Database);
Biosis Previews PreMedline;
Open Grey (System for Information on Grey Literature).
We will identify ongoing studies using:
Searching other resources
We will handsearch the following sources: The Society on Sarcopenia, Cachexia and Wasting Disorders (SCWD); the American Cancer Society; the British Association for Cancer Research (BACR); and the European Clinical Guidelines. We will check reference lists of relevant studies and reports citing all retrieved studies.We will contact corresponding authors of retrieved studies, experts and organizations in the field to seek potentially relevant research material, including unpublished and ongoing studies.
Data collection and analysis
Selection of studies
Reference management software will be used to merge results from different electronic databases and remove duplicate studies. Two review authors (AJG, VS or SV) will independently assess titles and abstracts of articles for relevance (Higgins 2011a). We will obtain full-text reports of potentially relevant studies for assessment against the inclusion criteria. If missing information impairs the study selection, study authors will be contacted by email to clarify the necessary information. Any disagreements in the selection of studies will be discussed and resolved by consensus from both review authors. In cases of persistent disagreement, a third author (MSP or MM) will be consulted. No language restrictions will be applied in the selection of studies.
We will include a PRISMA study flow diagram in the full review (Liberati 2009) to document the screening process, as recommended in Part 2, Section 11.2.1 of the Cochrane Handbook (Higgins 2011a).
Data extraction and management
Two review authors (AJG and VS or SV) will independently extract data from the included studies. An online extraction form will be developed to store data relating to the study source and eligibility, methods and bias (study design, sequence generation, allocation sequence concealment, blinding), participants (number, age, sex, ethnicity, diagnosis, disease severity, setting) and intervention (exercise type and intensity, session length and frequency, and overall programme duration), adherence to the exercise programme (either self-reported or objective) and the occurrence of any adverse events. Disagreements will be discussed and resolved by consensus from all three review authors.
Outcome data collected at baseline, immediately following a programme of exercise and at first follow-up will include:
lean body mass, generally assessed by anthropometry, e.g. skin fold thickness, or imaging, e.g. dual x-ray absorptiometry, and expressed as a weight (e.g. kilograms, kg), cross-sectional area (square centimetres, cm2) or volume (cubic centimetres, cm3) normalised to height;
muscle strength, either isometric or isotonic, generally assessed using myometry and expressed as a measure of force (e.g. kilograms, kg, or Newton metres, Nm);
muscle endurance, generally assessed as time or number of repetitions to a specified decline in muscle performance;
maximal and submaximal exercise capacity, generally assessed by a walking or cycling test and expressed as a measure of oxygen uptake (VO2) or performance, e.g. distance walked in metres (m);
fatigue, generally assessed on a numerical or categorical scale with a higher score representing more severe fatigue;
health-related quality of life, generally assessed on a numerical or categorical scale with a higher score representing a better quality of life. We will examine the content items and known psychometric properties of instruments used.
Assessment of risk of bias in included studies
Two authors (AJG and VS or SV) will independently assess each study for risk of bias using the Cochrane Collaboration's tool, which addresses seven specific domains: sequence generation, allocation concealment, blinding of study participants and personnel, blinding of outcome assessment, completeness of outcome data, selective reporting and other potential sources of bias, for example carry-over or blocking, where bias may be introduced. For each domain, the tool first identifies what is reported to have happened in the study. Where it was unclear, information to aid this assessment will be sought from additional study reports, protocols, published comments and personal contact with study authors. Thereafter, a judgement will be made as to the level of risk of bias for that domain: low, high or unclear (Higgins 2011b).
Measures of treatment effect
Considering the review objectives and outcomes, counts, dichotomous, categorical and continuous data may be extracted.
Outcome data will be analysed as continuous when possible. In cases where there are missing data or insufficient data to perform meta-analysis, we will attempt to contact the study authors. The mean difference (MD) or standardised mean difference (SMD) in outcome between the intervention and control group will be calculated with 95% confidence intervals (CI) (Deeks 2011).
Unit of analysis issues
In parallel-group randomised controlled trials, the individual patient will be considered as the unit of analysis. If we include cross-over randomised controlled trials, both periods will be analysed, separated by periods, and altogether. If we include cluster-randomised trials, the unit of analysis will be the group.
Dealing with missing data
Authors will be contacted by email if the primary studies do not report the outcome measures of interest, or do not describe randomisation, or do not describe intention-to-treat analysis or have any other missing data, detected by AJG and VS or SV. If no answer is obtained from authors, the findings will be presented and discussed in the main text.
Assessment of heterogeneity
We will assess clinical heterogeneity using the I2 statistic (Higgins 2002; Higgins 2003) to quantify inconsistency across trial conditions and its impact on the meta-analysis. We will also assess the percentage of the variability in effect estimates which is due to the condition rather than sampling error, determined by the Chi2 test. Ideally an inverse variable fixed-effect model will be used to estimate the overall direction, size and consistency of an effect from exercise immediately post-programme. If considerable (I2 > 50%) or substantial clinical heterogeneity (I2 > 75%) is confirmed, we will apply a random-effects model or separate fixed-effect model calculation to estimate an effect from exercise for subgroup (see below) (Deeks 2011).
Assessment of reporting biases
If there are ≥10 included studies, a funnel plot test for asymmetry will be conducted to assess for any evidence of reporting bias.
Where there are sufficient data and consistent or comparable outcomes, we will perform a meta-analysis using an inverse variable fixed-effect model to estimate the overall direction, size and consistency of an effect from exercise immediately post-programme. For other types of data, likely to arise from secondary outcomes, findings from individual studies will be described or presented in tabular form. We also plan to create a 'Summary of findings' table using the methods and recommendations described in Section 8.5 and Section 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b) using the GRADEpro software.
Subgroup analysis and investigation of heterogeneity
Where sufficient data are available, we will use descriptive comparisons to consider differences in effect between subgroups according to the following participant characteristics: type of cancer (lung, pancreatic, etc.); stage of cachexia (pre-cachexia, cachexia, refractory cachexia Fearon 2011), and intervention characteristics; type of exercise (aerobic, resistance, combined), intensity of exercise (light, moderate, high).
Where sufficient data are available, we will perform a sensitivity analysis to consider the difference in pooled effect when studies at high or unclear risk of bias, or those with substantial (>20%) missing data, are omitted from analyses. We will present findings in tabular format.