Description of the condition
Cancer cachexia is defined as "a multi-factorial syndrome characterized by an ongoing loss of skeletal muscle mass, with or without a loss of fat mass, that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment" (Fearon 2011). Prevalence varies with cancer type, but is highest in people with cancer arising from the upper gastro-intestinal tract or lung, where over half of all patients are affected at the point of diagnosis (Fearon 2011; Laviano 2005). The pathophysiology of cancer cachexia is complex and characterized by a negative energy balance and abnormal metabolism (Fearon 2012; Tisdale 2009). The combination of a persistent inflammatory response, tumour-derived catabolic factors and a stress response, leads to reduced food intake, increased resting energy expenditure, and an overall loss of skeletal muscle mass; the result of reduced protein synthesis, increased protein breakdown and reduced insulin sensitivity (Evans 2008; Fearon 2011; Tisdale 2009). The loss of lean body mass contributes to a progressive decline in muscle strength and endurance (Stephens 2012; Weber 2009), exercise capacity (England 2012; Jones 2012) and physical activity levels (Dodson 2011; Wilcock 2008), and is associated with increased risk of dose-limiting chemotherapy toxicities (Prado 2007; Prado 2008; Prado 2009) and poor survival (Antoun 2013; Martin 2013).
Description of the intervention
There are no standard interventions for cancer cachexia and some consider it refractory once established, for example, in patients with progressive disease and a limited prognosis (Fearon 2011). As such, it is recommended that greater emphasis be placed on applying a proactive approach, early in the course of the disease, with the aim to maintain or slow down the loss of physical function (Fearon 2011; Muscaritoli 2010). Due to the complex nature of the condition, multimodal intervention is also considered necessary as it is unlikely that a single intervention will increase food intake, attenuate the metabolic disturbances and address the imbalance between muscle protein synthesis and breakdown (Fearon 2008). Three main component interventions are being developed alone or in combination (Solheim 2012): nutritional therapies to increase energy and protein intake (Dewey 2007); drug therapies to stimulate appetite and reduce inflammation (Berenstein 2005; Lee 2011; Reid 2012); and exercise therapies.
Exercise is defined by the American College of Sports Medicine as a "planned, structured and repetitive bodily movement done to maintain or improve one or more components of physical fitness" (Thompson 2010). Different types of exercise may use everyday activities, such as walking, or specialist equipment, such as free-weights, for the purposes of training. Exercise programmes also vary widely according to the frequency, intensity and type of training used, as well as contextual factors such as the programme setting and level of supervision. For example, both a hospital-based programme of twice weekly, high-intensity, stationary cycling for six weeks, and a home-based programme of low-intensity, flexibility training throughout chemotherapy would be defined as exercise (Thompson 2010).
How the intervention might work
Exercise may attenuate the effects of cancer cachexia via several mechanisms, including the modulation of muscle metabolism, insulin sensitivity and levels of inflammation (Maddocks 2012). Resistance exercise is a potent stimulator of muscle protein synthesis, particularly when performed in conjunction with the provision of amino acids (Glover 2010; Marimuthu 2011). Improved insulin action in peripheral tissues following exercise may inhibit muscle protein breakdown (Wang 2006). Exercise also triggers the formation of a cohort of cytokines from muscle fibers, including Interleukin-6, which increases insulin sensitivity and reduces the production of pro-inflammatory cytokines (Starckie 2003). Repeated exercise has an overall anti-inflammatory effect, which has been observed in healthy populations (Gleeson 2011) and patients with early stage cancer (Betof 2013). This effect would be beneficial in cancer cachexia as levels of systemic inflammation are associated with reduced weight, exercise capacity and survival (Macmillan 2013; Moses 2009; Proctor 2011). Thus, by preventing or slowing down the loss of lean body mass, exercise may ultimately help patients with or at risk of cancer cachexia maintain their independence for longer.
Why it is important to do this review
Despite a growing evidence base for nutritional and drug interventions for cancer cachexia, including Cochrane reviews (Berenstein 2005; Dewey 2007; Payne 2012; Reid 2012), studies of exercise interventions in the field are few in number. Reviews examining the use of exercise in cancer cachexia are generally narrative (Gould 2013), opinion based (Argilés 2012; Maddocks 2011; Maddocks 2012) and/or based on animal models of the condition (Argilés 2012). Nonetheless, there are reports of small studies from conference proceedings as well as ongoing/planned studies (e.g. Kaasa 2013). Thus, there is a need to synthesise the evidence for the use of exercise for cancer cachexia and, if data permit, explore the optimal programme characteristics for this group of patients.
The primary objective is to determine the effectiveness of exercise, compared to usual care or no treatment, on biomarkers and outcomes of cachexia in adults with cancer. Secondary objectives, subject to the availability of data, are to examine the acceptability and safety of exercise in this setting and to compare effectiveness according to the characteristics of the exercise intervention or patient population.
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/m
2and 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);
- SciVerse SCOPUS;
- Biosis Previews PreMedline;
- Open Grey (System for Information on Grey Literature).
We will identify ongoing studies using:
- ClinicalTrials.gov (clinicaltrials.gov/);
- the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com/);
- International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/en/);
- Pan African Clinical Trials (www.pactr.org); and
- the EU Clinical Trials Register (www.clinicaltrialsregister.eu/).
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.
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, cm
2) or volume (cubic centimetres, cm 3) 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 (VO
2) 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 I
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.
The authors acknowledge Dr Fiona Cramp and Yvonne Roy for their comments on the protocol and Jane Hayes for developing the search strategy. We thank the Cochrane Handbook Study Group from the Brazilian Cochrane Centre for the opportunity to discuss Cochrane methodology.
Appendix 1. MEDLINE search strategy for Ovid
1 exp Neoplasms/
2 (cancer* or tumor* or tumour* or neoplas* or malignan* or carcinoma* or adenocarcinoma* or choricarcinoma* or leukemia* or leukaemia* or metastat* or sarcoma* or teratoma*).mp.
3 1 or 2
4 exp Weight Loss/
5 (cachexia or cachexic).mp.
6 exp Malnutrition/
7 (weight or underweight or malnutrition or wasting).mp.
8 4 or 5 or 6 or 7
9 exp Exercise/
10 exp Exercise Movement Techniques/
11 exp Exercise Therapy/
12 Physical Fitness/
13 (exercis* or aerobic* or resistance* or strength* or walk* or endurance*).mp.
14 (physical* adj5 (fit* or activ* or movement*)).mp.
15 9 or 10 or 11 or 12 or 13 or 14
16 3 and 8 and 15
17 randomized controlled trial.pt.
18 controlled clinical trial.pt.
21 clinical trials as topic.sh.
24 17 or 18 or 19 or 20 or 21 or 22 or 23
25 16 and 24
mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier
Contributions of authors
AJG co-ordinated and is the guarantor of the protocol. All authors were involved in the planning and drafting of the protocol, and approve the final version of the protocol. AJG, VS, SP will search for, extract data from and assess risk of bias in studies, enter data into RevMan (RevMan 2012) and perform the analysis.
Declarations of interest
The authors have no involvement in any organisation or entity with a vested interest in the outcomes of this review. MM is funded by an NIHR Post-Doctoral Fellowship award. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
Sources of support
- None, Not specified.
- None, Not specified.